Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics
Online ISSN : 1882-8272
Print ISSN : 0388-1601
ISSN-L : 0388-1601
Volume 14, Issue 4
Displaying 1-10 of 10 articles from this issue
  • Noboru MIZUTANI, Yasuhiro NISHIYAMA, Tadashi KOBAYASHI, Tsutomu WATANA ...
    1983 Volume 14 Issue 4 Pages 559-571
    Published: December 30, 1983
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    It has recently been reported that the renin-angiotensin-aldosterone system plays a role in controlling cardiac load in heart failure. Captopril (SQ-14225), an orally active angiotensin converting enzyme inhibitior, was therefore administered in 10 patients with heart failure due to acute myocardial infarction and in dogs with coronary occlusion. In clinical studies, after administration of captopril, oral doses of 25mg, cardiac index increased (2.9±0.8→3.1±0.71/min/m2, P<0.05), stroke volume index increased (36.7±2.7→41.4±3.6ml/beat/m2), systolic arterial pressure decreased (139± 14.5→127±42.8mmHg), heart rate decreased (90±7.4→87±2.3beat/min2), pulmonary capillary wedge pressure reduced markedly (20±2.6→13±2.→3mmHg, P<0.01) and systemic vascular resistance reduced (1408±162→1151±148dyne·sec·cm-5, P<0.05). These effects were started 5 minutes after, reached peak 90-120 minutes after and lasted an average of 5 hours. Plasma renin activity rose after captopril (2.0±0.7→3.9±1.7ng/ml, P<0.05), plasma concentration of angiotensin II fell (140±140→85±91pg/ml) and plasma concentration of aldosterone fell (8.2±4.4→4.7±0.8ng/dl). In five cases, we measured plasma concentration of bradykinin (31±18→34±18pg/dl). It is considered that captopril has a substantial effect on both peripheral vascular resistance and venous capacitance by inhibition of vasoconstriction due to angiotensin II. In experimental studies in dogs, we found coronary sinus flow increased (62±32→83±40ml/min, P<0.01), coronary vascular resistance decreased (2.8±1.2→1.8±0.8mmHg/ml/min) and myocardial oxygen consumption increased (5.7±2.0→8.2±3.3ml/min) in dogs with coronary occlustion. Our study suggests that captopril applied in patient with acute myocardial infarction produces significant improvement in left ventricular function and myocardial metabolism without any serious complication.
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  • Phase I Study
    Kazuo HANAOKA, Megumi TAGAMI, Yutaka INADA, Hideo YAMAMURA
    1983 Volume 14 Issue 4 Pages 573-591
    Published: December 30, 1983
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    We carried out a Phase I Study of midazolam in healthy Japanese male volunteers and studied the safety of the drug in different 3 doses (0.1, 0.2, 0.3 mg/kg) administered intravenously and 1 dose (0.2mg/kg) intramuscularly.
    No remarkable change was seen in either psychosomatic symptoms, vital signs or laboratory tests.
    Sedation was observed characteristically in almost every case. Respiratory depression in dose-independent manner was observed in 0.3 mg/kg administered intravenously. Plasma half-life of midazolam, 1.82-2.68 hr, is far shorter than that of diazepam.
    The above results confirmed the safety of midazolam in healthy male Japanese volunteers.
    Therefore, we conclude that we can proceed to a Phase II Study with this drug.
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  • Akira KISHIMOTO, Chikara OGURA, Toshio TSUTSUI, Rokuro MIZUKAWA, Minor ...
    1983 Volume 14 Issue 4 Pages 593-604
    Published: December 30, 1983
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The adverse reactions due to single oral doses of nomifensine (NOM) 50 mg and maprotiline (MAP) 50 mg were compared in 10 healthy young (22 to 24 yrs of age, average 22.1 yrs) male volunteers in double-blind, corss-over fashion. Including self-rating, some physiological and psychological measurements were applied before and at times through 24 hrs after the administrations.
    The numbers who complained of adverse reactions were almost equal in both drugs, but severity of drowsiness and physical tiredness was significantly higher in the cases of MAP administration than in those of NOM administration. Pulse rate increased by 3.4% to 19.8% after NOM administration, but decreased slightly 2 to 3 hrs after the administration of MAP and significant difference was detected between the two drugs (P<0.05). No significant difference was observed on the blood pressure between both drugs. NOM did not decrease critical fusion frequency of flicker. On the other hand, MAP decreased it by 7.6% 6 hrs after the administration and significant difference was observed at 4, 5, 6 and 8 hrs after the drugs (P<0.01). Regarding the influence on salivary rate, NOM did not change the rate, but MAP decreased it severely (morethan 50% of before drug level) and significant difference was observed between the two drugs from 4 to 8 hrs after the administration (P<0.01). There was no difference between the two drugs on the function equilibrium, simple reaction time and correct response in immediate memory test.
    In conclusion, these results suggest that NOM 50 mg lacks the sedative effect and the depressing effect on salivation in normal young volunteers, while MAP 50 mg showed these effects markedly. The difference between the two drugs on these effects was prominent.
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  • Mitsuyoshi GOTO, Chieko OHNISHP, Shinji NAKAJIMA, Hajime YAMASHINA, Sa ...
    1983 Volume 14 Issue 4 Pages 605-611
    Published: December 30, 1983
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The effect of cimetidine and ranitidine administration on hepatic drug-metabolizing enzyme activity was investigated in 7 healthy volunteers using the ratio of 6-hydroxycortisol (6-OHF) to total 17-hydroxycorticosteroids (17-OHCS) in 24 hr urine as an index of the hepatic P-450-dependent enzyme system. Although the ratio of 6-OHF to 17-OHCS in different individuals varied from 0.043 to 0.074, the values obtained in three trials at one month intervals are highly reproducible within the same subjects. In contrast with very little effect of ranitidine ingestion at a 150 mg dose on hepatic P-450 systems, oral cimetidine administration at a dose of 200 mg four times a day immediately reduced the ratio from 0.058±0.008 to 0.045±0.009 (mean±S. D., P<0.02). This reduction continued at the same degree as the initial decrease during the cimetidine treatment for 15 consecutive days, whereas the ratio returned to the control value as soon as cimetidine was discontinued. The extent of reduction by a 200mg dose twice a day is slightly smaller than by the same dose four times a day. These results suggest that the rise of plasma concentration of some drugs may occur immediately following cimetidine administration, even at lower dosage, that drug interaction with cimetidine is to be avoided if cimetidine therapy is stopped, and that ranitidine dose not influence drug-metabolizing enzymes.
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  • Satoru MINESHITA, Robert EGGERS, Neil KITTERINGHAM, Edgar E. OHNHAUS
    1983 Volume 14 Issue 4 Pages 613-620
    Published: December 30, 1983
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    A method for quantifying phenacetin and its major metabolites has been developed. Metabolites that can be separated include glucuronide and sulphate, cysteine and mercapturic acid conjugates of acetaminophen as well as acetaminophen. The method used high-performance liquid chromatographic separation of these compounds on a C18 reversed-phase column. The mobile phases were methanol, 1% glacial acetic acid and 0.1 M KH2PO4 (33: 3: 64) for the unchanged phenacetin and (0: 3: 97) for the separation of metabolites.
    4-Fluorophenol was used as an internal standard. The minimum detectable limits (signal to noise ratio≥2) were 20-50ng injected onto column using UV detection at 254nm.
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  • A Double-blind Comparative Study with Placebo Ointment
    Koshichiro HIROSAWA, Morie SEKIGUCHI, Michiaki HIROE, Takashi HONDA, Y ...
    1983 Volume 14 Issue 4 Pages 621-636
    Published: December 30, 1983
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The hemodynamic effect of nitroglycerin ointment (NG), as vasodilator, was evaluated in 98 patients with heart failure, comparing with placebo ointment (PL) in a double-blind study using dopamine hydrochloride as basal treatment. The number of patients was 49 in both NG and PL group.
    1. There was no significant difference in patient characteristics between NG and PL group.
    2. Hemodynamic parameters in NG group revealed significant decrease in mean pulmonary arterial pressure (PA: 11.3%), pulmonary capillary wedge pressure or pulmonary arterial diastolic pressure (PCWP or PADP: 17.0%) and mean right atrial pressure (RA: 22.8%). There was significant difference between the two groups in PCWP or PADP, ‾RA, cardiac index (CI) and stroke work index (SWI), and the cardiac function was remarkably improved in NG group.
    3. In NG group, adverse effects were observed in two patients (slight hypotension and headache).
    4. Clinical usefulness was proven in 61.5% of the patients with NG and in 23.8% with PL, showing a significant difference between the two groups (P<0.001 by a U-test and P<0.01 by a χ2-test).
    From these results, it is concluded that nitroglycerin ointment is a useful vasodilat ing drug in the treatment of heart failure.
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  • Mitsuyoshi NAKASHIMA, Hifakuni HASHIMOTO, Katsuyoshi OGURO, Sadao OGUC ...
    1983 Volume 14 Issue 4 Pages 637-648
    Published: December 30, 1983
    Released on J-STAGE: February 25, 2011
    JOURNAL FREE ACCESS
    The pharmacokinetics and effects of guanabenz on blood pressure, heart rate and increases of plasma catecholamine levels and double products during physical exercise by ergometer were evaluated by 8 mg single oral dose of drug in 10 healthy male volunteers. Following results were obtained:
    Mean plasma levels of unchanged guanabenz were reached to peak of 2.14±0.60ng/ml at 2 hrs and decreased with a half-life of 5.37 hrs. Individual differences in peak levels and AUC0-48 of the plasma levels of unchanged guanabenz were about 12-15 times, indicating the extensive “first-pass effect”.
    Mean of cumulated urinary excretion of guanabenz and its metabolites for 48 hrs was 41.2% of the administered dose, in which unchanged guanabenz was only 0.4% of the dose. Individual differences of this cumulated urinary excretion were rather small (1.9 times) than those of plasma peak levels and AUC0-48, suggesting that individual differences of absorption are negligible.
    Maximal reduction of blood pressure was-16.4/-16.8mmHg at 5 hrs, and blood pressure at 24 hrs still showed significantly lower level (-6.5/-6.0mmHg). Heart rates showed no significant changes at any time of observation . Increases of blood pressure and heart rate during physical exercise were not affected by guanabenz.
    Resting plasma noradrenaline level was significantly decreased, while significant increase of plasma adrenaline level during physical exercise was blocked by guanabenz.
    Double product at rest was significantly reduced by guanabenz, probably due to the result of its hypotensive effect. No influence of guanabenz was however observed on the increase of double product during physical exercise.
    These results indicate that guanabenz has no effect on the circulatory regulations during physical exercise at the dose level which produces significant and long-lasting hypotensive effect in normotensive subjects.
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  • Muneyasu SAITO, Ken-ichi FUKAMI, Tetsuya SUMIYOSHI, Kazuo HAZE, Katsuh ...
    1983 Volume 14 Issue 4 Pages 649-654
    Published: December 30, 1983
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    Evaluation was made on central hemodynamic effects of isosorbide dinitrate (ISDN) spray (Isomack spray®, Heinlich Mack Nachf., Germany) with special refference to the onset and duration of action compared to sublingual nitroglycerin and ISDN.
    In nine patients with uncomplicated acute myocardial infarction, ISDN spray (2 sprays, 2.5 mg), nitroglycerin (TNG, 0.3 mg) and ordinary ISDN tablet (5mg) were administered by single-blind cross-over method under hemodynamic monitoring with Swan-Ganz catheter. Systolic pulmonary artery pressure (s-PA), systolic blood pressure (s-BP) measured by sphyngomanometry and heart rate were measured. every one minute for 10 min, every 5 min for next 20 min and every 15 to 30 min thereafter up to 120 min. Using s-PA as an index for nitrate action, the onset and duration of the effect as well as the extent of the changes were compared among these three drugs.
    ISDN spary had quick onset of action (2.67±2.4min, mean±SD) which was comparable with TNG (2.67±1.00 min), while ISDN spray had long duration of action (57.4±42.1 min) which was comparable with sublingual ISDN (85.6±39.5, ns) and was significantly longer than TNG (11.4±6.4 min, P<0.05). ISDN spray (2.5mg) showed same extent of hemodynamic changes as 0.3 mg of TNG and 5 mg of ISDN. It is concluded that ISDN spray is a useful agent for the abortion of anginal attacks by its quick onset and long duration of action.
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  • 1983 Volume 14 Issue 4 Pages e1
    Published: 1983
    Released on J-STAGE: February 25, 2011
    JOURNAL FREE ACCESS
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  • 1983 Volume 14 Issue 4 Pages e2
    Published: 1983
    Released on J-STAGE: February 25, 2011
    JOURNAL FREE ACCESS
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