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Volume 26 (1995)
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Virtual issue
Volume 26, Issue 4
Displaying 1-14 of 14 articles from this issue
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Junko FUJII, Akimasa HIGASHI, Nobuo INOTSUME, Norio ASO, Ichiro MATSUD ...1995 Volume 26 Issue 4 Pages 779-784
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.779JOURNAL FREE ACCESSSerum levels of amphotericin B (AMPH) following oral administration of large doses were studied in 7 children and 11 adult patients. Serum levels of AMPH were analyzed by high-performance liquid chromatography (HPLC). The detection limit of the method employed in this study was 0.01μg/ml. The coefficients of variation were below 6%. Serum concentration profiles of AMPH after oral administration of 1000mg showed plateaus for 24 hours in the children at steady state. The serum concentrations of AMPH were 0.05-0.15μg/ml after oral administration of 10-50mg/kg at steady state. The serum levels did not correlate with the doses of AMPH, and individual differences were large. Further, the serum levels were not correlated with age. The results of this study may suggest that there are limits to the absorption of AMPH following oral administration of large doses. Administration of large doses of AMPH raised serum levels to about 0.1μg/ml, and these concentrations exceeded the minimal inhibitory concentration of Candida albicans. These results suggest that oral administration of large doses of AMPH is clinically effective and safe for the prophylaxis or the treatment of fungal infection in patients.View full abstractDownload PDF (671K) -
Analysis of Heart Rate-ST Segment LoopHiroshi TSUNAKAWA, Yutaka SHIMIZU, Masahiro NAKAYAMA, Yasushi KUSAHANA ...1995 Volume 26 Issue 4 Pages 785-792
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.785JOURNAL FREE ACCESSTo study the effect of nipradilol, a new antianginal agent with vasoactive property as well as β-blocking action, on exercise electrocardiogram, multi-stage treadmill tests were performed after the administration of nipradilol and propranolol in 10 patients with stable effort angina pectoris. The effect of nipradilol on conventional measures in exercise ECG (heart rate, systolic BP, ST segment deviation, exercise duration, pressure rate product) was not significantly different from that of propranolol. An analysis of heart rate-ST loop (HR-ST loop), ST segment deviation plotted as a function of heart rate, during exercise and recovery revealed that nipradilol shifted the HR-ST loop rightward, indicating less prominent ST segment depression relative to the increase in HR when compared with propranolol. Calculated ST segment depression relative to the change in HR was smaller with nipradilol than with propranolol during exercise (ΔST/ΔHR from rest to peak exercise: nipradilol 5.57±0.81 vs propranolol 6.71±1.07μV/bpm, p<0.05) and recovery (recovery index: nipradilol 1.83±0.65 vs propranolol 3.01± 0.74μV/bpm, p<0.05). These results indicated that nipradilol may have beneficial effects on exercise ECG in angina pectoris other than β-blocking action, such as a vasoactive property.View full abstractDownload PDF (925K) -
Satoshi TSURUTA, Kanako MATSUMURA, Satoru TSURUTA, Keiko IMAMURA, Kazu ...1995 Volume 26 Issue 4 Pages 793-801
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.793JOURNAL FREE ACCESSThe purpose . of the present study was to evaluate the pharmacokinetic interaction between nifedipine and quinidine sulfate. To investigate any potential interaction, 6 male beagle dogs orally received 10 mg nifedipine or the combination of 10 mg nifedipine and 100 mg quinidine sulfate. These investigations were done using a randomized cross-over study design with a one-week wash-out period between treatments. Following the oral administration of nifedipine, the maximum serum concentration of nifedipine was signifi cantly increased by coadministration of quinidine sulfate. The mean residence time was significantly reduced by coadministration of quinidine sulfate. The dogs then received intravenously 4 mg nifedipine withor without 100 mg of oral quinidine sulfate . Following intravenous administration of nifedipine, the volume of distribution was significantly reduced, and the elimination rate constant was significantly increased by coadministra tion of quinidine sulfate.
The effects of quinidine sulfate on the metabolism of nifedipine to metabolite (M-1) were studied using dog liver microsomes. Quinidine sulfate inhibited microsomal nifedipine oxidation in a noncompetitive manner. To determine whether quinidine sulfate interferes with the protein binding of nifedipine in vitro, the free fraction of nifedipine was determined by an ultracentrifugation technique. These data indicate that quinidine sulfate inhibits the binding of nifedipine to human albumin and α1-acid glycoprotein in a competitive manner. The results of the in vitro experiments suggest that quinidine sulfate inhibits the hepatic first pass metabolism and the serum protein binding of nifedipine. This pharmacokinetic interaction may result in an enhanced pharmacologic response.View full abstractDownload PDF (745K) -
Satoshi TSURUTA, Naomi TANOUE, Kanako MATSUMURA, Keiko IMAMURA, Kazuhi ...1995 Volume 26 Issue 4 Pages 803-809
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.803JOURNAL FREE ACCESSThe protein binding parameters of four dihydropyridine calcium antagonists; nifedipine, nilvadipine, nicardipine andnisoldipine to purified human serum albumin (HSA) and α1-acid glycoprotein (AAG) were examined using ultracentrifugation. The four dihydropyridine calcium antagonists were predominantly bound to HSA and AAG. Nilvadipine showed the highest affinity to both HSA and AAG among the four dihydro-pyridine calcium antagonists.
In HSA solution (40g·L-1) the mean bound fractions of the four dihydropyridine calcium antagonists did not differ from those reported in serum, suggesting that HSA is the major binding protein for nifedipine, nilvadipine, nicardipine and nisoldipine in serum. A slight difference was observed in the stereoselective binding of nilvadipine and nicardipine to HSA.View full abstractDownload PDF (27K) -
A Multicenter Placebo-Controlled Double-Blind TrialSaichi HOSODA, Takeshi MOTOMIYA, Takashi KATAGIRI, Teruo TAKANO, Shige ...1995 Volume 26 Issue 4 Pages 811-830
Published: December 31, 1995
Released on J-STAGE: February 25, 2011
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.811JOURNAL FREE ACCESSWe conducted a multi-center two-stage randomized double-blind placebo-controlled study to assess the efficacy and safety of NKH477. This drug, a newly synthesized water-soluble forskolin derivative, has been previously shown to improve hemodynamics and subjective symptoms in patients with acute heart failure.
In the first stage (study 1), 78 patients with acute heart failure were randomly assigned to receive either NKH477 by intravenous administration at 0.5μg/kg/min for 30 min or a lower dose of NKH477 as a “substitute” placebo, namely 0.2μg/kg/min for 30 min. The second stage (study 2) began within 10 min after the end of dosing in study 1. Forty-seven patients were randomly assigned to either continue treatment with NKH477 at 0.5 μg/kg/min for 1 hr or toreceive matching vehicle placebo.
In study 1, the percentage improvement in hemodynamic and subjective and objec tive conditions in the control group as judged by attending physicians was 34.3 %. In contrast, improvement in the NKH477 group was 71.4 %, this difference being significant (p<0.01). No significant difference was seen between the groups with respect to side effects and abnormal changes in laboratory data. Usefulness as rated according to the above assessment was 31.6 % in the lower dose group and 71.4 % in the NKH477 group, this difference again being significant (p<0.01).
Moreover, in study 2, the percentage improvement was even greater in the NKH477 group compared to the placebo group, at 82.4 % and 16.7 %, respectively. Again, there was no significant difference between the groups with respect to side effects and abnor mal changes in laboratory data. Respective usefulness values were 76.5 % and 16.7 %, this difference again being significant (p<0.01).
These results indicate that NKH477 is useful and safe in the treatment of acute heart failure.View full abstractDownload PDF (1742K) -
Shouji YAMAZAKI, Kazuhiro HARADA, Masashi ARAKAWA, Toshimoto KUROSU, A ...1995 Volume 26 Issue 4 Pages 831-838
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.831JOURNAL FREE ACCESSIn order to perform appropriate drug therapy, patients should be provided with information regarding such therapy. In Japan, however, the explanation of the therapy given by the doctor is often very limited and no other information about the prescribed drugs is available. In this preliminary study, information sheets were prepared about various drugs (42 for hypertension, 4 for hyperlipidemia and 4 for diabetes mellitus).The sheets were distributed to 184 out-patients and were followed up with questionnaires designed to investigate the utility value of the information sheets.
The study produced the following meritorious results. 1) Improved patient/doctor and medical staff relationships. Thirty-six percent of the patients who responded, felt more at ease to communicate with their doctor after receiving the information sheets. 2) Improved drug compliance measures. Drug compliance was improved in 21 percent of the patients once having received the information sheets. 3) All patients that participated in the study judged that providing information about their drug therapy was beneficial. In order to further confirm the usefulness of the drug information sheet, additional studies should be performed with a larger sample of patients and a wider variety of drugs.View full abstractDownload PDF (902K) -
Tsuyoshi SHIGA, Akio FUJIMURA, Akio EBIHARA1995 Volume 26 Issue 4 Pages 839-844
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.839JOURNAL FREE ACCESSThe blood pressure (BP) lowering effect of a new transdermal clonidine, M-5041T (M) was evaluated in 11 subjects with essential hypertension. After application of a placebo patch for 4 weeks, a patch of M containing clonidine 2 mg (M-2 mg), 4 mg (M-4 mg), 6 mg (M-6 mg), or 8 mg (M-8 mg) was applied for 10 weeks. When an adequate response of office BP [1) areduction in systolic BP (SBP) ≥20 mmHg and diastolic BP (DBP) ≥10 mmHg, 2) areduction in mean BP≥13 mmHg or 3) SBP<150 mmHg and DBP<90 mmHg] was not obtained after 2 weeks of therapy, the dose of clonidine was increased as follows: M-2 mg→M-4 mg→M-6 mg→M-8 mg. BP was measured for 24 hours by a noninvasive automatic device and urine samples for catecholamines were collected from 7am to 10pm (active period) and from 10pm to 7am (resting period) at the end of treatment with placebo (4 weeks) and active drug (10 weeks). The office and ambulatory mean BP was decreased by 12.4% and 4.2%, respectively, by treatment with M. SBP, but not DBP was significantly decreased during the active period by treatment with M. Although a significant BP lowering effect of M was not obtained during the resting period as a whole. An excessive hypotensive episode was observed in one subject. Urinary excretion of norepinephrine was significantly reduced by treatment with Mduring the active period, but not during the resting period. Two subjects complained of itching under the application site of M and discontinued the study.
These results suggest that although the BP lowering effect of, M is relatively small during the resting period, an excessive hypotensive episode might occur in some hypertensive patients during this period with treatment with M. In addition, skin reactions might occur during a repeat application of M.View full abstractDownload PDF (740K) -
Dose Escalating Study Including the Effects of Meals and SmokingEiji UCHIDA, Tadayuki TSUCHIYA, Masahisa HASHIMOTO, Ichirou FUKAZAWA, ...1995 Volume 26 Issue 4 Pages 845-856
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.845JOURNAL FREE ACCESSThe safety, tolerability and pharmacokinetics of DO-309 (doxofylline: DOX), a new anti-asthmatic agent, were investigated in 30 healthy male volunteers after single oral administration of 200 mg, 400 mg, 800 mg, 1, 000 mg and 1, 200 mg DO-309 in a doseescalating fashion. During the study, the effect of food intake on the kinetics of DO-309 was determined in 6 subjects after a 400 mg single dose during fasting and at 30 minutes after a meal with a cross-over design. The effect of smoking was also evaluated in 8 subjects (4 smokers and 4 non-smokers) given 400 mg DO-309 during fasting.
All subjects completed the study without any adverse effects. No apparent changes in blood pressure, pulse rate, body temperature or clinical laboratory data were observed in any subject. In the dose-escalating study, the absorption of DOX was rapid (tmax: 0.60 -0.86 h) following administration of DO-309. Non-linear pharmacokinetics were observed for t1/2, Cmax and AUC of DOX with a dose-dependent increase after each dose. A dose-related increase, however was observed for Cmax and AUC of the main metabolites of DOX, theophylline-7-acetic acid (T-7 A) and hydroxyethyl theophylline (OH-ET). Total urinary excretion of DO-309 for 48 hours was around 70-80% of the dose adminis tered in each step.T-7 A was a major component of the total excreted into urine ; a very slight amount of DOX was found. Food intake slightly delayed tmax and decreased Cmax of DOX but did not change t1/2 and AUC of the drug. Regarding the influence of smoking on the pharmacokinetics of DO-309, AUC and Cmax of DOX were remarkably decreased in smokers, while no change was observed for those of the metabolites.
Single oral administration of DO-309 was well tolerated within the dose range used in this study and the results support the feasibility of repeat administration of DO-309 in healthy male volunteers.View full abstractDownload PDF (1393K) -
Repeated Oral AdministrationEiji UCHIDA, Toshihiro CHOU, Ichirou HUKAZAWA, Akihiko NAGUMO, Kuninob ...1995 Volume 26 Issue 4 Pages 857-865
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.857JOURNAL FREE ACCESSThe safety, tolerabillity and pharmacokinetics of DO-309 (doxofylline: DOX) a new anti-asthmatic agent, were investigated in 18 healthy male volunteers after repeated oral administration of DO-309 (400 mg and 600 mg b.i.d.) or its placebo for 7 days. Values are mean±SD.
All subjects completed the study without any adverse effects. No apparent changes in blood pressure, pulse rate, body temperature or clinical laboratory data were observed in any subjects. Steady-state plasma concentration of DOX was reached within 5-6 days in both treatments. Since non-linear phar-macokinetics was observed for DOX in the single dose study, the accumulation ratio was calculated for each pharmacokinetic parameter obtained from the plasma concentration-time curves after the first and the final dose. In 400 mg b.i.d. treatment, the AUC(0→12h) ratio of DOX was 20.23±13.31, Cmax 6.86±2-97, t1/2 3.70±1.06 and AUMC/AUC 3.23±0.63. About 70% of the total dose administered was recovered in the urine by 48 hours after the final administration. Michaelis-Menten Kinetics failed to simulate plasma concentration-time curves of DOX for the repeated administration. However, a similar value of the accumulation ratio was observed for each pharmacokinetic parameter of DOX in 600 mg b.i.d. traetment as seen in 400 mg treatment suggesting the probabillity of the prediction of a steady state concentration of DOX using the parameters obtained from the first dose.
Repeated dosing of DO-309 both 800 mg/day and 1, 200 mg/day treatments were well tolerated. We concluded that the results support the feasibility of early Phase II study in asthmatic patients.View full abstractDownload PDF (1538K) -
Drug-drug Interaction between the Quinolones (Norfloxacin, Ofloxacin) and Al3+ and/or Mg2+ Containing AntacidsNobuyuki GOTO, Hisao HATTA, Mikio MASADA, Masahiro SAWADA, Hisasi NOMU ...1995 Volume 26 Issue 4 Pages 867-873
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.867JOURNAL FREE ACCESSIn a pharmacoepidemiological study, the response to norfloxacin and ofloxacin (duration of treatment and total dose prescribed) was analyzed in order to determine whether norfloxacin and ofloxacin in combination with metal cation-containing prepara tions have an effect on the outcome of treatment.
The treatment duration and total dose prescribed were significantly greater (p<0.005, respectively ; using the Mann-Whitney test) in the patients given norfloxacin in combination with metal cation-containing agents than in those on monotherapy. However, the effects ofloxacin showed no change by combination administration with drugs containing magnesium and/or aluminum.View full abstractDownload PDF (697K) -
Masaki SANAKA, Kikuo TAKANO, Yuichi KOIKE, Takatsugu YAMAMOTO, Satoru ...1995 Volume 26 Issue 4 Pages 875-882
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.875JOURNAL FREE ACCESSA previous study concerning beta-methyldigoxin (BMD) in the elderly has suggested that serum glycoside concentration (SGC) can be predicted based on the daily dosage of BMD and serum albumin (Alb). From 73 elderly inpatients receiving BMD, we have derived the equation to predict SGC based on the daily dosage of BMD/body weight (=dosage/BW), serum creatinine (Scr), and Alb using stepwise forward multiple regression analysis as follows:
SGC=1.3+318 (dosage/BW)-0.25/Scr -0.22Alb
where SGC is in ng/ml, dosage in mg/day, BW in kg, Scr in mg/dl, and Alb in g/dl . The adjusted multiple correlation coefficient between the actual and predicted SGC was 0.829, and adjusted coefficient of determination was 0.687. This indicated that 69% of the variability in actual SGC could be explained by the three predictors of dosage/BW, 1/Scr, and Alb. As is expected, 1/Scr is considered to reflect renal clearance of BMD. On the other hand, it remains unknown as to what Alb specifically represents . Further studies are needed regarding the impact of Alb on SGC.View full abstractDownload PDF (1041K) -
Koichi NAKAMURA, Shigeyuki NAKANO1995 Volume 26 Issue 4 Pages 883-887
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.883JOURNAL FREE ACCESSThe percutaneous absorption rate of the topical formulation of a drug (PAR) hasbeen calculated and expressed in percentage using the amount of the drug applied (Da) and the amount of the drug collected (Dc) as in the following equation:
apparent PAR= (Da-Dc) /Da
where Dc is measured by swabbing the drug remaining on the skin after a certain periodof time has passed following application . One problem is that after swabbing, still a slighttrace of the drug remains on the skin, even when it is carefully swabbed, this trace mightcause an erroneous estimation of PAR, especially for drugs with a low PAR . To improvethe accuracy in the estimation of PAR, we introduced the idea of “collection rate at time0” into the above equation as follows:
collection rate at time 0=Dc at time 0/Da
“Collection rate at time 0” indicates the technical efficacy of swabbing the drug appliedto the skin. With the above equations, we calculated the corrected PAR for 5 g of 1 %omoconazole nitrate cream applied in a single dose to the skin of the subject's back over24 hours in 9 healthy male volunteers. Three of the 9 volunteers served as the subjects forthe calculation of “collection rate at time 0” . The mean corrected PAR (±SD) for 1%omoconazole nitrate cream was found to be 13.6 (±6.3) %.The difference between thecorrected and apparent PAR ranged from 2.5 to 3.0 %. If this expanded equation isemployed, it would make a large difference in the estimation of PAR of the topicalformulation of a drug with a low PAR or a drug poorly absorbed by a particularindividual. With the “collection rate at time 0” incorporated into the calculation of PAR, even a simple calculation method using swabbing will provide more precise and usefulinformation for pharmacokinetic studies of the topical formulation of a drug .View full abstractDownload PDF (628K) -
Koichi NAKAMURA, Shigeyuki NAKANO1995 Volume 26 Issue 4 Pages 889-896
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.889JOURNAL FREE ACCESSHOC-155 Cream is a topical antifungal formulation containing the imidazole derivative, omoconazole nitrate. The pharmacokinetics and safety of HOC-155 Cream wereexamined as a part of a phase I study in healthy male volunteers aged 24 to 28 years. Weapplied 5 g of 1 % HOC-155 Cream in a single dose on the skin of the subiects' back over24 hours. No effect attributable to HOC-155 Cream was observed in either the physicalexamination or -the laboratory tests during the period of the study. The average percutaneous absorption rate of HOC-155 Cream over 24 hours was found to be 13.6 % of thedose applied on the skin. Neither omoconazole nitrate nor its principal metabolite (M1) was detected using GC-MS assay in serum samples taken from all subjects studied for144 hours after the application of HOC-155 Cream. Less than 0.1 % of the omoconazolenitrate applied was excreted in the urine, mostly as a conjugated form of M1 withglucuronic acid. We concluded that the safety of HOC-155 Cream is confirmed under thepresent study conditions and that the degree of percutaneous absorption of HOC-155Cream is almost the same as that of other topical antifungal agents reported.View full abstractDownload PDF (1550K) -
Akikazu NOMURA, Kihito TAKAHASHI, Akira KITABATAKE1995 Volume 26 Issue 4 Pages 897-902
Published: December 31, 1995
Released on J-STAGE: June 28, 2010
DOIhttps://member-cnki-net-s-1416.res.gxlib.org.cn:443/rwt/1416/https/MSYXTLUQPJUB/10.3999/jscpt.26.897JOURNAL FREE ACCESSThree years have passed since the enforcement of GCP (good clinical practice). Weinvestigated the understanding and reaction of patients and doctors toward informedconsent for clinical trials. The questionnaires were given to outpatients in our clinic anddoctors in our clinic as well as in our related clinic. Regarding knowledge of clinicaltrials, 48% patients did not know that clinical trials are undertaken in order to developnew drugs. It took less than 10 minutes for 51% of the patients to agree to informedconsent and for 67% of the physicians to obtain a consent. Interestingly, 44% of thepatients consistently signed the written informed consent and 28% of the doctors alwaysobtained consent. In conclusion it is necessary to establish the patient-doctor relationshipthrough adequate information. Informed consent is an important integral part of clinicaltrials which are critical for the development of the field of medicine.View full abstractDownload PDF (610K)
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