Biomedical subjects

A Ebihara

Publications and source records attributed to A Ebihara.

At least 19 recordsLinked to original sources

PubMed1997

Long-term evaluation of combined antihypertensive therapy with lisinopril and a thiazide diuretic in patients with essential hypertension.

For the treatment of hypertension, the combination of an angiotensin-converting enzyme (ACE) inhibitor and a thiazide diuretic is supported by multiple lines of evidence, because these drugs have synergistic action and are expected to cancel out each other's adverse side effects. However, the long-term outcome of this combination antihypertensive therapy is not entirely clear. In the present multicenter open trial, we investigated the long-term efficacy and safety of combined antihypertensive therapy with an ACE inhibitor, lisinopril, and a thiazide diuretic, trichlormethiazide. A total of 466 patients with essential hypertension were treated with lisinopril alone (monotherapy group, n = 360) or with a combination of lisinopril with trichlormethiazide (combination therapy group, n = 106) for 1 year. The average blood pressure was effectively lowered to below 150/90 mmHg in both the monotherapy and the combination therapy groups throughout the study period. The average maintenance dose of lisinopril was lower when combined with thiazide than when given alone (9.8 vs. 11.5 mg/day, p < 0.001). Dry cough was the major side effect of lisinopril; no severe adverse effects were observed. The incidence of cough was not significantly different between the monotherapy group (13.1%) and the combination therapy group (11.3%). The increase in serum potassium observed in the monotherapy group was reversed by the concurrent use of the thiazide diuretic in the combination therapy group. Fasting blood glucose was significantly reduced in the monotherapy group; the reduction observed in the combination therapy group was not significant. Thus, the present results provide useful information as to the effectiveness and safety of combined antihypertensive therapy with lisinopril and a thiazide in comparison with monotherapy with lisinopril.

Adult↗

PubMed1996

Influences of bathing and hot weather on the pharmacokinetics of a new transdermal clonidine, M-5041T.

The influences of bathing and hot weather on plasma concentrations of clonidine were examined during application of a new transdermal clonidine system, M-5041T, in eight healthy volunteers. An M-5041T patch containing 6 mg of clonidine was applied on the right chest for 96 hours during winter with or without bathing (40 degrees C for 5 minutes) and also during summer without bathing. Plasma concentrations and urinary excretion of clonidine were determined for a 160-hour period after application. Plasma concentrations of clonidine in the winter trials did not differ significantly with or without bathing. Plasma drug concentration as a whole was significantly higher in the summer trial than in the winter trial, however. The maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), and urinary excretion (Ae) of clonidine also tended to be higher in the summer trial. These results suggest that plasma levels of clonidine are higher after application of M-5041T during hot weather. Although the period of bathing used in this study was short, the influence of bathing seems to be negligible.

Administration, Cutaneous↗

PubMed1996

Clinical pharmacology of multiple-dose losartan, an angiotensin II receptor antagonist, in patients with essential hypertension.

The pharmacokinetic and pharmacodynamic alterations of multiple doses of losartan, an angiotensin II receptor antagonist, were examined in nine patients with essential hypertension. Participants were given placebo once daily for the first 7 days (from day -7 to day -1), and then 50 mg of losartan for the next 9 days (from day 1 to day 9). The 24-hour blood pressure was measured on days -1, 1, and 7 and blood samples for measurement of losartan and its active metabolite, E-3174, were obtained on days 1 and 7. Plasma concentrations of uric acid and plasma clearance were determined before and during treatment with losartan, and at the end of the study. Pharmacokinetic parameters after the seventh dose, including maximum plasma concentration (Cmax) and time to Cmax (tmax) of losartan and E-3174, did not differ significantly from those after the first dose. The blood pressure lowering effect of losartan, however, was significantly greater after the seventh dose than after the first dose. Plasma uric acid decreased and its plasma clearance (ClUA) increased significantly during repeated administration with losartan. These values returned to pretreatment levels after the end of treatment. These results suggest that although the pharmacokinetic profiles of losartan and E-3174 do not change during repeated administration, the blood pressure lowering effect in hypertensive patients is greater after multiple doses than after a single dose.

Adult↗

PubMed1996

Pharmacokinetics of a new thromboxane A2 receptor antagonist, S-1452, and its effect on platelet aggregation in healthy volunteers.

To study the pharmacokinetics of a new thromboxane A2 (TXA2) receptor antagonist, S-1452, eight healthy volunteers were given placebo or S-1452 orally on four occasions in step-wise increasing doses of 10 mg, 25 mg, and 50 mg separated by 2-week intervals. Blood samples for measurement of plasma concentrations of the drug and of its inhibitory effect on platelet aggregation were obtained for 24 hours after administration. Bleeding time after administration was measured. S-1452 was rapidly absorbed, with a peak plasma concentration at 30 minutes after administration. Thereafter, the drug was rapidly eliminated (elimination half-life, 0.4-0.5 hours), and no drug was detected at 6 hours. The inhibitory effect of S-1452 on platelet aggregation, which was stimulated by the TXA2 receptor agonist U-46619, persisted more than 6 hours after drug administration. Bleeding time was slightly prolonged after a single dose of S-1452. These results suggest that although S-1452 is rapidly eliminated in plasma, its inhibitory effects on platelet aggregation persist for a longer period. Careful observations are needed to prevent potential bleeding episodes during repeated treatment with the drug.

Administration, Oral↗

PubMed1996

Clinical pharmacology and clinical trials in Japan.

Clinical pharmacology is the pursuit of rational therapeutics by following the scientific principles of medicine and pharmacology. In Japan the roles for clinical pharmacology and clinical pharmacologists have been evolving since the discipline appeared in the 1950s. Clinical pharmacology and clinical trials for drug development depend on each other, and clinical pharmacologists play an important role in drug development in Japan. As the discipline becomes more important and complicated, many issues regarding drug therapeutics and clinical trials in Japan have been raised, and several points of view have been expressed. The following suggestions have been made to improve clinical pharmacology in Japan: (a) Medical education in the field of clinical pharmacology must be improved by creating or improving clinical pharmacology programs in medical schools. (b) The appropriate infrastructure for clinical trials must be established so that the physicians' workload is reduced, and patients' participation in clinical trials becomes much easier. (c) Scientific and ethical standards of the pharmaceutical industry must be improved, and the effort should be made to produce drugs with new mechanisms of action or with significant expected benefits. (d) The regulatory agency must provide stronger support, encompassing all the various points of view of academic institutes and the pharmaceutical industry. In light of the enthusiasm demonstrated by the government, physicians, and pharmaceutical industry in Japan for continued progress in clinical pharmacology, it seems likely that all its challenges will be overcome in the near future. Hence, despite the various problems discussed here the future seems promising for the continued development of clinical pharmacology.

Clinical Trials as Topic↗

PubMed1996

Effect of alpha 1-adrenoceptor antagonists, prazosin and urapidil, on a finger skin vasoconstrictor response to cold stimulation.

OBJECTIVES: Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of alpha-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different alpha 1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these alpha 1-adrenoceptor antagonists in human subjects. METHOD: In thirteen healthy male subjects (20-42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg). RESULTS: Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The alpha 1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil. CONCLUSION: These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative alpha 1-adrenoceptor blocking potency of drugs.

Administration, Oral↗

PubMed1996

Effect of food intake on pharmacokinetics and effects of a new thromboxane A2 receptor antagonist, S-1452.

OBJECTIVE: To examine the effect of food ingestion on the pharmacokinetics of a new thromboxane A2 (TXA2) receptor antagonist, S-1452, and the inhibitory effect on platelet aggregation. METHODS: Fifty milligrams of S-1452 was given orally to eight healthy subjects with or without food. Blood samples for determinations of plasma drug concentrations and of its effects on platelet aggregation were taken for a 12-h post-drug period. RESULTS: The maximum plasma concentration of S-1452 was reduced by 47% and the time to maximum concentration was prolonged from 0.5 to 1.9 h after dosing with food. The inhibitory effect of S-1452 on platelet aggregations induced by U-46619, a TXA2 receptor agonist, and collagen persisted up to 9 h after dosing with and without food. The degrees of inhibition in the two trials did not differ significantly at any point. CONCLUSION: These results suggest that although the absorption of S-1452 is delayed and, consequently, its plasma concentration is decreased after dosing with food, the inhibitory effect on platelet aggregation is not significantly influenced after 50 mg of the drug.

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

PubMed1996

Pulpal blood flow assessed by laser Doppler flowmetry in a tooth with a horizontal root fracture.

Horizontal root fractures of both maxillary central incisors were diagnosed radiographically; neither responded to electric pulp testing nor to cold testing. The pulp of the right incisor was necrotic, whereas the pulpal status of the left incisor was uncertain. Pulpal blood flow of the teeth was measured with laser Doppler flowmetry. The blood flow of the left central incisor was 4.0. Eight months after the injury, a local anesthetic with a vasoconstrictor was administered to confirm pulp vitality. The blood flow of the tooth was decreased to 51% of the preanesthesia value after the local anesthesia. At 19 months after the injury, it responded to both the electric pulp test and cold test. Laser Doppler flowmetry is a noninvasive method of evaluating the blood flow status in human teeth, and it may provide a clinically reliable method of assessing pulpal vitality.

Adolescent↗

PubMed1996

Long-term effects of doxazosin, an alpha 1-blocker, on serum lipids in hypertensive patients.

Nowadays practical antihypertensive therapy involves not only simple normalization of blood pressure but also a reduction of the risks of cardiovascular disease. In this multicenter open-label study, the long-term effects of doxazosin, an alpha 1-adrenergic receptor blocker, on serum lipids were prospectively investigated in 253 patients with essential hypertension. They were treated with doxazosin for 1 year. The averaged the blood pressure was maintained at levels lower than 150/90 mmHg throughout 1 year, but heart rate did not increase. After 3 months of doxazosin therapy, total and low density lipoprotein-cholesterol levels in serum were significantly reduced by 3.3% and 3.4%, respectively, and these levels were maintained throughout the study period. This effect of doxazosin on serum lipids was especially prominent in patients with hypercholesterolemia. In addition, the lipid profile of these patients was favorably altered even when other antihypertensive drugs or lipid-lowering drugs had already been used or were used concurrently. These results constitute useful information for physicians who treat hypertension with alpha 1-blockers to reduce the overall risk of cardiovascular disease.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1995

Effect of losartan, an angiotensin II receptor antagonist, on response of cortisol and aldosterone to adrenocorticotrophic hormone.

Many imidazole derivatives are shown to inhibit adrenal steroid biosynthesis. The present study was undertaken to examine an effect of another imidazole derivative, losartan (an angiotensin II receptor antagonist), on responses of cortisol and aldosterone to adrenocorticotrophic hormone (ACTH). Nine patients with essential hypertension were given placebo orally for 7 days and 50 mg of losartan for the next 9 days. Response of serum cortisol and plasma aldosterone to intramuscular ACTH injection were determined before and at the end of the treatment with losartan. Serum cortisol and plasma aldosterone significantly increased after ACTH injection in both periods of treatment (placebo and losartan). The increments in these parameters during treatment with losartan were not significantly different from those during treatment with placebo. These results suggest that the inhibitory effect of losartan on adrenal steroid biosynthesis is negligible.

Adrenocorticotropic Hormone↗

PubMed1995

Chronopharmacology of enalapril in hypertensive patients.

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E2 (PGE2), which are likely to be involved in the mechanism of enalapril-induced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE2 did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be diminished or eliminated by a switch to night-time administration.

Adult↗

PubMed1995

Influence of aging on the oxidative and conjugative metabolism of propranolol.

The influence of aging on the hepatic metabolism of propranolol, i.e. conjugation, side-chain oxidation and ring oxidation, was investigated in 32 in-patients aged 30 to 84 yrs. Plasma propranolol concentration and main urinary metabolites [propranolol glucuronide (PPLG), naphthoxylactic acid (NLA), and 4-hydroxypropranolol (40HP)] were determined after a single oral dose of 20 mg propranolol. There were significant correlations between age and 1) maximum propranolol concentration, 2) area under the plasma concentration-time curve, and 3) elimination half-life. The apparent oral clearance of propranolol was inversely correlated with age. Partial metabolic clearance (PMC) to 40HP (ring oxidation) and PMC to NLA (side-chain oxidation) were significantly correlated with age, while PMC to PPLG was not. These observations suggest that there are age-related reductions in two oxidizing capacities, while there is no significant influence of aging on the conjugating capacity. The age-related reduction in oral clearance of propranolol may be mainly caused by the decline in the capacity of two different oxidation pathways.

Adrenergic beta-Antagonists↗

PubMed1994

Comparison of the pharmacokinetics, pharmacodynamics, and safety of oral (Catapres) and transdermal (M-5041T) clonidine in healthy subjects.

The pharmacokinetic as well as pharmacodynamic properties of a transdermal clonidine, M-5041T (M) and its safety were compared with those of oral clonidine, Catapres (Nippon Boehringer Ingelheim, Hyogo, Japan). One patch of M containing 6 mg of clonidine was applied on the right chest for 3 days or one tablet of Catapres (.075 mg) was given orally every 12 hours for 3 days in eight healthy subjects. The study was conducted by a crossover design with 14 to 16 days' interval between the cross-over. Blood and urine samples for clonidine concentration were obtained, and blood pressure (BP) was measured for a 168-hour period after application of M and for a 96-hour period after initiation of Catapres therapy. Plasma concentration of clonidine increased gradually after application of M and decreased gradually after removal, whereas this parameter increased rapidly during the absorption phase and decreased rapidly in the elimination phase after each dosage of Catapres. Elimination half-life of clonidine after removal of M was significantly greater than that after the final dosage of Catapres. No significant difference was observed in maximum plasma concentration or area under the plasma concentration-time curve between the two trials. The BP lowering effects of M and Catapres did not differ significantly. Adverse symptoms occurred more frequently during Catapres therapy than during treatment with M. Most of these symptoms were observed when plasma clonidine concentration was relatively higher in each trial. These results suggest that M is effective for the treatment of hypertension with a lower incidence of adverse symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗

PubMed1994

Renal clearance of lomefloxacin is decreased by furosemide.

The interaction between lomefloxacin, a new quinolone, and furosemide, a loop diuretic, has been examined. Oral lomefloxacin 200 mg and furosemide 40 mg were given together or separately to 8 healthy subjects, and blood and urine samples were obtained over the following 12 h. The plasma concentrations of lomefloxacin following coadministration with furosemide were higher than after lomefloxacin alone and its AUC was increased, and its total and renal clearances were decreased. No change in the pharmacokinetics of furosemide was found after coadministration of lomefloxacin. As quinolones and furosemide are reported to be excreted in urine by the renal tubular anion transport system, the present results suggest that the renal tubular secretion of lomefloxacin is diminished by furosemide. It is not clear whether this pharmacokinetic interaction might be clinically important.

Adult↗

PubMed1994

Time-dependent change in the toxic effects of amikacin on renal functions.

The present study was undertaken to examine whether there was a time-dependent change in the toxic effects of amikacin, an aminoglycoside, on renal functions. Male Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Amikacin (1.2 g/kg) was injected intraperitoneally to animals at 4 am, 10 am, 4 pm or 10 pm. Glomerular function estimated by creatinine clearance (Clcr) and tubular function estimated by urinary excretion of a loop diuretic, furosemide, which was excreted in urine mainly by tubular secretion, were determined before and 24 hours after amikacin injection. The values of these parameters were reduced by amikacin at each observation point. The magnitude of these decrements was greatest at 4 pm both for Clcr and urinary furosemide excretion. These results suggest that the toxic effects of amikacin on renal glomerular and tubular functions vary with its time of administration.

Amikacin↗

PubMed1994

Daily variation in the urinary excretion of furosemide in young and aged rats.

We have recently demonstrated that the time-dependent difference in urinary excretion of furosemide, a loop diuretic, diminishes during the aging process and disappears by 18 months of age in rats. The present study was undertaken to examine whether the amplitude of the daily variations in the urinary excretion of furosemide or their pattern, or both, are influenced in aged animals. Young (3 months of age) and aged (30 months of age) Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Furosemide (30 mg/kg) was given orally at 4 am, 8 am, 12 am, 4 pm, 8 pm or 12 pm. Urine was collected for 8 hours after furosemide administration and urinary excretion of furosemide was determined. There were significant daily variations in the urinary furosemide and the urine volume with the peak at 8 am and the trough at 12 pm in both groups of rats. The differences in these parameters between the 8 am and 12 pm trials were significantly smaller in the aged than in the young rats. These results suggest that the age-related alteration in the time-dependent phenomenon of furosemide is caused by the decreased amplitude of the daily variation in the urinary furosemide excretion and its diuretic effect.

Age Factors↗

PubMed1994

Effect of angiotensin II type 1 receptor antagonist on urinary prostaglandin E2 excretion following furosemide in rats.

The present study was undertaken to examine an effect of an angiotensin II type 1 (AT1) receptor antagonist on urinary prostaglandin E2 (PGE2) excretion following furosemide, a loop diuretic, in rats. Furosemide (30 mg/kg) was given orally with or without pretreatment with derapril (30 mg/kg), an angiotensin converting enzyme inhibitor, TCV-116 (1 mg/kg), an AT1 receptor antagonist, or losartan (10 mg/kg), another AT1 receptor antagonist. The 6-hour urine was collected following furosemide, and the urinary excretion of PGE2 was determined. The urinary PGE2 increased significantly following furosemide alone. However, such a furosemide-induced increase was not observed with pretreatment with derapril, TCV-116 or losartan. These results suggest that the increased urinary excretion of PGE2 following furosemide is blunted by derapril, TCV-116 and losartan. As TCV-116 and losartan are selective AT1 receptor antagonists, the effect of furosemide on renal PGE2 production, as reflected by the urinary PGE2, might be mediated by an activation of AT1 receptors.

Angiotensin II↗

PubMed1994

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

We have previously demonstrated that the natriuretic effect of spironolactone, a competitive antagonist of mineralocorticoid, varies with its administration time in young rats. The present study was undertaken to examine the influence of aging on chronopharmacological profiles of the agent. Spironolactone (10 and 50 mg/kg) was given orally at 12 am or 12 pm in young (12 weeks old) and aged (28 months old) Wistar rats. The 8-hour urine was collected after each administration, and the urinary sodium excretion was determined. The urinary sodium excretion increased dose-dependently following spironolactone in the young and aged groups of rats. The increments in this parameter in the 12 pm trial were significantly greater than those of the 12 am trial in the young rats. However, such an administration time-dependent difference in the effect of spironolactone was diminished and did not reach statistical significance in the aged animals. These results suggest that the mode of the administration time-dependent change in the effect of spironolactone is altered with age.

Aging↗