Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics
Online ISSN : 1882-8272
Print ISSN : 0388-1601
ISSN-L : 0388-1601
Volume 21, Issue 4
Displaying 1-13 of 13 articles from this issue
  • Minae KOBAYASHI, Shigeki MATSUKT, Shigenori ARAI, Hisao SHIBATA, Hiroa ...
    1990 Volume 21 Issue 4 Pages 675-681
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    Ketoprofen, a non-steroidal anti-inflammatory drug, was given to 7 elderly subjects at a single rectal dose of 75mg. Any abnormalities were not seen in clinical and physical findings.
    Serum GOT and GPT were slightly elevated in one subject, and serum urea was a little increased in two subjects. Besides these, no abnormalities of clinical and physical findings were indicated.
    We found that ketoprofen had a wide safety region even in elderly subjects. The maximum concentration of ketoprofen in plasma was reached at 0.5-2.0 hr.
    The urinary excretion of total ketoprofen (unchanged plus conjugated) during 72 hr after administration was 35.82±6.25% of dose, and approximately 97% of the urinary total ketoprofen in the form of glucuronide. Cumulative urinary excretion (% dose) of the elderly subjects was lower than that of adults, and its clearance of the elderly was also lower.
    The half-life in the plasma of the elderly subjects was 1.54±0.35 hr, which was not different from the half-life of healthy adult subjects. This result shows that elderly subjects are capable of metabolizing ketoprofen as effectively as healthy adult subjects.
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  • Hiroo KIMOTO, Yasuo KODAMA, Masaharu TAKEYAMA, Yuichi KOIKE
    1990 Volume 21 Issue 4 Pages 683-689
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    Valproic acid is highly bound to serum protein, mainly albumin. Valproic acid exhibits concentration-dependent protein binding, which partly accounts for considerable variability in the unbound fraction, even within the therapeutic range. Therefore, valproic acidprotein interaction and determination of the corresponding binding parameters should be considered. In the present study, we investigated the binding characteristics in epileptic adults and children under valproic acid chronic monotherapy, and determined the binding parameters of valproic acid to serum protein.
    There was a curvilinear relationship between total and unbound concentrations orunbound fraction, using a second-degree polynomial equation. The unbound fraction increased curvilinearly in proportion to the increase in total concentration . Averages of unbound fraction obtained from adults and children were not significantly different from each other (P>0.05). The unbound fraction ranged from 4.1 to 16 .7% (adults), and from 5.6 to 16.7% (children). There were marked about three-fold variations of unbound fraction in both adults and children.
    On the other hand, as the Scatchard plot was shown to be linear in both adults and children, valproic acid was bound to only one class of binding sites on the protein molecule. The binding parameters calculated by Scatchard plot were as follows: association constants (Ka) were 1. 14×104l/mol (adults) and 1.44×104l/mol (children), total number of binding sites (n (Pt)) was 1.36×10-3mol/l (adults) and 1. 20×10-3mol/l (children). There was no significant difference in the two parameters between adults and children (P>0 .05). Therefore, we determined the binding parameters from all samples (n=96) by using Langmuir plot. These results showed that dissociation constant (Kd) was 3 .89×10-5mol/l, total number of binding sites (n (Pt)) was 8.46×10-4 mol/l.
    These results suggested that valproic acid had the same binding characteristics in both adults and children. The molecular interaction between valproic acid and serum albumin involved one class of binding sites within the investigated range.
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  • Toshihiro SAITO, Yoshiaki INAGAKI, Yasushi NAKAMURA, Takaaki AIISO, Yo ...
    1990 Volume 21 Issue 4 Pages 691-702
    Published: December 31, 1990
    Released on J-STAGE: February 25, 2011
    JOURNAL FREE ACCESS
    The relationship between the plasma concentration and the hypotensive effect of DHP-218 after a single oral administration was investigated in 5 inpatients with essential hypertension. And, at the same time, a pre-pilot study of DHP-218 in essential hypertension was conducted in 20 patients using fixed and flexible dose method. Starting with the initial dose of 0.5mg twice daily, the dosage was raised with a two-fold increase considering the effect and the tolerance of patients. The following findings were obtained from the studies.
    1. The time course of plasma concentration of DHP-218 after a single oral administration to patients with essential hypertension was found to be almost the same as the result obtained in the phase I study.
    2. The hypotensive effect of DHP-218 was parallel with the changes of the plasma concentration, and the effect lasted for 12 hr.
    3. A significant decrease of blood pressure was observed at the dose of 1mg/day. From the evaluation of the hypotensive effect, a moderate or more-than-moderate decrease of blood pressure was observed in 18 out of the 20 cases at the maximum.
    4. The hypotensive effect of DHP-218 was found to be dose-dependent: i. e., the cumulative percentages of hypotensive effect were 20%, 50%, 75%, and 90% at 1mg, 2mg, 4mg, and 8 mg/day, respectively.
    5. Four cases experienced side effects including headache and facial hot flush, which were regarded as typical adverse reactions of calcium antagonists. None of them required dose reduction or discontinuation of the drug and none were considered to be of any safety problem.
    6. There were no changes in laboratory test findings after administration of DHP-218. The above findings suggested that DHP-218 can be expected to be a clinically useful antihypertensive drug having a long-lasting effect at low dosage level.
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  • Yoshihiro MATSUBARA, Kazutoshi HAYASHI, Takashi SATO, Yasunori SAKAMOT ...
    1990 Volume 21 Issue 4 Pages 703-712
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    It this paper, we evaluated the clinical efficacy and safety of dobutamine hydrochloride (Dobutrex), based on the data collected as a part of postmarketing surveilance of the drug. Taking into account the results of the evaluation, we explored profiles of the adapted patients to this drug, constructed by combining categories of patients' background and treatment factors. Namely, at first, we focused on the improvement ratings as a measure to evaluate clinical efficacy, and evaluated relationships between the improvement ratings and patient factors and those between improvement ratings and treatment factors by applying regression tree method with improvement ratings as response and patient and treatment factors as explanatory variables. The background factors that contributed to clinical efficacy judged by improvement ratings were severity, and presence or absence of underlying diseases and complicasions, and seven “patients profiles”were exposed based on these factors. The treatment factors that contributed to clinical efficacy were the dose used for the longest period duration administration and presence or absence of concomitant drugs, and seven“treatment profiles”were exposed on these treatment factors as well. Joint evaluation of“patients profiles”and“treatment profiles”suggests that high ratings in efficacy are expected for patients with myocardial infarction or other diseases of mild to moderate severity when their morbid states can be controlled by dose less than 10μg within 24 hr.
    Then, we evaluated safety in the same manner as we did efficacy, using incidence of side effects as a measure to evaluate safety. As a result, it was seen that the percentage of side effects became relatively high when a high dose was given in a short time to the patients with severe disease. On the whole, the risk of side effects was related more closely to treatment factors than to background factors. Thus, it is necessary to take maximal notice that side effects are liable to occur in patients who are given high doses of the drug in a short time.
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  • Tomohiro KANAZAWA, Mamoru MIURA, Wataru SASAKI, Ken KADOWAKI, Toshihid ...
    1990 Volume 21 Issue 4 Pages 713-723
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    In order to determine the relationship between efficacy and plasma level of flecainide in ventricular premature contractions (VPC), a study was carried out through multipleadministration method in 15 patients with VPC at dose level of 50mg b.i.d., 100mg b.i.d., or 150mg b.i.d. The results of this study were as follows.
    1) Flecainide was effective in 50% of patients at 50mg b.i.d. and all patients at 100 mg b.i.d. and 150mg b.i.d. Judging from the supression ratio of VPC by flecainide, the dose level from 50mg b.i.d. to 100mg b.i.d. seems to be appropriate for clinical applications.
    2) The minimum effective plasma level may be placed at 200ng/ml, and a reliable suppressive effect on VPC can be expected of flecainide at plasma level of 400ng/ml or more.
    3) Plasma level at steady state increased dose dependently up to 100mg b.i.d., though the plasma level at 150mg b.i.d. was greatly elevated to the extent of 1, 000ng/ml or more.
    4) Six laboratory data in 3 patients showed abnormal values, but the elevations in GOT, GPT and BUN seemed to have slight if any relationship to the treatment. The PQ and QTc intervals on the electrocardiogram were prolonged significantly.
    Therefore, it may be concluded that flecainide is a useful drug for the treatment of VPC and that 100mg b.i.d. is suitable as a usual clinical dose.
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  • Tomonori TATEISHI, Kyoichi OHASHI, Tetsuo SHITOH, Hajime NAKASHIMA, Ak ...
    1990 Volume 21 Issue 4 Pages 725-730
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The pharmacokinetic and pharmacodynamic interactions between diltiazem and propranolol, or atenolol were investigated in healthy volunteers. Diltiazem (30mg) or placebo was given three times daily for 3 days, and 30 min before administration of a β-adrenoceptor blocking drug given on the 4th day. A single dose of propranolol (20mg), or atenolol (50mg) was administered in a randomized, double-blind, crossover fashion. Exercise tests on a cycle ergometer were carried out before and after β-adrenoceptor blocking drug. Diltiazem significantly increased the AUC and elimination half-life of propranolol. The cardiac β-adrenoceptor blocking effect, as indicated by the percentage reduction in heart rate during exercise, tended to increase following diltiazem pretreatment, in comparison with placebo. In contrast, diltiazem did not significantly affect atenolol pharmacokinetics and pharmacodynamics. These results indicated that diltiazem impaired the total clearance of propranolol, which is principally metabolized by oxidative pathway in the liver. This kinetic interaction between diltiazem and propranolol may be partly related to the reduction in exercise-induced tachycardia.
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  • Haruhiko SATO, Masahiko HOSHI, Akira WAKUI, Maroh SUZUKI
    1990 Volume 21 Issue 4 Pages 731-738
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    Angiotensin-II-Induced Hypertension Chemotherapy is an approach to selective enhancement of drug delivery to tumor tissue for increase of chemotherapeutic effects. TY-10721 (TY) is a newly synthesized compound of human type of angiotensin II ([Asp1-Ile5] angiotensin II) by TOA EIYO Ltd.(Tokyo).
    Along with and after stopping of the continuous infusion of TY, blood pressure and plasma concentration of angiotensin II, aldosterone, renin activity, and other biochemical parameters were measured in six healthy male volunteers.
    Using 2.5 and 5 μg/ml of TY, the mean arterial blood pressure (diast. BP+1/2 press. diff.) elevated to 138.7±8.9 mmHg (before, 85.7±7.0) in about 4 min after start of the infusion, and maintained the level of 144.1±8.3 mmHg. After stopping of TY, blood pressure immediately fell down to the previous level (87.0±4.9 mmHg) in 3-4 min.
    Plasma concentration of angiotensin II was 207.6±99.1 and 260.0±100.3 pg/ml during hypertension state compared with that of 23.2±8.3 (before) and 18.4±11.5 (30 min after).
    Half-life of TY in the plasma was 69.3±16.9 sec.
    Although elevation of blood pressure could be obtained by the infusion of TY, there was no proportional relation between the elevation level and the administrating doses. Response of elevation of blood pressure had individual variations.
    Significant rise of aldosterbfie and suppression of renin activity, though within the physiological deviation range, was observed. There were no particular changes in the plasma sodium and potassium level and in the'ECG monitoring.
    Phase II study of induced hypertension chemotherapy using TY is now under way.
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  • Haruhiko SATO, Masahiko HOSHI, Masanobu URUSHIYAMA, Katsuo SUGIYAMA, K ...
    1990 Volume 21 Issue 4 Pages 739-745
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    Using TY-10721, induced-hypertension chemotherapy (IHC) was performed in 12 patients with various types of advanced cancer.
    The procedure of IHC, as already reported, consisted of the induction of hypertension within 150 mmHg of the mean blood pressure (MBP), and of the maintenance at the MBP level after drug administration along with the continuous infusion of angiotensin II.
    Totally, 100 procedures were recorded. After 2.5-4 min of start of the infusion of TY, the level of the MBP could reach 135.7 ± 10.0 mmHg and 139.3±10.0 mm Hg by using 2.5 and 5 μg/ml of TY, respectively.
    Administrated dose of TY was 29.8±9.7 (range: 11.7-72.1) ng/kg/min in the induction periods and 31. 8±12.1 (9.4-106.9) ng/kg/min in the maintenance periods. These coefficient variations (CV) were 32.6% and 38.1%, respectively.
    Conclusively, it is necessary for the control the adequate hypertensive state during IHC to adjust dose of angiotensin II according to the MBP level, not to administer a certain dose.
    Though there observed some slight accompanying symptoms such as dull pain and hotness at tumor region and chest oppressive sense, these did, not interrupt the treatment procedure.
    Randomized controlled study would have a role in the investigation of clinical merit of IHC for the selective enhancement of drug delivery to tumor tissue, based on the characterization of tumor microcirculation.
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  • Circadian Stage-Dependent Kinetics
    Shigehiro OHDO, Shigeyuki NAKANO, Nobuya OGAWA
    1990 Volume 21 Issue 4 Pages 747-754
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    This study was designed to examine how the dosing time of the day influenced the accuracy in predicting plasma valproate (VPA) concentrations at steady state. Eight healthy male volunteers took 400-mg doses of VPA for 9 days on a twice-daily basis (08: 30 and 20: 30). The circadian changes in VPA kinetics occurred at the absorption phase. The prediction of plasma VPA concentrations at 2hr (around Cmax) and at 12hr after both the morning and the evening dose on the ninth day was performed using the individual subject's pharmacokinetic parameters and population pharmacokinetic parameters (Bayesian method) obtained from the morning trial on the eighth day. The predictive accuracy for VPA concentration around Cmax after the morning dose was better, but that for VPA concentration after the evening dose was significantly biased toward overestimation. The individual pharmacokinetic parameters obtained from the morning trial became better sources for the prediction of VPA concentrations around Cmax after the morning dose, but worse sources for that after the evening dose. The predictive performance based on the Bayesian approach also showed the similar finding to that based on individual pharmacokinetic parameters. The overestimation of the target points around Cmax after the evening dose is closely related to that of Ka value produced by using population parameters obtained from morning trial. Therefore, these results suggest that the time in the circadian stage at which VPA is administered is important for evaluating exactly the predictive accuracy.
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  • Toshihiro SAITO, Fujio DEGUCHI, Masako KISHI, Toshiaki NAKATUKA, Kazut ...
    1990 Volume 21 Issue 4 Pages 755-763
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    Celiprolol is a β1 selective β-adrenoreceptor antagonist with intrinsic sympathomimetic activity. The effect of celiprolol on the hemodynamics during exercise loading and the responses caused by adrenergic drugs and the changes of body position were investigated in 9 patients with mild to moderate essential hypertension. Patients were treated with celiprolol 200 mg once a day for 4 to 6 wks, followed by the increased dose of 400 mg for 12 to 14 wks. The hemodynamics during exercise loading were measured in the observation and treatment periods using a bicycle ergometer in the supine position with the constant load of 1.25 W/kg for 6 mins. Blood pressure, heart rate, and cardiac output were measured and the total peripheral resistance was calculated. As sympathomimetic drugs, noradrenaline (NA) and isoproterenol (ISP) were used. Changes of body position were investigated using the electric tilt table.
    The results were as follows.
    (1) Celiprolol significantly reduced the increase of blood pressure and heart rate during exercise loading. The increase of cardiac output was not reduced significantly but there was a tendency to decrease. No significant change was found in the total peripheral resistance during exercise loading.(2) The increase of blood pressure caused by NA was not affected by celiprolol but the increase of systolic blood pressure and heart rate caused by ISP was significantly suppressed.(3) Celiprolol did not have an apparent effect on the response of blood pressure and heart rate caused by standing up.
    Based on the above, celiprolol is considered to suppress the increased blood pressure during exercise loading by reducing the increase of heart rate and cardiac output, and no significant change was found in the total peripheral resistance during exercise loading. On the other hand, as reported before, the hypotensive effect of celiprolol under resting state seems to depend not on the reduction of cardiac output but on mainly the decrease of total peripheral resistance. Therefore, it is suggested that the mechanism of the hypotensive effect of celiprolol from a hemodynamic viewpoint is different during the effort and resting state. The study with sympathomimetic drugs shows that celiprolol has no effect on the vascular α1-adrenergic receptor but significantly blocks the heart β1-adrenergic receptor. Further, celiprolol is considered to have few effects on the baroreceptor reflex according to the result of study with a change of body position.
    The above study evinces the conclusion that celiprolol is a unique β-adrenoreceptor antagonist which is different from the previously reported drugs. It seems very important for the evaluation of antihypertensive drugs to investigate not only the conventional antihypertensive effect, 24-hr ambulatory blood pressure and hemodynamics during resting state, but also the response to adrenergic drugs, the effect to baroreceptor reflex and hemodynamics during exercise loading.
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  • Akira SAKUMA
    1990 Volume 21 Issue 4 Pages 765-769
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    Under some clinical circumstances, statistical test for establishing equivalence with respect to the response rate between standard (S) and test (T) drugs specifying a maximum allowable value Δ0 of the true difference Δ=ρST is not feasible, because of the difficulty or impracticality in specifying the allowable difference. Instead of defining a crisp difference, a fuzzy tolerable difference may be introduced by formulating a membership function, say, by asking opinions of clinicians and/or patients.
    The membership function μ (Δ), taking values between 0 and 1, indicates the degree of reluctance of accepting a seemingly less effective but much less toxic or more convenient therapy; namely, at the lower boundary μ (ΔL)=0 and at the upper booudary μ (ΔU)=1. If ΔLU0, then the function jumps up from 0 to 1 at the crisp tolerable difference Δ0. Thus the crisp argument is a special case of the fuzzy one.
    Combining the membership function with the distribution for the difference in response rate, a more flexible fuzzy equivalence test is formulated . The probability density function for the difference obtained by joining beta functions is replaced by a normal approximation without the continuity correction to give fairly good results.
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  • Comparative Study with Disopyramide
    Tsutomu KURODA, Yasuaki HASHIMOTO, Yasuhiro YOSHIHARA, Satoshi ISHIDO, ...
    1990 Volume 21 Issue 4 Pages 771-776
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The influence of alpha-i-acid glycoprotein (AAG.) concentration on plasma protein binding of mexiletine and of disopyramide were investigated in patients with acute myocardial infarction and other heart disorders. The following results were obtained:
    (1) There was a linear relationship between the dose and plasma total concentration of mexiletine. There was no significant correlationship between the dose and plasma total concentration of disopyramide.
    (2) There was no significant correlationship between the concentration of AAG and free fraction of mexiletine, and negative correlation was observed between the concentration of AAG and free fraction of disopyramide.
    (3) No significant differences were observed in patients with acute myocardial infarction and other heart disorders between total plasma concentration and free fraction of mexiletine.
    There was no significant difference in total plasma concentration of disopyramide between the patients with acute myocardial infarction and other heart disorders. The free fraction in patients with acute myocardial infarction was significantly lower than that in those with other heart disorders (P<0.01).
    (4) The influence of AAG concentration on free fraction percent of mexiletine was not appreciated. Therefore, we concluded that the monitoring of total plasma concentration of mexiletine was important.
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  • Hiroshi IJIRI, Shigeo MUKAIYAMA, Ikuo TSURUTA, Takao KOMAYA, Hiroyuki ...
    1990 Volume 21 Issue 4 Pages 777-783
    Published: December 31, 1990
    Released on J-STAGE: June 28, 2010
    JOURNAL FREE ACCESS
    The purpose of this study was to evaluate the efficacy of captopril chronobiologically in the treatment of essential hypertension. Nine patients with essential hypertension were examined with ambulatory blood pressure (BP) monitoring (Nippon Colin, Japan). The monitorings were repeated before and after the treatment for 48 hr every 30 min. Captopril (12.5-25mg, three times daily) was administered for at least 6 wks. These data were analyzed with conventional statistical method and cosinor method. The hyper-/hypobaric indices of BP and heart rate (HR) were calculated based on the reference limits. The least squares fit of a cosine curve with a period of 24 hr was calculated to obtain MESOR (midline estimating statistic of rhythm), amplitude and acrophase. A circadian rhythm cycle of about 24 hr was found in BP and HR of all cases. MESOR of systolic and diastolic BP decreased from 138.1±1.1 mmHg to 129.0±8.8 mmHg and from 78.8± 8.5 mmHg to 72.5±7.0 mmHg, respectively (P<0.01). The hyperbaric index of systolic BP significantly decreased (P<0.05). MESOR of HR decreased from 73.0±9.5 bpm to 68.6±6.8 bpm (P<0.05). However, amplitude and acrophase of BP and HR showed no significant changes. In conclusion captopril showed definite antihypertensive effect preserving circadian rhythm of BP and HR.
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