Phase I clinical study was performed in 6 healthy male subjects. Three of the subjects received a 0.3 mg suppository and the other 3 received a 0.6 mg suppository by rectal route, and the safety and blood levels of buprenorphine were determined. The results obtained were as follows.
After the administration of a 0.3 mg or 0.6 mg suppository, there were no clinically significant changes in blood pressure, pulse rate, respiratory rate, and body temperature ; no abnormalities were observed on ECG.
C_max and AUC were 0.24ng/ml and 2 .60ng·hr/ml at a dose of 0.3mg and 0.47ng/ml and 5. 14 ng·hr/ml at a dose of 0. 6 mg, both of which increased in proportion with the increase in the dose. T_max was 2. 17 hr at a dose of 0.3 mg and 1.67 hr at a dose of 0.6 mg.
Subjective or objective findings included sedation, headache, dull headedness, dry mouth, dizziness, vomiting, sweating, and local uneasiness ; all of these were mild.
No abnormal values were seen in hematology, biochemistry, and urinalysis.
From these results, buprenorphine suppositories at doses of 0.3 mg and 0.6 mg were confirmed to be safe in healthy subjects and its clinical usefulness was considered to be promising.

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Long-acting nicardipine hydrochloride was given at 100 to 150 mg/day for more than 6 months to 30 patients with angina pectoris, to evaluate the clinical response and safety of the drug during long term therapy. The results were as follows.
1) Twenty-seven of the 30 patients received the drug for more than 6 months, while the treatment was discontinued in the remaining 3 before 6 months (24 weeks) had elapsed. The reasons for withdrawal were a request by one patient to change the therapy, change of address for one, and a surgical operation for the other. No patient was withdrawn from the study because of adverse reactions.
2) Overall improvement was calculated by moderate improvement or better. It was 66. 7% in patients receiving long-acting nicardipine hydrochloride alone, and 84.2% in those receiving long-acting nicardipine hydrochloride together with other drugs. Response was good, whether the drug was used alone or together with other treatments.
3) Adverse reactions developed in 3 of the 30 patients (10. 0%). Headache was reported from one, dizziness and dysarthria from one, and degree I A-V block from one. In the patient with A-V block, the treatment was considered to be slightly unsafe. No severe adverse reactions were detected during the long-term use of the drug. Clinical laboratory tests revealed no abnormalities related to the long-term use of the drug.
4) The drug was judged to be useful or better in 62. 5% of the patients receiving the drug alone, and 89. 5% in those receiving the drug together with other treatments.
In conclusion, long-acting nicardipine hydrochloride produced good response and high safety during long term therapy. It was shown to be a very valuable anti-anginal drug in practice.

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The influence of captopril on the diuretic effect of furosemide was investigated in fluid-intake controlled 8 healthy subjects.
Furosemide (20mg) was injected intravenously and urine samples for sodium and furosemide were collected over a 60-min period. Plasma samples for plasma renin activity (PRA) and angiotensin II (AII) were obtained just before and 60min after furosemide administration. Blood pressure (BP) was also determined just before and 60 min after the drug. A second-study was carried out one week after the first-study. On this occasion, the subjects were pretreated with captopril (50mg) and the protocol of the first-study was repeated.
No significant difference was observed in urine volume, urinary sodium or furosemide excretion between the two studies. Although PRA increased after furosemide with captopril, AII did not elevate. BP did not change significantly after furosemide with or without captopril.
These results indicate that the diuretic effects of furosemide might not be influenced by captopril.

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We investigated the tolerance and pharmacokinetics of omeprazole, a new anti-ulcer drug, in single- and multiple-dose studies in healthy male volunteers. The results are summarized as follows. No abnormal findings in subjective and objective symptoms, blood pressure, heart rate, body temperature, respiratory rate, ECG, or body weight were seen in either study. In the laboratory investigations, some clinical values were outside the normal range. However, these changes were slight and not clinically relevant.
Mean plasma concentrations of the drug after single doses of 10, 20, and/or 40 mg peaked at 1. 3-2. 3 hours and thereafter declined with half-lives of 1. 6-2. 8 hours. In all the dose groups, less than 1% of the given dose was excreted as unchanged in the urine, and 12-14% of the dose was excreted as the hydroxylated metabolite in the 24-hour urine.
Similar plasma concentration profiles were obtained after dosing before breakfast and under fasting conditions in the single-dose study, and no food effects on the absorption of the drug were seen.
In the multiple-dose study in volunteers given 20mg once a day for 7 days before or after breakfast, the time required to reach the peak concentration (T_max) did not differ significantly between days 1 and 7, and the area under the plasma concentration curve (AUC) was greater on day 7 than on day 1. This indicates that the amount of the absorption increased after multiple dosing.

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The effect of terfenadine on actual car driving performance was investigated in ten healthy male subjects by a double-blind, cross-over comparison with d-chlorpheniramine and placebo, using the onset and degree of sleepiness during driving.
Six out of ten subjects receiving d-chlorpheniramine could not complete 150 minutes of continuous driving, and the percentage of alpha waves in the electroencephalogram was higher than in those receiving terfenadine or placebo. These findings indicate that in subjects receiving d-chlorpheniramine a risk of falling asleep while driving.
In the case of terfenadine, on the other hand, the extent of sleepiness during driving was no different from placebo, and it was concluded that terfenadine has no detectable depressant effect on the central nervous system during car driving.

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Nitrendipine (NTD), a newly developed calcium antagonist was administered to 12 Japanese healthy volunteers to evaluate its safety, pharmacokinetics and pharmacological properties.
Five, 10, and 20 mg of NTD and 10 mg of nifedipine (NFD) were orally administered to 6 subjects in single-dose study. NTD (10 mg) was administered to 6 subjects once a day for 7 days in multiple-dose study. Subjects complained of headache and dull headedness after administration of NTD and NFD in single-oral-dose study but there were no reported side effects in multiple-dose study.
Plasma concentration elevated more gradually after a single dose of NTD . Time to maximum plasma concentration and the elimination half-life were longer in NTD than in NFD. The time to maximum plasma concentration and the elimination half-life after multiple dosing were almost the same as those after first dosing . Unchanged NTD was not detected in any urine sample.
Blood pressure decreased and pulse rate increased after single administration of NTD and NFD. Blood pressure decreased more gradually after NTD than after NFD.
Plasma concentration of norepinephrine increased significantly after NFD but not after NTD. In multiple dosing, the exercise-induced elevation of plasma concentration of nore-pinephrine was inhibited significantly by NTD after the first dosing but not after the last dosing.
Plasma renin activity elevated after single administration of NTD and NFD. Plasma concentration of aldosterone did not change after single administration of NTD. In multiple dosing, plasma renin activity did not change significantly and plasma concentration of aldosterone decreased significantly.
These results suggested that NTD would be a safe and useful antihypertensive agent with long duration of action.

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Hemodynamic effects of intravenous cibenzoline administration were studied in 16 patients with various arrhythmias using Swan-Ganz catheter method.
1) Cibenzoline injection produced slight decrease in heart rate and cardiac index, and slight increase in pulmonary capillary wedge pressure and systemic vascular resistance. In patients with acute myocardial infarction, the decrease in cardiac index and the increase in diastolic blood pressure and systemic vascular resistance were statistically significant.
2) Nine out of the 15 patients responded successfully to cibenzoline injection. However, aggravation of arrhythmia was observed in 3 patients.
3) Hypotension with vomiting occurred in 1 patient.
In conclusion, intravenous cibenzoline exerts slight, but significant negative inotropic effects. It must be used with caution in patients with depressed left ventricular function.

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Randomized comparative study was conducted with periarthritis scapulohumeralis to determine the efficacy, safety, and usefulness of SPH using 2.5ml of 1% SPH solution (S) or of 0.01% SPH solution (P) for intra-articular, intra-subacromial bursa or intrabiceps tendon sheath injection five times continuously in weekly intervals.
1) Total number of patients examined was 152 (S: 76, P: 76). Among those patients, 139 (S: 67, P: 72) were adopted for the analysis of final global improvement and usefulness, and 150 (5: 74, P: 76) for analysis of general safety.
2) With respect to final global improvement, the effective rate (more than “moderately improved”) of S group was 70.2% (47/67), and 36.1% (26/72) for P group.S group was significantly superior to P group.
3) With respect to overall safety, incidence of side effects was 2.7% (2/74) for S group, 2.6% (2/76) for P group, and no significant difference was observed between S and P groups.
4) With respect to usefulness, the rate of usefulness (more than “moderately useful”) of S group was 68.7% (46/67), and 38.9% (28/72) for P group.S group was significantly superior to P group.
5) As for the change of global improvement and of patient's impression, S group was significantly superior to P group.As for improvement on symptoms, S group was significantly superior to P group in “rest pain, ” “pain under movement, ” “motion of washing face, ” “motion of arranging hair, ” “tying a string behind one's back, ” “put the hand on the opposite side of shoulder” and S group tended to be superior in “oppressive pain.” On the other hand, as for the range of motion, both S and P groups were equally improved, and no significant difference was observed between the two groups, but S group was superior in the rate of improvement. High effectiveness of SPH was proved in patients whose duration of symptoms is within one year and global severity is slight to moderate.
With pespect to injection site, S group was superior to P group, both in subacromial bursa and biceps tendon sheath, and S group tended to be superior in glenohumeral joint.
6) As an adverse side effect, slight to moderate local pain after injection of drugs was noted in 4 patients (S: 2, P: 2).
No abnormality caused by the drugs was found in laboratory test values.
In conclusion, SPH is considered to be useful in the treatment of periarthritis scapu-lohumeralis.

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In this study, the dosage regimen for rantidine in patients with renal dysfunction, which was previouly proposed, has been evaluated in patients with renal impairment.
1. Twenty patients with renal impairment with the creatinine clearance (Clcr) of less than 70 ml/min were chosen. The oral dose of ranitidine 50 mg b. i. d. was repeatedly given to five non-dialyzed patients with severe renal impairment with the Clcr of less than 30 ml/min for 14 days, and also ranitidine, 100 mg b. i. d., to five non-dialyzed patients with moderate renal impairment with the Clcr of 30 to 70 ml/min for the same period. The oral dose of ranitidine of 50 mg b. i. d. was repeatedly given for 4 to 5 weeks to ten hemodialyzed patients with renal failure.
2. In the non-dialyzed patients, actual measurement values of plasma ranitidine concentrations after 7 and 14 days of medication were almost in keeping with simulation curve of plasma concentrations at the repeatedly administered period, which were calculated from the results obtained when initially administered. In addition, it was assumed that the maximum steady state plasma concentrations (Css, max) were 409.3±122. 5 ng/ml (patients with severe renal impairment), and 558.0±62.4ng/ml (patients with moderate renal impairment), and the minimum concentrations in steady state (Css, max) were 101.9±26.0ng/ml (patients with severe renal impairment) and 103.3±254ng/ml (patients with moderate renal impairment).
3. Ranitidine was effectively removed from blood by hemodialysis, and Css, max and Css, min in the hemodialyzed patients were considered approximately 320ng/ml and 180ng/ml, respectively.
As stated above, an excess rise of plasma ranitidine concentrations in both non-dialyzed and dialyzed patients was not observed and the sufficient concentrations for proper clinical effects were obtained. Thus, the appropriate ranitidine regimen was proposed for each: 50 mg b. i. d. for the patients with Clcr less than 30 ml/min and 100 mg b. i. d. for the patients with Clcr of 30 to 70 ml/min.

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A compartment model with zero-order release in the gastrointestinal tract, first-order absorption to plasma and first-order elimination from plasma was examined in a series of studies on the clinical pharmacokinetics of BKU, a sustained release preparation of urapidil. The plasma levels of urapidil were measured for 24 hours after a single oral dosing of BKU to six healthy male volunteers, followed by the repeated dosing at each 12 hours for 6 days. On day 7, the plasma levels were again measured for 24 hours after a single dosing. For the expression by the formulation of this model, the reduced model wherein the absorption rate constant is equivalent to the elimination rate constant was taken into consideration to the ordinary model. The reduced model was applied to the cases in whom fitting of the ordinary model failed to apply due to no distinction in two rate constants. Time lag from dosing to initiation of zero-order release was also considered. A simplex method was used for model fitting and parameter estimation to the data of a single administration. Without consideration of time lag, the reduced model was fitted in three cases out of 6, while the ordinary model was fitted in the other 3 cases. With considera tion of time lag, the reduced model was fitted in only one case. Akaike's Information Criterion revealed that the incorporation of the time lag improved the fittings. Plasma levels of repeated dosing were simulated using the parameters estimated from the data of a single dosing and were revealed to be close to the observed levels except for one case. However, the meanings or interpretations of the estimated parameters were not necessarily valid in the model with or without time lag.

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The kinetics and metabolic disposition of valproic acid following a single oral administration of two preparations of sodium valproate (sustained-release tablets, KW-6066 N ;and standard tablets, Depakene) were investigated by a Latin square cross-over method insix subjects. Determination of valproic acid and its metabolites in the serum and urinewas performed by GC/MS method.
The mean elimination constants (k_e), apparent volumes of distribution (V_d), areas underthe serum concentration-time curve (AUC) of the parent drug, and the sum of valproicacid and its metabolites excreted in urine showed no significant differences in the twopreparations. Therefore the extent of bioavailability of Depakene and KW-6066 N seemedto be equivalent.
The pharmacokinetic parameters were estimated according to one-compartment openmodel by simultaneous least squares curve fitting method. KW-6066 N exhibited a moreprolonged absorption of valproic acid, showed a more delayed peak time (t_max), and yieldeda longer mean residence time (MRT). Maximum serum concentration (C_max) obtained afteradministration of KW-6066 N was lower than those following the standard tablets of Depakene. These results indicate that KW-6066 N provides slow release of valproic acid.
Using the pharmacokinetic parameters of valproic acid obtained in the study, serumconcentrations of valproic acid after repeated oral administration of Depakene or KW-6066N were simulated. KW-6066 N was expected to be effective even when administeredonce a day.

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To examine antianginal effects of nisoldipine, a new calcium channel blocker, 10 patientswith effort angina pectoris were studied. Hemodynamic data were obtained by anginalimited supine multistage bicycle ergometer exercise testing before and after single oraladministration of 10mg of nisoldipine.
After nisoldipine, chest pain at peak exercise disappeared or abated, and ST segmentat peak exercise also showed less significant depression. At rest and peak exercise, meanblood pressure, pulmonary artery wedge pressure and systemic vascular resistance decreasedsignificantly, whereas, heart rate increased significantly after nisoldipine. At rest, cardiacindex increased significantly after nisoldipine. At peak exercise, coronary sinus flowtended to increase after nisoldipine. Stroke volume index and myocardial oxygen consumption did not change significantly. Average time to peak plasma nisoldipine concentration was 1.6 hours and average peak plasma concentration was 13.8ng/ml with anelimination half-life of 1.6 hours.
Thus, nisoldipine is an active antianginal drug; its major mechanism of action is to lowersystemic vascular resistance and to improve coronary blood flow during exercise.

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Although there are some reports which state that phenacetin is unlikely to be theprimary causative agent in analgesic nephropathy (Prescott, 1982), 80% of the 285phenacetin abusers observed in our clinic between 1962 and 1979 were suffering fromchronic interstitial nephritis (Nitzsche et al., 1980). In order to ascertain whether phenacetin itself or one of its metabolites is responsible for this nephritis we have comparedthe pharmacokinetics and metabolic profile of phenacetin in 2 groups of phenacetinabusers with and without nephritis.
Phenacetin (900 mg), contained in gelatin capsules, was administered orally after anovernight fast. Blood and urine samples were collected. Plasma and urine concentrations of unchanged phenacetin and its major metabolites were determined by HPLCwith spectrophotometric detection (254 nm).
Urinary elimination of phenacetin and metabolites was quantified as the total amount (percentage of dose) in 24 h.
The results suggest that the cause of nephritis in susceptible phenacetin abusers isnot associated with altered elimination of either phenacetin itself or the metabolitesmeasured in this study.

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Diuretic effects of furosemide (FM) alone or combined with dopamine (DA) were inves-tigated in subjects with normal renal function and in patients with renal impairment. The renal excretion rate constant and the urinary recovery of FM were significantly decreased in the patients. However, there was no correlation between pharmacokinetic parameters and diuretic responses to FM in the patients. In contrast, linear regression line for urine flow rate vs.(Na⁺+K⁺) excretion rate (UV_Na+K), and that for Cl^- excretion rate vs. UV_Na+K showed high correlations, regardless of DA infusion, although diuretic responses and creatinine clearance in the patients were increased with DA. To clarify the variations of the sensitivity to FM, a urinary excretion-response curve, which was expressed by UV_Na+K vs. urinary excretion rate of FM, was analyzed. Increased apparent sensitivity to FM diuresis was observed in patients with renal failure, although the max imal and total diuretic responses were decreased. Therefore, highdose FM may not always be effective for patients with severe renal impairment. The sustained administration of FM or the co-administration of low-dose DA, by which the hemodynamics in the kidney are improved, may be a more effective treatment.

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A patient with phenobarbital overdose was treated with gastric administration of multiple doses of activated charcoal suspensions with alkaline diuresis. The decline of serum phenobarbital concentrations was sharper during the therapy than a control period. Elimination half-lives of phenobarbital of 15. 5 and 39. 1 h were obtained for the period of charcoal treatment with and without alkaline diuresis, respectively. As a normal elimination half-life of the patient was 82. 2 h, combined use of oral activated charcoal with alkaline diuresis proved to be an effective, safe, and inexpensive therapeutic measure in a case of phenobarbital overdose.

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