Influence of the imbalance between calorie intake and calorie consumption in an excess intake condition during 7-day hospitalization was studied in healthy male volunteers. Each member of one group (constrained state ; n=6: group C) kept his calorie consumption, by exercise, to less than 200 kcal/day and each member of the other group (exercise; n=6: group E) kept it to more than 500 kcal/day. The results are summarized as follows:
(1) The mean body weight of group C increased from 57.5 kg on day 1 to 58.5 kg on day 8, while that of group E increased from 62.8 to 62 .9kg.
(2) The mean daily calorie intake was calculated to be about 2, 500 kcal in both groups. On the other hand, the mean to talcalorie consumption was 1, 654.1±19.6kcal/day in group Cand2, 362, 7±79, 1kcal/day in group E. The mean calorie consumption attributable to exercise was 110.3±18.3kcal/day and 706.1±80.6kcal/day, respectively.
(3) Five subjects in group C showed the elevation of s-GOT value on day 8, but all values remained within the normal limits. The mean value of s-GOT in all subjects of group C showed a statistically significant increase on days 7 and 8 as compared with the value of day 1. The value of s-GPT of group C also el evated with time in a similar way and the values were out of the normal range in 2 out of 6 subjects on day 8. The ratio of GOT/GPT in group C decreased significantly after day 6. The values of these parameters in group E showed no significant changes.
(4) The value of ChE elevated until day 5, and decreased from day 6 in group C.In group E the same parameter lowered throughout this trial.
(5) Some serum lipids showed an elevation in group C, and showed a decrease in group E.
These results indicate that healthy volunteers under a condition of excess calories may show abnormalities of liver function test due to lipid deposit in the liver. To prevent these occurrences, the control of calorie intake and moderate calorie consumption by exercise are recommended.

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To study the pharmacokinetics of flecainide acetate (FLC) and its suppressive effects on ventricular premature contractions (VPC), twenty-five patients with frequent VPCs were studied following single oral administration method. Either one of the dosages of 100 mg, 200 mg, or 300 mg of FLC was administered and blood samples were drawn before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48hr after the drug administration to measure the plasma drug concentration using high-performance liquid chromatography. Standard 12-lead ECG and 24-hr dynamic ECG were recorded to assess the effects on VPC and ECG parameters.
The maximum plasma concentration (C_max) and the area under the time-concentration curve (AUC) increased in a dose-dependent manner and there was a linear relationship between the dose and C_max or AUC (P<0.01).
The time of C_max (T_max: 3.0 to 4.0 hr) and the plasma half-life in the elimination phase (t_1/2: 12to15hr) were independent of the dose.
The suppressive effects on VPC were assessed in 20 patients who had more than 5, 000 VPCs/day before drug administration (baseline). The reduction of more than 75% of the baseline frequency of VPC was found in 13 of the patients studied (65%), and the effects on VPCs increased in a dose-dependent manner (100mg, 50%; 200mg, 63%; 300mg, 80%).
The minimum effective plasma concentration was 197.1ng/ml to 303.8 ng/ml. Blood pressure or ECG parameters showed no significant changes after the drug administration. No serious side effects were found in any patients. In conclusion, , FLC possesses a long plasma half-life and a linear pharmacokinetics. The suppressive effects on VPCs increased in a dose-dependent manner, and the minimum effective plasma concentration to suppress VPCs was considered to be 200-300ng/ml.

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A phase I study by single oral administration of beraprost sodium (TRK-100), a prostacyclin derivative, was performed in 32 healthy male volunteers. The safety, pharmaco-kinetics, and pharmacological effects were studied in two single oral administration clinical trials.
Study 1 was performed in 12 volunteers to investigate the safety and pharmacokinetics of TRK-100. The 12 men received 50, 100, and 200 μg of TRK-100 at intervals of two wk.
Study 2 was performed in 20 volunteers, randomly divided into three groups, to investigate the pharmacological effects and safety of TRK-100 at the dose of 25, 50, and 100μg. The results were as follows:
1) Subjective symptoms: Facial flushing, feeling of congestion, dull headache, headache, and sleepiness, etc., appeared in some subjects. These symptoms were observed more frequently in the groups receiving 100 and 200μg. Almost all symptoms disappeared within 2 or 3 hr after administration.
2) Physical and laboratory tests: Plasma calcification time and prothrombin time were prolonged slightly. But no abnormality was observed in other test items.
3) Pharmacokinetics: Following a single oral administration of 100 and 200μg, C_max was twice as high in the group receiving 200μg as in the group receiving 100μg. T_max was 1. 42 hr in the group receiving 100μg and 1.07 hr in the group receiving 200μg. T_1/2 was 1.11 hr and 0.89 hr, respectively.
4) Pharmacological effect: TRK-100 inhibited platelet aggregation induced by ADP, collagen, and epinephrine dose-dependently.
The above results indicated the safety and pharmacological effects of TRK-100 in single oral administration in healthy male volunteers.

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A phase I study by repeated oral administration of beraprost sodium (TRK-100), a pros-tacyclin derivative, was performed in 12 healthy male volunteers. The safety, pharmaco-kinetics, and pharmacological effects were studied in repeated oral administration for 10days.
The volunteers were randomly divided into two groups. Six men received 75μg/day t.j.d.for 10 days and the remaining six men were given 150μg/day t.i.d. for 10 days.
1) Subjective symptoms: Facial flushing, feeling of congestion, dull headache, and headache, etc., appeared in some subjects. These symptoms were observed more frequently in the group receiving 150μg/day.
2) Physical and laboratory tests: No abnormality was observed.
3) Pharmacokinetics: No accumulation of TRK-100 was observed in the group receiving 150μg/day.
4) Pharmacological effect: TRK-100 inhibited platelet aggregation induced by ADP, collagen, and epinephrine, and platelet adhesion.
The above results indicated the safety and the pharmacological effects of TRK-100 in repeated oral administration in healthy male volunteers.

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MS Contin tablet is a newly formulated controlled-release morphine sulfate tablet. It has the advantage of less frequence of dosing over conventional dosage forms because of the long-lasting effective plasma concentration.
In this study, pharmacokinetics of morphine and its metabolites (M-6-G, morphine-6-glucuronide ; M-3-G, morphine-3-glucuronide) were studied in patients with advanced cancer, following multiple administrations of MS Contin.
Morphine was well absorbed from MS Contin tablet, comparably with aqueous morphine hydrochloride. The plasma concentrations of M-6-G and M-3-G were 5- to 10-fold and 40- to 70-fold higher, respectively, than those of morphine, indicating that morphine is substantially metabolized at the first pass through the intestine and liver.
The elimination half-lives of morphine and its metabolites were constant during multiple dosing, but the ratios of C_max and AUC of morphine at steady state to those after the first dose were greater than the calculated accumulation factor. On the other hand, the ratios of C_max of M-6-G and M-3-G were comparable with the accumulation factor. The nonlinearity observed for morphine and the linearity found for the two metabolites during multiple doses may be explained by the very small reduction of first-pass metabolism which is thought to be caused by advances of cancer.

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Clinicopharmacological study of bevantolol, a newly developed β₁-selective β-blockingagent was carried out in Japanese healthy male volunteers. The pharmacokinetics, pharmacodynamics, and safety were investigated after single and once-daily repeated oraladministration of 100 mg and 200 mg of bevantolol. The following results were obtained.
(1) The time to the maximum plasma concentration (t_max) on an empty stomach was about 0.7 hr and the elimination half-life in α-phase (t1/2α) and in β-phase (t1/2β) were about 1. 4 hr and 9 to 10 hr, respectively. The area under the plasma concentration curve (AUC) and the maximum plasma concentration (C_max), which showed about a threefold interindividual variation, were about two times greater after the 200 mg dose than after the100 mg dose.
(2) On a full stomach, t_max was prolonged to 2 hr. No sign of accumulation was noted after seven days of once-daily repeated doses.
(3) The reduction in resting blood pressure after dosing of bevantolol was mild, while pulse rate decreased singnificantly. Fall in blood pressure after postural change from supine to standing position was not evident.
(4) Exercise-induced tachycardia and increase in rate-pressure product were significantly attenuated by bevantolol. A high correlation existed between the percent reduction [%R] _HR in exercise-induced tachycardia and the logarithm of the plasma concentration of bevantolol.
(5) Resting fingertip blood flow measured by venous occlusion plethysmography did not decrease after repeated doses of 100 mg of bevantolol.
(6) Regarding subjective symptoms, complaints of headache, dull headache, and gastrointestinal disturbance were noted in some subjects. No profound influence was recognized on the clinical laboratory data. After repeated doses of 100 mg of bevantolol, one subject developed transient loss of consciousness accompanied by a fall in blood pressure and pulse rate. Therefore, careful attention should be paid when the drug isused.

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The pharmacokinetics of diltiazem (DTZ) was investigated in 7 control patients with normal liver function and 7 patients with liver cirrhosis. After chronic oral adminis tration of DTZ, 30 or 60 mg t. i. d., serum levels of DTZ and its active metabolites, deacetyl DTZ (DAD) and N-demethyl DTZ (DMD), were determined by HPLC. Mean peak serum concentrations (nmol/l) in control patients were 280 for DTZ, 58 for DAD, and 101 for DMD. In cirrhotic patients, the serum DTZ tended to increase and the DAD increased (P<0. 05) while the DMD decreased (P<0.05) compared with that of the control (335 for DTZ, 133 for DAD, and 77 for DMD, nmol/l). Pharmacokinetic analysis using a one-compartment model revealed no change in the absorption but a decrease in the elimination for cirrhotic patients (t_1/2, 5. 3 to 7. 2 hr, P<0.1). The elimination rate constant correlated with some biochemical indices for hepatocyte func tion. These results may be explained by the impaired oxidative metabolism of DTZin liver cirrhosis.

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The population pharmacokinetic parameters of tobramycin were estimated by the computer program NONMEM in 14 newborn infants, 6 children, and 5 obese children with normal renal function. All of them were administered tobramycin with i. v. drip infusionfor 30min.
Two models were used to obtain the population pharmacokinetic parameters: in the first model, it is assumed that volume of distribution and clearance are directly proportional to the body weight (linear model), and the other is exponentially related to the body weight (power model). The values of the objective function obtained by the population pharmacokinetic analysis for all of the patients indicated that the power model appeared signif icantly superior to the linear model.
The results were used prospectively to forecast tobramycin concentrations in newborn infants by the Bayesian method. Firstly, the most suitable sampling time for predictive performance of the Bayesian method with single sampling point was determined by comparing various sampling times (4, 8, 12 hr). The predictions of serum concentrations using the single point of 12 hr after a single dose were best fitted to the observed data in 7 newborn infants. Secondly, the Bayesian method was applied to the dosage regimen during the multiple dosing in another 5 newborn infants using the population pharmacokinetic parameters estimated by the power model. The predicted serum concentrations of tobramycin were in good agreement with the observed data.

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In order to investigate the antianginal effects of celiprolol (NBP-582), a randomized double-blind crossover study controlled with placebo was carried out in 17 patients with stable effort angina pectoris. Multistage treadmill exercise testing was performed before and at 4, 7, and 24 hr after a single oral administration of 400mg celiprolol or placebo. The exercise testing was terminated at moderate angina pain.
The treadmill exercise duration showed no statistically significant time effects or order effects either before or after administration of the test drugs.
Celiprolol significantly prolonged exercise duration, time to angina, and time to onset of ST-segment depression≥0.1mV at 4, 7, and 24hr after administrationin comparison with placebo. However, there was no significant difference in time to angina disappear ance at 4, 7, and 24 hr after administration between celiprolol and placebo.
Celiprolol significantly reduced systolic blood pressure at rest in a standing position and peak exercise, and peak exercise at 4 and 7hr after administration respectively in comparison with placebo. At 24hr after administration, tendency of reduction of systolic blood pressure was observed at peak exercise.
There was no significant difference in diastolic blood pressure at 4, 7, and 24hr after administration between celiprolol and placebo. Celiprolol significantly reduced heart rate and pressure rate product (PRP) at peak exercise at 4, 7, and 24hr after administration in comparison with placebo.
No significant difference in ST deviation was observed at peak exercise at 4, 7, and 24hr after administration between celiprolol and placebo. A tendentious or significant prolongation of alleviated exercise-induced ST depression (ST _SXT) was observed at 4hr or at 7and 24hr after administration.
Celiprolol significantly reduced heart rate, PRP, and ST deviation during exercise over 24hr.
These results indicate that celiprolol significantly increases exercise tolerance in patients with stable effort angina pectoris over 24hr after a single oral administration of 400mg. It is concluded that celiprolol is a clinically useful antianginal agent.

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The purpose of this study is to examine the possibility of using the data file of computerized health insurance billing system maintained by our University Hospital for postmarketingsurveillance (PMS) for adverse drug reactions (ADRs).
We selected 12 widely used drugs now requiring special attention because of their potentially serious ADRs and certain diseases that might relate to the ADRs. The coverage period is January 1982-November 1988. The total number of the patients covered was 109, 088.
First, the ratios of patients with the diseases to patient groups of the following two kinds were determined: (A) all the patients who took the drugs; (B) all the patients who did not take the drugs. Then, fourfold tables were prepared. The association between the drug and the disease was decided to be significant when the odds ratio computed from the tables was larger than 1.0 and X² value was larger than 3.84.
Second, focusing on the cases having the said significant associations, we tried to set the control group (C) composed of patients having taken none of the drugs who matched with group (A) patients in terms of the following four factors: consultation clinic, sex, age, and in- or out- or in-/out-patient.
Finally, we could choose from group (A) those who 1 to 1 matched to group (C) [group (A) ']. In this, random sampling [1/2 from group (A)] was required for two of the drugs. As a result, group (A) ' and (C) were judged to be comparable as to the four factors.
Then, the ratios of patients with the diseases to group (A) ' and group (C) were determined for comparison with the said method, using Fisher's exact test instead of x2 test because the numbers less than 5 were included in the cells of the fourfold tables.
There were 44 drug-disease combination cases (8 drugs) which showed significant associations when groups (A) and (C) were compared; 3 cases (3 drugs) out of the 44 also showed significant associations when (A) ' and (C) were compared.
In conclusion, it was suggested that such a data file of our hospital might be applied to PMS for ADRs. Some issues, however, have remained unsolved. For example, it is not certain that all of the disease names recorded in the data file are scientific ones because they were given for the health insurance billing purpose. Therefore, it must be ascertained in the near future whether or not our proposal can be effectively applied.

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A multicenter, double-blind study was performed in 46 patients with stable effort angina pectoris on maintenance doses of long-acting nitrate in order to evaluate the effect of levocarnitine chloride (LC-80) tablets, containing 200 mg of levocarnitine chloride, on exercise tolerance. Multistage treadmill exercise testing was performed according to the modified Bruce protocol at the pre-treatment period and after 4 and 8 wk of oral daily doses of 1800 mg of LC-80 or placebo therapy.
In the pre-treatment period, there were no significant differences in treadmill exercise duration, time to the onset of angina, pressure-rate product (PRP), and ST deviation between the placebo and LC-80 groups.
The time to the onset of angina was significantly longer after 4 (P<0.05) and 8 wk (P<0.01) of LC-80 therapy than in the pre-treatment period and the increment in the time to the onset of angina was significantly greater (P<0.05) after 8 wk of LC-80 therapy as compared to placebo administration. In-exercise ST segment depression tended to be of lesser magnitude after 8 wk of LC-80 therapy than in the pretreatment period (P<0.1). Resting and in-exercise blood pressure, heart rate, and PRP were unaffected by LC-80.
In conclusion, the results of the present study suggest that LC-80 may improve exercise tolerance in patients with stable effort angina pectoris with no significant effects on the circulatory response to exercise, and the agent may be clinically employed as an adjunct to the conventional anti-anginal agent in the management of ischemic heart disease.

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This study was designed to elucidate the basic changes in electrocardiogram during phase I study. Lead II electrocardiograms were recorded from 10 healthy male volunteers (Group P) with placebo administration and blood sampling, and 16 healthy male volunteers (Group N) with no placebo and no blood sampling by the time schedules of phase I study of some cardiovascular drugs. The RR intervals were significantly prolonged (P<0.01) before lunch and then shortened (P<0.05) by taking lunch, in both groups. Prolongation of RR interval was more pronounced in Group N. Maximum prolongation was observed at 3 hr (9.6%) in Group P, and at 2. 67 hr (12. 5%) in Group N. The PR intervals and QRS width revealed no significant change during observation period. The QT interval was significantly prolonged (P<0.05) before lunch in Group N, but not in group P, and significantly shortened (P<0.05) after lunch in Group P but not in Group N, whereas the QTc was significantly shortened (P<0.05) in both groups before lunch. These results indicated that the RR interval was lengthened with bed rest but this effect was attenuated by drawing blood sample, and suggested that rate-dependent QT prolongation and dis cordant shortening of QTc before lunch resulted in overcorrection by Bazett's formula The T wave amplitude was significantly increased (P<0.01) by 4 hr-check up point and then suddenly reduced by taking lunch. This suggests that T wave amplitude might be controlled by blood glucose level.
It should be noted that the electrocardiographic effects of phase I study of cardiovascula: drugs might be affected by these changes.

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Longitudinal pharmacokinetic study of β-carotene as a photoprotective agent was performed in vitro and in vivo.
During long-term administration, changes in the serum β-carotene concentration were investigated in a man and his son who both had erythropoietic protoporphyria. Over a period of 4yr, 150mg of β-carotene were administered per day to the man and 50mg per day to his son.It took one yr for both patients to reach 1μg/ml of β-carotene concentration in serum. The serum concentration of β-carotene remained constant at 1-2 μg/ml in serum after continued administration for 3yr.
In a single-dose study, 50 mg of β-carotene were administered to 3 healthy male volunteers, but the β-carotene was undetectable in serum in all 3 cases.
β-carotene was stable in artificial gastric and enteric juices.
In enterohepatic circulation experiments with rats, the amount of β-carotene absorbed from gastrointestinal tract was low.
Fifteen nanograms of β-carotene were adsorbed to the erythrocyte membrane per 1 hematocrit.
Since β-carotene is hardly absorbed from the gastrointestinal tract, and is rapidly adsorbed on the erythrocyte membrane, we can conclude that it took a very long time to reach the steady state of β-carotene concentration in serum under the longitudinal administration.

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Forty-two patients (19 men, 23 women) with NIDDM recruited from the out-patient clinic were studied to evaluate the effect of dilazep dihydrochloride (dilazep) on abnormal urinary NAG excretion. All patients, who showed persistently high NAG excretion in urine, had no other complications including hypertension, proteinuria, and clinically significant retinopathy. Patients whose HbAic or fasting plasma glucose levels had been altered over 10% of pre-administration levels throughout the observation period were excluded. The mean age was 57±12 yr (range 29-75). Blood and urinary analyses were attained before, at one month, three months, and six months after the administration of dilazep (300mg/day). In three months, urinary NAG/Cr ratio as well as NAG concentra tion were significantly reduced (P<0.001). This effect has been observed throughout the observation period of six months. No adverse effects were observed in our patients. These results suggest that dilazep is a useful drug for the improvement of latent diabetic nephropathy indicated by the abnormal NAG excretion in urine.

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Controlled-release morphine sulfate tablet (MS-Contin: MS-C) has been reported to have the same analgesic effect on a twice-a-day regimen as aqueous morphine every 4hr.
In this study, the pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) in cancer patients at steady state following oral administrations of three MS-C 10mg tablets every 12hr were compared with those following oral administrations of aqueous morphine (10mg) every 4hr.
Elimination half-lives of morphine and M-6-G after administration of MS-C were found to be 2.58±0.85hr and 4.66±1.11hr, respectively, which were comparable to those after administration of aqueous morphine. On the other hand, absorption rate of morphine from MS-C was one-fourth of that obtained from the aqueous solution and the peak concentration from MS-C was less than three times that from the aqueous morphine and was observed about 3hr later compared with that from aqueous morphine solution. These results show that MS-C has sustained-release characteristics . The simulated curves of morphine and M-6-G plasma concentrations after MS-C administration were shown to be comparable to those after aqueous morphine administration. Moreover, in the two patients who received MS-C and aqueous morphine, the observed plasma concentration profiles were the same as the simulation.

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