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)     

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.     

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.     

Dose- and administration time-dependent effects of nifedipine gits on ambulatory blood pressure in hypertensive subjects

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow-release, once-a-day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest-activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1±10.7 yrs of age, with grade 1-2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up-titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non-responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose-dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.     

PERSPECTIVES ON THE CHRONOTHERAPY OF HYPERTENSION BASED ON THE RESULTS OF THE MAPEC STUDY

Appreciation of chronotherapy in hypertension continues to lag, despite clear demonstrations by many studies of (i) clinically relevant dosing-time differences of the beneficial and adverse effects of most blood pressure (BP) medications and (ii) significant association between reduced sleep-time BP decline of non-dippers and their heightened risk of cardiovascular disease (CVD). The Syst-Eur and HOPE outcome trials showed evening administration of nitrendipine and ramipril in these respective studies impacts sleep-time BP, converting the 24-h BP pattern to a more dipper one and in the HOPE study decreasing CVD risk. The CONVINCE study intended to compare BP control and CVD protection afforded by conventional β-blocker and diuretic medications versus a special drug-delivery verapamil formulation as a bedtime hypertension chronotherapy; however, the trial was terminated prematurely, not based on inadequate performance of the chronotherapy but on a corporate business decision. The just completed MAPEC study is the first trial specifically designed to prospectively test the hypothesis that bedtime administration of ≥1 conventional medications exerts better BP control and CVD risk reduction than the traditional approach of scheduling all medications in the morning. The results of this 5.6-yr median follow-up study establish that bedtime chronotherapy more effectively improves BP control, better decreases prevalence of non-dipping, and, most importantly, best reduces CVD morbidity and mortality. This chronotherapeutic approach to hypertension is justified by the fact that BP is usually lowest at night as is sodium excretion, but when sodium intake is excessive or its daytime excretion hampered, nocturnal BP is adjusted higher, to a level required for compensation overnight, via the pressure/natriuresis mechanism, resulting in non-dipping 24-h BP patterning. In diurnally active persons, the entire circadian BP pattern may be reset to a lower mean level and to a “more normal” day-night variation, simply by enhancing natriuresis during the night—the time-of-day when it can be most effective. A modification as simple and inexpensive as switching ≥1 hypertension medications from morning to evening may be all that is needed to normalize nighttime BP, exerting an effect exactly like sodium restriction. Current clinical concepts such as “normotensive non-dipper” (with higher CVD risk than a hypertensive dipper), broad recommendation of pharmacotherapy with exclusively high “smoothness index” medications (without attention to individual patient needs defined by the features of the 24-h BP pattern), and reliance upon static daytime diagnostic BP thresholds based solely on single office cuff assessment necessitate urgent reconsideration. (Author correspondence: prf@unife.it)     

Dose‐ And Administration Time‐Dependent Effects Of Nifedipine Gits On Ambulatory Blood Pressure In Hypertensive Subjects

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow‐release, once‐a‐day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest‐activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1±10.7 yrs of age, with grade 1–2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up‐titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non‐responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose‐dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.     

Administration‐Time‐Dependent Effects of Olmesartan on the Ambulatory Blood Pressure of Essential Hypertension Patients

Previous studies established that a single daily dose of olmesartan remains effective for the entire 24 h without alteration of the day‐night blood pressure (BP) pattern. On the other hand, the administration of valsartan or telmisartan at bedtime, as opposed to upon wakening, improves the sleep‐time relative BP decline toward a greater dipper pattern without loss of 24 h efficacy. Yet to be determined is whether this administration‐time‐dependent efficacy is a class‐related feature, characteristic of all angiotensin‐receptor‐blocker (ARB) medications. We studied 123 grade 1 and 2 hypertensive patients, 46.6±12.3 yrs of age, randomly assigned to receive olmesartan (20 mg/day) as a monotherapy either upon awakening or at bedtime for three months. BP was measured by ambulatory monitoring for 48 consecutive hours before and after treatment. The 24 h BP reduction was similar for both treatment times. Administration of olmesartan at bedtime, however, was significantly more efficient than morning administration in reducing the nocturnal BP mean. The sleep‐time relative BP decline was slightly reduced with olmesartan ingestion upon awakening but significantly increased with ingestion at bedtime, thus reducing the prevalence of non‐dipping from baseline by 48%. Olmesartan administration at bedtime, as opposed to in the morning, improved the awake/asleep BP ratio toward a greater dipper pattern without loss of 24 h efficacy. Nocturnal BP regulation was significantly better achieved with bedtime as compared to morning dosing of olmesartan. These effects are comparable to those previously reported for valsartan and telmisartan, thus suggesting that they may be class‐related features of ARB medications in spite of differences in their half‐life kinetics. These administration‐time‐dependent effects should be taken into account when prescribing ARB medications for treatment of essential hypertension     

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.     

Chronotype,gender, and time for sex

The study aimed at testing chronotype and gender differences in the time of day when humans feel the greatest need for sex and the time of day they actually undertake sexual activity. A Polish sample of 565 participants aged between 18 and 57 was tested. In females, regardless of chronotype, the greatest need for sex occurred between 18:00 and 24:00, but a secondary peak appeared only in morning types at 6:00–9:00. In males, the greatest need for sex occurred either in the morning or evening hours: in evening types at 9:00–12:00 and 18:00–3:00; in neither types at 6:00–9:00 and 18:00–24:00; in morning types at 6:00–12:00 and 18:00–24:00. Considering time of day when subjects were undertaking sexual activity most frequently, this appeared between 18:00 and 24:00 for all the participants, and prolonged until 3:00 at night in evening type males. Morningness preference was more strongly related to the timing of need for sex than to the timing of actual sexual activity (r?=??0.275 vs. r?=??0.174), while the timing of desire and the timing of sexual activity were positively, but moderately related (r?=?0.320).     

Administration time-dependent effects of valsartan on ambulatory blood pressure in elderly hypertensive subjects

Previous results have indicated that valsartan administration at bed-time, as opposed to upon wakening, improves the diurnal/nocturnal ratio of blood pressure (BP) toward a normal dipping pattern, without loss of 24 h efficacy. This ratio is characterized by a progressive decrease with aging. Accordingly, we investigated the administration time-dependent antihypertensive efficacy of valsartan, an angiotensin blocking agent, in elderly hypertensive patients. We studied 100 elderly patients with grade 1-2 essential hypertension (34 men and 66 women), 68.2+/-4.9 years of age, randomly assigned to receive valsartan (160 mg/d) as a monotherapy either upon awakening or at bed-time. BP was measured for 48 h by ambulatory monitoring, at 20 min intervals between 07:00 to 23:00 h and at 30 min intervals at night, before and after 3 months of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately determine the duration of sleep and wake spans to enable the accurate calculation of the diurnal and nocturnal means of BP for each subject. There was a highly significant BP reduction after 3 months of valsartan treatment (p < 0.001). The reduction was slightly larger with bed-time dosing (15.3 and 9.2 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively) than with morning dosing (12.3 and 6.3 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively). The diurnal/nocturnal ratio, measured as the nocturnal decline of BP relative to the diurnal mean, was unchanged in the group ingesting valsartan upon awakening (-1.0 and -0.3 for systolic and diastolic BP; p > 0.195). This ratio was significantly increased (6.6 and 5.4 for systolic and diastolic BP; p < 0.001) when valsartan was ingested at bed-time. The reduction of the nocturnal mean was doubled in the group ingesting valsartan at bed-time, as compared to the group ingesting it in the morning (p < 0.001). In elderly hypertensive patients, mainly characterized by a diminished nocturnal decline in BP, bed-time valsartan dosing is better than morning dosing since it improves efficacy during the nighttime sleep span, with the potential reduction in cardiovascular risk that has been associated with a normalized diurnal/nocturnal BP ratio.     

Angiotensin receptor blockers shift the circadian rhythm of blood pressure by suppressing tubular sodium reabsorption

Recently, we found that an angiotensin II receptor blocker (ARB) restored the circadian rhythm of the blood pressure (BP) from a nondipper to a dipper pattern, similar to that achieved with sodium intake restriction and diuretics (Fukuda M, Yamanaka T, Mizuno M, Motokawa M, Shirasawa Y, Miyagi S, Nishio T, Yoshida A, Kimura G. J Hypertens 26: 583-588, 2008). ARB enhanced natriuresis during the day, while BP was markedly lower during the night, resulting in the dipper pattern. In the present study, we examined whether the suppression of tubular sodium reabsorption, similar to the action of diuretics, was the mechanism by which ARB normalized the circadian BP rhythm. BP and glomerulotubular balance were compared in 41 patients with chronic kidney disease before and during ARB treatment with olmesartan once a day in the morning for 8 wk. ARB increased natriuresis (sodium excretion rate; U(Na)V) during the day (4.5 ± 2.2 to 5.5 ± 2.1 mmol/h, P = 0.002), while it had no effect during the night (4.3 ± 2.0 to 3.8 ± 1.6 mmol/h, P = 0.1). The night/day ratios of both BP and U(Na)V were decreased. The decrease in the night/day ratio of BP correlated with the increase in the daytime U(Na)V (r = 0.42, P = 0.006). Throughout the whole day, the glomerular filtration rate (P = 0.0006) and tubular sodium reabsorption (P = 0.0005) were both reduced significantly by ARB, although U(Na)V remained constant (107 ± 45 vs. 118 ± 36 mmol/day, P = 0.07). These findings indicate that the suppression of tubular sodium reabsorption, showing a resemblance to the action of diuretics, is the primary mechanism by which ARB can shift the circadian BP rhythm into a dipper pattern.     

Administration Time‐Dependent Effects of Valsartan on Ambulatory Blood Pressure in Elderly Hypertensive Subjects

Previous results have indicated that valsartan administration at bed‐time, as opposed to upon wakening, improves the diurnal/nocturnal ratio of blood pressure (BP) toward a normal dipping pattern, without loss of 24 h efficacy. This ratio is characterized by a progressive decrease with aging. Accordingly, we investigated the administration time‐dependent antihypertensive efficacy of valsartan, an angiotensin blocking agent, in elderly hypertensive patients. We studied 100 elderly patients with grade 1–2 essential hypertension (34 men and 66 women), 68.2±4.9 years of age, randomly assigned to receive valsartan (160 mg/d) as a monotherapy either upon awakening or at bed‐time. BP was measured for 48 h by ambulatory monitoring, at 20 min intervals between 07∶00 to 23∶00 h and at 30 min intervals at night, before and after 3 months of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately determine the duration of sleep and wake spans to enable the accurate calculation of the diurnal and nocturnal means of BP for each subject. There was a highly significant BP reduction after 3 months of valsartan treatment (p<0.001). The reduction was slightly larger with bed‐time dosing (15.3 and 9.2 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively) than with morning dosing (12.3 and 6.3 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively). The diurnal/nocturnal ratio, measured as the nocturnal decline of BP relative to the diurnal mean, was unchanged in the group ingesting valsartan upon awakening (?1.0 and ?0.3 for systolic and diastolic BP; p>0.195). This ratio was significantly increased (6.6 and 5.4 for systolic and diastolic BP; p<0.001) when valsartan was ingested at bed‐time. The reduction of the nocturnal mean was doubled in the group ingesting valsartan at bed‐time, as compared to the group ingesting it in the morning (p<0.001). In elderly hypertensive patients, mainly characterized by a diminished nocturnal decline in BP, bed‐time valsartan dosing is better than morning dosing since it improves efficacy during the nighttime sleep span, with the potential reduction in cardiovascular risk that has been associated with a normalized diurnal/nocturnal BP ratio.     

Diurnal changes of ERP response to sound stimuli of varying frequency in morning-type and evening-type subjects

In order to study the cognitive function rhythm related to the auditory frequency system for people who prefer to be active in the morning and at night, we conducted an experiment during morning (09:00), evening (17:00) and late-night (01:00) periods. On the basis of a morningness/eveningness questionnaire, six moderately morning-type subjects (M-types) and seven evening-type subjects (E-types) were selected. Diurnal variation of event-related potential (ERP) were assessed under low-frequency (250/500 Hz) and high-frequency (1000/2000 Hz) condition using an oddball task. M-types were tested during the morning (09:00) and evening (17:00) periods, and E-types were tested during the evening (17:00) and midnight (01:00) periods. Subjects were asked to press a button when the target stimulus was detected. We found that the P300 amplitude at 09:00 was significantly greater than that at 17:00 for M-types, was significantly greater at 17:00 than that at 01:00 for E-types. A significant difference of P300 latency and P300 amplitude was observed at 17:00 between M-types and E-types. The P300 amplitude obtained after a low-frequency stimulus was significantly greater than that after a high-frequency stimulus at 09:00 for M-types, and at 01:00 for E-types. These results revealed that stimulus frequency had effects on the diurnal changes of human cognitive function, and circadian typology had a direct effect on the diurnal change of human cognitive function. This study has extended the previous findings of auditory P300 studies on diurnal variations in terms of circadian typology and stimulus parameter.     

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)     

Time-of-day effects of ethanol consumption on EEG topography and cognitive event-related potential in adult males

Time-of-day effects of ethanol consumption on EEG topography and cognitive event-related potential in adult males were studied. Ethanol (0.5 g/kg) or control drink was orally administered to nine healthy males at 10:00 and 18:00. The alpha 2 amplitude was significantly lower than that of the control at 0.5, 2.5 and 4.5 hours after ethanol consumption in the morning. These effects were observed in the left hemisphere and were only found after consumption in the morning. The subjectively rated attention was significantly lower than that of the control at 0.5 and 2.5 hours after ethanol consumption in the morning and at 0.5 hours after ethanol consumption in the evening. In contrast, the search speed of serial search task and P300 amplitude was significantly lower than that of the control at 2.5 hours after ethanol consumption in the evening. These results demonstrate that effects of ethanol are dependent on time-of-day of consumption. Ethanol consumption significantly lowered the alpha 2 amplitude when consumed in the morning, and lowered P300 amplitude when consumed in the evening.     

Treatment of Asthma by a Controlled-Release Theophylline Tablet Formulation: A Review of the North American Experience with Nocturnal Dosing

As many as 80 percent of asthmatics experience nighttime or early-morning episodes, which are difficult to treat and potentially fatal. The greater-than-normal amplitude of circadian airflow variation in many asthmatics contributes heavily to the genesis of the early ‘morning dip’. Beta-agonists and corticosteroids are of limited usefulness in nocturnal asthma, and slow-release theophylline drugs, while potentially effective, vary in 24-hr blood profile and hence their influence on nocturnal episodes. Traditional 12-hr ‘symmetric’ theophylline regimens, instead of meeting increased nocturnal demands, may actually produce lower night- than daytime blood levels. On the other hand, appropriately timed administration of a once-daily theophylline drug might provide maximum blood levels when needed and help stabilize 24-hr airflow.

Accumulated data, summarized in this review, demonstrate the chronotherapeutic potential of single-daily evening doses of a controlled-release theophylline preparation (Uniphyl® 400-mg tablets*) in nocturnal and early morning asthma. Nighttime blood concentrations with this regimen were higher than were those with Theo-Dur® tablets, ? B.I.D., in the same total daily doses, or with once-daily morning Uniphyl administration. In fed and fasted subjects, evening administration of Uniphyl 400-mg tablets was well tolerated and did not lead to ‘dose dumping.’ Clinically, this treatment demonstrated advantages over B.I.D. theophylline, over single-daily morning regimens, and over prior theophylline therapy. Advantages of the evening regimen included better early-morning airflow (without significant decline later in the day), more effective symptom control, better patient acceptance, fewer night awakenings, and the obvious convenience of once-daily dosing. In addition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with traditional 12 hr dosing.

Uniphyl 400-mg tablets may be administered once daily to provide maximum blood levels at the time of peak bronchoconstriction, whether at night or during the 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)     

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)