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Biomedical subjects

A Fujimura

Publications and source records attributed to A Fujimura.

At least 163 records · Page 9Linked to original sources
PubMed1994

Administration time-dependent change in the effect of spironolactone in rats.

The present study was undertaken to examine whether the natriuretic effect of spironolactone, a competitive antagonist of mineralocorticoid, varies with its time of administration. Wistar rat maintained under the condition of light from 7 hr to 19 hr were divided into two groups. The first group had a bilateral adrenalectomy and received a 50-mg deoxycorticosterone acetate (DOCA) tablet intraperitoneally (DOCA group). The second group had a sham operation (control group). Spironolactone (50 mg/kg) was given orally at 12 hr or 24 hr, and the 8-hr urine was collected. At the end of the experiment, the blood sample for measurement of aldosterone was obtained at 12 hr and 24 hr in the control group. The natriuretic effect of spironolactone in the 24 hr-trial was significantly greater than that of the 12 hr-trial in the control group. However, such a time-dependent difference was diminished and did not reach statistical significance in the DOCA group. The plasma aldosterone concentration at 24 hr was significantly higher than that at 12 hr in the control group. These results suggest that the natriuretic effect of spironolactone varies with its time of administration. Daily variation in mineralocorticoid activity might be involved in this chronopharmacological phenomenon of spironolactone.

Administration, Oral↗
PubMed1994

Decrease in the time-dependent difference in urinary excretion of furosemide with age.

The influence of age on the time-dependent difference in urinary excretion of furosemide, a loop diuretic agent, was examined in this longitudinal study. Male Wistar rats were maintained under conditions of light from 07:00 to 19:00 h and dark from 19:00 to 07:00 h. Furosemide (30 mg/kg) was given orally at 12:00 h (day trial) or 00:00 h (night trial) to rats at 3 months of age, and urine was collected for 8 h after dosage. Thereafter, the identical protocol was repeated using the same animals at 6, 9, 12, 15, 18, and 21 months of age. The urinary excretion of furosemide was significantly greater in the day than in the night trial at 3 months of age. Such a time-dependent difference was observed for up to 15 months, but disappeared at 18 and 21 months of age. The time-dependent difference in urinary excretion of furosemide (day trial - night trial) decreased gradually throughout the observation period of the study. These results suggest that the time-dependent difference in the urinary excretion of furosemide diminishes during the aging process and disappears by 18 months of age in male Wistar rats.

Administration, Oral↗
PubMed1993

Influence of application site of a new transdermal clonidine, M-5041T, on its pharmacokinetics and pharmacodynamics in healthy subjects.

Influence of application site of a new transdermal clonidine, M-5041T(M), on its pharmacokinetics and pharmacodynamics were evaluated in eight human subjects. One patch of M-6 mg was applied for 3 days on the right chest (first trial), on the left arm (second trial), and on the upper abdomen (third trial). Blood samples for clonidine concentration were taken, and blood pressure (BP) was measured for a 120-hour postapplication period. Plasma concentrations of clonidine increased after application of M in each trial. This parameter in the second trial was significantly greater than that of the first and third trials. The values of maximum plasma concentration and area under the plasma concentration-time curve in the second trial were greater than those of other trials, but the differences did not reach significance. The BP-lowering effect of M in the second trial was significantly greater than that of the third trial. These results suggest that the plasma concentrations of clonidine after application of M and its hypotensive effect are affected by the site of application in human subjects.

Abdomen↗
PubMed1993

Pharmacokinetics and pharmacodynamics of a new transdermal clonidine, M-5041T, in healthy subjects.

The pharmacokinetic as well as the pharmacodynamic properties of a new transdermal clonidine, M-5041T (M), and its safety were evaluated after single and repeated applications. In the single-application study, one patch of M (4 mg-->6 mg-->8 mg) was applied for 3 days in eight healthy subjects. In the repeated-application study, first (0-72 hours), second (72-144 hours), and third (144-216 hours) patches of M 6 mg were applied in seven healthy subjects. In the single-application study, plasma clonidine concentration increased in a dose-dependent manner after application of M. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose-dependent manner, but the difference did not reach significance. Time to maximum concentration, elimination half-life, and total and renal clearance did not differ significantly among three trials. Blood pressure (BP) decreased gradually after application of each dose of M. The BP-lowering effect of M 8 mg was greater than that of M 4 mg and 6 mg. Adverse effects such as erythema and drowsiness were reported in some subjects. No subject had to be withdrawn from the study because of the appearance of adverse effects. In the repeated-application study, plasma concentration of clonidine increased up to 48 hours after application of first patch, and thereafter remained within a relatively narrow range until removal of third patch. The Cmax and AUC did not differ significantly among three trials. Blood pressure during an active period decreased significantly during treatment with M, whereas BP at midnight did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1993

Effects of diltiazem and cimetidine on theophylline oxidative metabolism.

The effect of diltiazem or cimetidine pretreatment on the inhibition of theophylline oxidative metabolism was investigated in nine healthy male nonsmokers. Diltiazem 60 mg, cimetidine 400 mg, or placebo was given orally three times daily for 3 days in a randomized three-way crossover manner. Both diltiazem and cimetidine pretreatment decreased the mean theophylline clearance (0.702 on placebo versus 0.641 on diltiazem, P < .05, and 0.542 mL/minute/kg on cimetidine, P < .01), resulting in prolonged mean theophylline half-life (7.58 on placebo versus 8.59 on diltiazem, P < .05, and 10.08 hours on cimetidine, P < .01) with no change in volume of distribution. The mean metabolic clearances for three major theophylline metabolites, 1-methyluric acid (1-MU), 1,3-dimethyluric acid (1,3-DMU), and 3-methylxanthine (3-MX), were reduced significantly by cimetidine (28%; P < .05, 32%; P < .01, and 33%; P < .01, respectively). Conversely, diltiazem significantly reduced only the mean metabolic clearance of 1,3-DMU by 21% (P < .05) without changes in that of 1-MU or 3-MX. These results suggest that cimetidine inhibited both N-demethylation and 8-hydroxylation of theophylline, whereas diltiazem exerted little influence on N-demethylation in spite of inhibition in 8-hydroxylation.

Adult↗
PubMed1993

The influence of pretreatment periods with diltiazem on nifedipine kinetics.

The effect of durations of diltiazem pretreatment on nifedipine kinetics was evaluated. Eighteen healthy male subjects were randomly allocated to three groups, 6 subjects each, for single doses of 60 mg diltiazem, and 3 days and 6 days with diltiazem 60 mg three times a day. All subjects received 20 mg nifedipine orally on two occasions using a double-blind cross-over, placebo-controlled method. No significant difference on pharmacokinetic parameters of nifedipine without diltiazem were observed among three groups. The single dose with 60 mg diltiazem significantly increased the area under the plasma concentration-time curve (AUC) for nifedipine compared with that in control an average of 35.1% (P < .05) and decreased the total body clearance (CL) an average of 24.0% (P < .05). Three days and 6 days pretreatment with diltiazem 60 mg three times a day significantly increased mean nifedipine AUC to 151.1% (P < .01), 188.0% (P < .05) of control values, and decreased CL to 58.2% (P < .01), 63.9% (P < .05) of control values, respectively. The elimination half-life (t1/2) of nifedipine were significantly prolonged both after 3 days' and after 6 days' pretreatment of diltiazem. These results suggest that diltiazem affects the nifedipine kinetics rapidly and pretreatment duration dependently. A clinically important drug interaction may occur when both drugs are administered simultaneously.

Administration, Oral↗
PubMed1993

Influence of lisinopril on urinary electrolytes excretion after furosemide in healthy subjects.

It has been reported that the urinary excretions of chloride (Cl), potassium (K), and magnesium (Mg), but not sodium (Na), after furosemide, a loop diuretic, were decreased by pretreatment with lisinopril, an ACE inhibitor in hypertensive subjects. The electrolytes disturbance induced by furosemide might be ameliorated by lisinopril. The present study re-examines this potential drug interaction in healthy subjects. Lisinopril (20 mg) or its matching placebo was given orally using a double-blind, crossover design. Four hours after lisinopril administration, furosemide (20 mg) was injected intravenously and urine was collected during the following intervals: 0-0.5, 0.5-1, 1-1.5, 1.5-2, 2-3, 3-4, and 4-6 hours. Blood samples for plasma furosemide concentration were obtained at 0.5, 1, 1.5, 2, 3, 4, and 6 hours after the agent. There were no significant differences between the two trials in plasma concentrations of furosemide or urinary excretions of the agent. Urine volume and urinary excretions of electrolytes (Na, Cl, K, and Mg) after the furosemide with lisinopril administration were not significantly different from those of placebo at any observation period. These results suggest that the urinary excretions of electrolytes after furosemide administration are not influenced by pretreatment with lisinopril.

Adult↗
PubMed1993

The effect of nifedipine on the pharmacokinetics and dynamics of diltiazem: the preliminary study in normal volunteers.

To evaluate the influence of nifedipine on the pharmacokinetics and the pharmacodynamics of diltiazem, five healthy subjects received 60 mg diltiazem orally on two occasions, diltiazem alone or after nifedipine pretreatment (10 mg three times daily for 3 days). After nifedipine pretreatment, the maximum concentration (Cmax) of diltiazem was increased and the time of Cmax was shortened, and the area under the concentration curve (AUC) tended to be increased. Although heart rate was increased, the corrected PQ interval tended to be prolonged after the nifedipine pretreatment. Both a decreased hepatic clearance and an increased bioavailability of diltiazem probably accounts for the increase in the Cmax and AUC of diltiazem after nifedipine pretreatment, and that might affect the pharmacodynamics of diltiazem.

Administration, Oral↗
PubMed1993

Differences of chronopharmacokinetic profiles between propranolol and atenolol in hypertensive subjects.

Previous studies have shown that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the night dosage than after the morning dosage in nocturnal rodents. The present study examines whether such a difference in chronopharmacokinetic profiles between lipophilic and hydrophilic agents also exists in humans. Propranolol (20 mg), a lipophilic beta-blocker, or atenolol (50 mg), a hydrophilic beta-blocker, was given orally to 13 hypertensive patients at 9:00 AM (day trial) or 9:00 PM (night trial) by a crossover design. Plasma concentrations of propranolol and its metabolites, 4-hydroxypropranolol and naphthoxylactic acid, and atenolol were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours after treatment. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of propranolol in the day trial were significantly greater than those in the night trial. Time to maximum plasma concentration (tmax) was significantly shorter in the day trial. No significant difference was observed in the elimination half-life between the two trials. There were similar administration time-dependent changes in the Cmax for 4-hydroxypropranolol and naphthoxylactic acid. On the other hand, although the Cmax of atenolol was greater and its tmax was shorter in the day trial, the differences did not reach significance. These results suggest that propranolol, but not atenolol is absorbed more rapidly after the morning dosage than after the night dosage. Based on these findings, the authors speculate that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the morning dosage than after the night dosage in humans.

Administration, Oral↗
PubMed1993

The effect of age on diurnal variation in the pharmacokinetics of propranolol in hypertensive subjects.

There is diurnal variation in the absorption rate of propranolol in younger subjects. This study was undertaken to examine the effect of age on the chronopharmacokinetics of propranolol. We gave 20 mg of propranolol orally to 13 younger and 11 older hypertensive subjects at 09.00 h (day study) or 21.00 h (night study) in a cross-over design. Plasma concentrations of propranolol and its metabolites, 4-hydroxypropranolol and naphthoxylactic acid, were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 h after dosage. In the younger subjects the absorption rate constant (ka) of propranolol and its maximum plasma concentration (Cmax) were significantly higher and the time to maximum concentration (tmax) was significantly shorter in the day than at night. There were similar time-variant changes in Cmax and tmax for 4-hydroxypropranolol and naphthoxylactic acid. In contrast, there were no time-variant changes in ka, Cmax and tmax of propranolol and its metabolites in the older subjects. These results suggest that propranolol is absorbed more rapidly after morning dosing than after night-time dosing in younger but not in older subjects. Based on these findings, we speculate that the time-variance in the absorption rate or first-pass elimination, or both, of propranolol diminish with age.

Adult↗
PubMed1993

Influence of clorgyline treatment on chronopharmacology of furosemide in rats.

Circadian variations in the adrenergic nervous system have been reported to be altered by chronic treatment with clorgyline, a monoamine-oxidase inhibitor. In the present study, the influence of clorgyline on the chronopharmacology of furosemide, a loop diuretic agent, was examined in rats maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Clorgyline (4 mg/kg/day) or its vehicle alone was infused subcutaneously by osmotic minipumps for 14 days. Furosemide (30 mg/kg) was given orally at 12 am [noon (N)] or 12 pm [midnight (M)]. Urine was collected for 8 hours after the agent, and urinary excretions of sodium and furosemide were determined. Urine volume and urinary excretions of sodium and furosemide were significantly greater at 12 N than at 12 M in the vehicle-infused group of rats. However these administration time-dependent changes in the effects of furosemide and its urinary excretion disappeared in the clorgyline-infused animals. These results suggest that the mode of the diurnal variation in the effects of furosemide is altered by chronic treatment with clorgyline. As chronic clorgyline is considered to disturb the adrenergic nervous system, the present findings are compatible with the hypothesis that this system is involved in the mechanism responsible for the time-dependent change in the effects of furosemide.

Analysis of Variance↗
PubMed1993

Chronopharmacology of amlodipine in rats.

The present study was undertaken to examine whether plasma concentrations of amlodipine, a calcium antagonist, and its diuretic effects vary with the time of dosage. Pharmacokinetic study; 20 mg/kg of amlodipine was given orally to rats at 10 am (day trial) or 10 pm (night trial), and blood samples were obtained during a 24-hour period. Pharmacodynamic study; two doses (10 and 20 mg/kg) of amlodipine were given orally at 10 am or 10 pm by a cross-over design, and urine was collected for 12 hours after dosage. Rats were maintained under condition of light from 7 am to 7 pm. The following results were obtained; The tmax of amlodipine was shorter and the Cmax was greater in the night trial than in the day trial. Its diuretic effects were greater in the night trial. These results suggest that the pharmacokinetic and pharmacodynamic profiles of amlodipine vary with its time of dosage.

Amlodipine↗
PubMed1993

Chronopharmacokinetic study of a new immunosuppressive agent, FK 506, in mice.

Chronopharmacokinetic profiles of a new immunosuppressive agent, FK 506, were examined in mice. FK 506 (1 mg/kg) was given orally at 10 AM (day trial) or 10 PM (night trial) once a day for 7 days. Blood samples for measurement of FK 506 concentration in whole blood were obtained just before and at 1, 2, 3, 4, 6, 8 and 12 hr after the final dosage. The time to maximum concentration was shorter and the maximum concentration was greater in the night trial than in the day trial. These findings suggest that absorption of FK 506 is faster and its blood concentrations is higher in the night trial.

Animals↗
PubMed1993

Influence of alpha-receptor blockade on the time-dependent change in the effect of furosemide.

Influence of alpha-receptor blockade on the time-dependent change in the effect of furosemide (a loop diuretic agent) was examined. Furosemide (30 mg/kg) was given orally to the doxazosin (an alpha 1-blocker)- or vehicle-treated rats at 12 AM or 12 PM. Urine volume and urinary excretions of of sodium and furosemide for 8 hr were significantly greater at 12 AM than at 12 PM in the vehicle-treated animals. However, such time-dependent changes in these parameters disappeared in the doxazosin-treated rats. These results suggest that the alpha 1-receptor-mediated stimuli are involved in the mechanism of the time-dependent change in the effect of furosemide.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1992

Diurnal effect on caffeine clearance.

Caffeine (300 mg) was given orally to nine healthy subjects at 10:00 AM (day trial) or at 10:00 PM (night trial) using a crossover design. Saliva was obtained at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after administration of caffeine. Urine was collected for 8 hours after caffeine dosing. Caffeine clearances in saliva during the day trial were not different from those in the night trial. No significant difference was observed in urinary molar ratios of metabolites (AFMU + 1X + 1U/17U) between the two trials. These data suggest that caffeine clearances in saliva do not vary with its administration time. Since caffeine clearances in plasma are reflected in the urinary ratios of caffeine metabolites, its clearance in plasma might also not be altered by the time of dosing.

Administration, Oral↗
PubMed1992

Chronopharmacology of furosemide in the elderly.

The authors have previously reported the time-dependent change in the diuretic effects of furosemide, a loop diuretic agent, in young and middle-aged subjects. The current study was undertaken to examine an influence of aging on this chronopharmacologic phenomenon. Ten milligrams furosemide was given intravenously to 12 elderly subjects (greater than 70 years of age) at 9:00 AM (day trial) or at 9:00 PM (night trial) by a cross-over design. One-hour urine samples were collected for 3 hours after each administration, and urine volume and urinary excretions of sodium and furosemide were determined. Urine volume and urinary sodium excretion increased after furosemide administration. Contrary to the findings in the young and middle-aged subjects, no significant differences were observed in these parameters at any observation period between the day and night trials in the elderly subjects. Urinary furosemide excretion of the day and night trials did not significantly differ. These results suggest that the chronopharmacologic profiles of furosemide are altered in the elderly.

Aged↗
PubMed1992

Effect of treatment at night with S-1452, a thromboxane A2 receptor antagonist, on the morning rise in platelet aggregation.

It is well known that platelet aggregation shows a morning rise, which may contribute to the increase in the onset of ischaemic heart diseases during the morning period. The present study was undertaken to determine whether nocturnal dosage with S-1452, a thromboxane A2 receptor antagonist, would blunt the morning rise in platelet aggregability. S-1452 50 mg or placebo were given orally to 8 healthy subjects at 10.00 h (day trial) or 22.00 h (night trial) according to a cross-over design. Plasma concentrations of S-1452 and its metabolites, bisnor-(+)-S-145 and tetranor-(+)-S-145, and platelet aggregation were determined during the 12-hour period following the dose. Mean plasma concentrations of S-1452, bisnor-(+)-S-145 and tetranor-(+)-S-145 during the absorption phase were lower after the nocturnal dose than after the morning dose. The maximum plasma concentration and area under the plasma concentration-time curve of the compounds were also lower and the time to the maximum concentration were delayed after the treatment at night. A morning rise in platelet aggregation was observed following placebo treatment. The inhibitory effect of S-1452 on platelet aggregation was observed at 3 hours and persisted for up to 9 h in both trials. The results suggest that S-1452 is absorbed more slowly after the nocturnal dose than after the morning dose. However nocturnal treatment with 50 mg S-1452 may blunt the morning rise in platelet aggregability.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗