Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics
Online ISSN : 1882-8272
Print ISSN : 0388-1601
ISSN-L : 0388-1601
Volume 27, Issue 4
Displaying 1-10 of 10 articles from this issue
  • Yasuaki HASHIMOTO, Akira SHIMIZU, Tsutomu KURODA, Masanori HAYAKAWA, K ...
    1996 Volume 27 Issue 4 Pages 665-671
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The effects of four dihydropyridine calcium channel blockers (nifedipine, nisoldipine, nitrendipine and manidipine) on the plasma digoxin level were studied in patients and the effects of nitrendipine and nisoldipine were compared in beagle dogs . In the clinical study, the mean plasma concentration of digoxin was significantly higher during combined administration with nitrendipine than with the other calcium channel blockers. In addition, the digoxin level was decreased by about 50% at one month after changing the calcium channel blocker from nitrendipine to nisoldipine. In dogs, combined administration with nitrendipine resulted in a significantly higher plasma digoxin level after 2 and 4 hrs and a significantly larger mean area under the plasma concentration time curvecompared with administration without nitrendipine (p<0.05). These findings demonstrate that the plasma concentration of digoxin is influenced by dihydropyridine calcium channel blockers, with nitrendipine increasing the digoxin level more than the other agents tested. Since digoxin has a narrow therapeutic range, careful monitoring of the plasma digoxin level during combined therapy with nitrendipine is suggested to minimize the risk of toxicity.
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  • Tomonori TATEISHI, Shinichi KOBAYASHI, Chika SHIGEYAMA, Tsuyoshi NAKAM ...
    1996 Volume 27 Issue 4 Pages 673-681
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    We evaluated the pharmacokinetics of KW-4679, a new antiallergic agent, in the elderly in single dosing and repeated dosing trials. In, the single dosing trial, the pharmacokinetics of a single dose of 10 mg KW-4679 in elderly male subjects [74±2yrs (mean±SD), n=6] were compared with these in young male subjects (21±1yrs, n=6). In the repeated dosing trial for 6 consecutive days, the pharmacokinetics of the last administration of 10 mg KW-4679 were compared with those of the first administration in elderly male subjects (74±3 yrs, n=6) to determine the accumulation of KW-4679 and/or its metabolites. In the single dosing trial, Cmaxand AUCin the elderly subjects were significantly larger than in the young subjects, while Cl/F was significantly smaller in the elderly subjects. There was no significant difference in the fraction of KW-4679 excreted in the urine between the elderly and the young subjects (69.3 ± 6.3% and 62.5±5.4% in the young and the elderly subjects, respectively). ClR in the elderly subjects (7.52 ± 2.18 L/hr) was significantly smaller than that in the young subjects (14.4± 2.20 L/hr). Although ClR was, correlated with Ccr, ClR was significantly larger than Ccr, implying that this agent undergoes renal tubular secretion. In the repeated dosing trial, all pharmacokinetic parameters examined, except for Cmax, showed no difference between the first and the last administration.
    The accumulation of KW-4679 and/or its metabolites could not be detected in the elderly subjects examined in the repeated dosing trial for 6 days, though these results suggested that the dose should be reduced in the elderly subjects who have lower Ccr.
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  • Takami YAGYU, Akemi SAITO, Takahiro NISHIMURA, Toshihiko KINOSHITA, Ma ...
    1996 Volume 27 Issue 4 Pages 683-690
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    A cross-over, placebo-controlled study was performed to compare the neuropsychotropic properties of fluvoxamine, a selective serotonin reuptake inhibitor, with those of imipramine, using psychomotor tests (a flicker test and an auditory reaction time) and the event-related potential (P300 component) in 8 healthy adult males who voluntarily participated in this study. As a result, no remarkable difference in the P300 amplitude or in the P300 latency was observed among the test drugs. In contrast, the psychomotor tests revealed that fluvoxamine produced an increased critical flicker frequency compared with placebo or imipramine. In conclusion, fluvoxamine was demonstrated to increase the excitability of the central nervous system, with little influence on the brain's data processing as reflected by P300 component and the reaction processing.
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  • Isao KOHNO, Hiroshi IWASAKI, Yasuaki MOCHIZUKI, Mitsuaki OKUTANI, Soui ...
    1996 Volume 27 Issue 4 Pages 691-698
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The aim of this study was to assess the differences in the characteristic effects of diltiazem and diltiazem-retard with 3 medication schedules on circadian profile of blood pressure and heart rate. The study was performed in 26 essential hypertensive patients.Blood pressure and heart rate were measured every 30 minutes before and after medication administration using an ambulatory blood pressure monitoring device (model ABPM-630, Nippon Colin, Aichi) for 48 hours. The data were analyzed with nonparametric estimation and cosinor method. The patients were divided into four groups; three groups with a dipper pattern and one group with a non-dipper pattern. Each group had different medication timing. Systolic and diastolic blood pressures were decreased significantly in the four groups. The time when the effect occured varied in the four groups. Diltiazem-retard (100 or 200 mg, sid, at 08: 00, 4 wks, n=7) had antihypertensive effects especially during the night rest span. Diltiazem-retard (100 or 200 mg, sid, at 19: 00, 4 wks, n= 6) had antihypertensive effects especially during the day active span and inhibited the morning rise of blood pressure. Diltiazem (30 or 60 mg, tid, 4 wks, n=5) had antihypertensive effects especially during the day active span in dipper hypertension.However, in non-dipper hypertensive patients, diltiazem (30 or 60 mg, tid, 4 wks, n=8) had antihypertensive effects especially during the night rest span. Evening administration with diltiazem-retard appears to be more efficacious than the other therapies.
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  • Hirofumi KANDA, Mitsuhiro YOKOTA, Toshikazu SOBUE, Hitoshi ISHIHARA, K ...
    1996 Volume 27 Issue 4 Pages 699-712
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    We examined the acute effects and safety of OPC-18790 (toborinone), a novel water-soluble quinolinone derivative, on mechanoenergetics in 12 patients with chronic congestive heart failure. OPC-18790 was intravenously administered at a rate of 5μg/kg/ min or 10 μg/kg/min. Left ventricular (LV) pressure-volume data were obtained by conductance methods and myocardial oxygen consumption (MVO2) was measured using a Webster catheter.
    Heart rate was slightly increased in all patients after receiving OPC-18790. Ventricular preload as assessed by LV end-diastolic volume index significantly declined, and mean and systolic pulmonary artery pressure also fell after OPC-18790 infusion. In addition to venodilation, systemic vasodilation was observed after OPC-18790 infusion. Systolic and mean arterial pressure, and systemic vascular resistance significantly declined after OPC-18790 infusion. Effective arterial elastance (Ea), which represents both the mean vascular resistance and the pulsatile components, fell significantly.
    LV contractility as assessed by end-systolic elastance (Ees) significantly rose after OPC-18790 infusion. Cardiac index and ejection fraction improved significantly. External work (EW) was unchanged.
    The isovolumic relaxation time constant was prolonged before OPC-18790 infusion and OPC-18790 shortened this time constant rate. MVO2 was reduced after OPC-18790 infusion probably due to a reduction of wall tension. Ventricular-arterial coupling (Ea/Ees) was far less than optimal before OPC-18790 infusion and was near optimal after OPC-18790 infusion. Mechanical efficiency (EW/MVO2) was improved along with the Ea/Ees ratio. Systolic arterial pressure fell by 40 or 50 mmHg after OPC-18790 infusion in 2 patients probably due to vasodilation.
    In conclusion, OPC-18790 had favorable mechanoenergetic effects in patients with congestive heart failure. Despite enhancing contractility, OPC-18790 reduced MVO2 and improved mechanical efficiency probably due to its favorable effects on loading conditions. These findings suggest that OPC-18790 may be useful for short-term treatment of patients with congestive heart failure.
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  • Hirotsugu ATARASHI, Hiroyuki SASAKI, Takeshi INO, Yuuji SUGIKI, Hiroka ...
    1996 Volume 27 Issue 4 Pages 713-723
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    Flecainide acetate is an antiarrhythmic agent of class Ic of Vaughan-Williams' classification. It has already been introduced for clinical use in numerous countries ; the oral preparation was launched in Japan in 1991.
    In the present phase I study, flecainide acetate injection was administered to healthy adults at doses of 0.5 to 2.0 mg/kg to evaluate its safety, pharmacokinetic behavior and pharmacological action.
    Throughout the study period no subjective symptoms were experienced by any subject except for mild transient numbness of the tongue in 3 patients in the 1.0 or 2.0 mg/kg groups. There were no abnormal laboratory test results.
    Plasma concentration of flecainide showed a biphasic pattern of elimination ; the elimination half-life in the λα phase was 2 to 3 min and that in the λβ phase was about 10 hours. Considering that these findings were relatively consistent with reported results from Western investigators, it appears that the pharmacokinetic behavior of flecainide does not differ from race to race. The P-R and QRS intervals were not clearly correlated with dose, but both intervals were prolonged after the administration of flecainide. The present study provides suggestive evidence that flecainide presents no safety problem if it is used in the dose range indicated above.
    The present study provides suggestive evidence that flecainide presents no safety problem if it is used in the dose range indicated above.
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  • Nobuyuki GOTO, Masaki SHIRAHASE, Hisao HATTA, Mikio MASADA, Jong-Dae L ...
    1996 Volume 27 Issue 4 Pages 725-730
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    We performed a pharmacoepidemiological study on the effect of different types of questionnaires on coughing and the prevalence of this symptom in out-patients taking angiotensin converting enzyme inhibitors (ACEI) in Fukui Medical School Hospital.
    The following three types of quentionnaires were prepared:
    Type 1 ; Questionnaire asking whether the patient has a cough or no after implying that ACEI might cause this symptom.
    Type 2 ; Questionnaire on the general adverse effects of ACEI, including coughing.
    Type 3 ; Questionnaire on the general adverse effects of ACEI other than coughing.
    All questionnaires included a blank space in which the patients were asked to write any adverse effects. The patients were randomly divided into three groups. Each group was given one of the three questionnaires. In the type 3 questionnaire, no patient com-plained of coughing. The prevalence of cough was higher in type 1 questionnaire than in type 2 quetionnaire patients. These results indicate that the prevalence of adverse effects varies greatly depending the type of questions in the questionnaire.
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  • Masaki SANAKA, Kikuo TAKANO, Satoru MINESHITA
    1996 Volume 27 Issue 4 Pages 731-739
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    It is relevant to measure the 24-hour creatinine clearance (CLcr) for prescribing renally eliminated drugs for geriatric patients, who have diminished renal function. However, the measurement of CLcr requires accurate sampling of 24-hour urine, which is often unreliable in the elderly. Hence, the prediction of CLcr can serve in place of the actual measurement in dosage adjustments. Indeed, predicted CLcr often differs from the measured CLcr. However, it should be emphasized that the renal function of aged patients is poorly assessed by serum creatinine (Scr) alone, while the predicted CLcr based on S, and easily obtainable parameters, such as age and body weight, can more reasonably approximate the renal clearance of the drugs. It should be noted however, in the use of such predicted CLcr, that the discrepancy between the predicted and measured CLcr may not be clinically acceptable in patients with acute renal failure, liver cirrhosis, muscle wasting, and excess fluid retention.
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  • Population Pharmacokinetic and Pharmacodynamic (PK/PD) Analysis
    Yuichi KOIKE, Yoshiro TOMONO, Hiroshi TANAKA, Satoru MINESHITA
    1996 Volume 27 Issue 4 Pages 741-757
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The present paper reports a new approach to building a population pharmacokinetic and pharmacodynamic (PK/PD) model and interpreting clinical data. We discuss about a historical background of PK/PD modeling, then, two special parametric models. One is the model to assess the time course of the disease progression and the effects of placebo and actual drug treatment. This model is able to distinguish active drug treatment quantitatively from placebo effect. The other model is a subject-specific PK/PD model for analgesia using population approach. It is capable of combining characteristic features of clinical trial, that is, a subject-specific random effect model for a multivariate response that consists of noncontinuous component responses, analyze of nonrandomly censored longitudinal data and statistics to estimate marginal distribution such as Monte Carlo integration. This approach is hopeful about the future in the field of drug development and drug evaluation.
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  • Ryuichi KATO, Toshio YASUMORI
    1996 Volume 27 Issue 4 Pages 759-769
    Published: December 31, 1996
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    In the development of new drugs, administration doses in a clinical phase I study and the expected final clinical dose were determined from the pharmacological data and nontoxic dose in repeated toxicity studies in an animal experiment. In this report, we comparatively examined the pharmacokinetic and toxicokinetic parameters in experimental animal studies and data from human clinical treatment of drugs under clinical development. Normalized AUC of rats, dogs and humans were calculated on the basis of 1mg/kg dose. The AUC ratios between rats, dogs and humans were widely distributed as one peak modality. The median of AUC ratio (human/rat) was 7.0 and that of AUC ratio (human/dog) was 2.89. However, the AUC ratios under 1.0 were found to be 12% and 20%, respectively, in human/rat and human/dog. The AUC obtained in the nontoxic dose of rats and dogs were compared with that obtained in the clinical (single) dose. The medians of the AUC ratios were 4.64 and 6.29, respectively, in rat/human and dog/human. However, the AUC ratios of under 1.0 were found to be 24% and 13%, respectively, in rat/human and dog/human. Normalized peak concentrations in plasma of rats, dogs and humans were calculated on the basis of 1mg/kg dose. The peak concentration ratios between rats, dogs and humans were widely distributed as one peak modality. The median of the peak concentration ratio in human/rat was 3.53 and that of human/dog was 1.96. However, the peak concentration ratios under 1.0 were found to be 18% and 32%, respectively, in human/rat and human/dog. The peak concentration obtained in nontoxic doses of rat and dog were compared with that obtained in the clinical dose. The medians of the peak concentration ratios were 2.21 and 5.19, respectively, in rat/human and dog/human. However, the peak concentrations under 1.0 were found to be 23% and 12%, respectively, in rat/human and dog/human. These results clearly revealed the presence of numerous drugs which showed lower exposure levels of dosed drugs in the nontoxic dose administration than in the clinical dose administration. These results might indicate that the safety of these drugs was not guaranteed from the viewpoint of toxicokinetics. However, these results rather might be due to following reasons that the metabolic rate in rats is faster than humans and the toxicity of metabolites may lower the nontoxic dose. Therefore, pharmacokinetic studies on toxic metabolites will be required and the evaluation of the contribution of metabolites in drug toxicity will be essential in future toxicokinetic studies.
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