The pharmacodynamic and pharmacological effects of MPC-1304, a new calcium channel blocking agent were studied in 6 healthy adult volunteers. Each subject received a single oral dose (1.25, 2.5, 5, 10, 20 mg) at two-week intervals.
Pharmacokinetics of MPC-1304 was assessed by measuring plasma and urine concentrations of MPC-1304 itself and its metabolites. The plasma concentration of MPC-1304-keto-H₂, the active metabolite, was approximately 10-20 times that of MPC-1304 itself. The maximum plasma concentration (C_max) of MPC-1304 and MPC-1304-keto-H₂ were dosedependent and their time to peak level (t_max) was 3.8-4. 8 hr and 4.8-6.0 hr and the elimination half-lives (t_1/2) were 1.0-1.1 hr, 2.7-3.4 hr, respectively.
MPC-1304 and five metabolites were found in urine after single administration. The percent excretion ratio of MPC-1304 and its metabolites in 24-hr urine was 6: 1-7.9%, independent of doses.
Following a single administration of 5-20 mg of MPC-1304, blood pressure was lowered during 2-24 hr and heart rate was transiently increased.
Subjective symptoms (e. g. headache and dull-headedness) were observed after 10 mg and 20 mg dosing. There were no remarkable abnormalities in laboratory findings during the study.
These results suggested the MPC-1304 would be a safe calcium channel blocker with hypotensive effect.

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The pharmacodynamic and pharmacological effects of MPC-1304 after multiple oral administration were studied in a cross-over double-blind fashion with sustained release formulation of nifedipine (10 mg Sepamit^® capsule) as reference drug, using 16 healthy adult male volunteers. They received 10 mg of MPC-1304 (once or twice a day) and 20 mg of nifedipine (twice a day) for 7 days.
Pharmacokinetics of MPC-1304 were assessed by measuring plasma and urine concentrations of MPC-1304 itself and its metabolites. After multiple administration of MPC-1304, plasma concentrations of MPC-1304 itself and MPC-1304-keto-H₂, the active metabolite, reached its plateau in 2 days and remained stable during the rest of the study.
The calculated pharmacokinetic parameters on the seventh day were almost the same as those on the first day and were not so different from those of the single-dose study.
The percent excretion ratio of MPC-1304 and its metabolites in 24-hr urine was not affected by multiple administration.
These results suggested that neither accumulation nor significant change of pharmacokinetics was observed in the plasma levels of metabolites even after multiple administration of MPC-1304.
Blood pressure did not change significantly both after MPC-1304 and nifedipine, though heart rate was transiently increased.
Following multiple administration of MPC-1304 and nifedipine, subjects complained of headache and dull-headedness but all of these were transient and tolerable. Notable abnormalities were not observed in laboratory findings during the study and so there was not significant difference for adverse effects between two drugs.
In conclusion, MPC-1304 can be expected to be a safe calcium channel blocker with hypotensive effect.

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To investigate the antianginal effects of carvedilol (DQ-2466), a randomized double-blind cross-over study controlled with placebo was carried out in 19 patients with stable effort angina pectoris. Multistage treadmill exercise testing was performed before and at 2, 7, and 24 hr after a single oral administration of 10mg of carvedilol or placebo. The exercise testing was terminated at moderate anginal pain.
The treadmill exercise duration showed no statistically significant time effects or order effects either before or after administration of the test drugs. In comparison with placebo, carvedilol significantly prolonged both the exercise duration and the time to onset of ST-segment depression ≥0.1mV at 2 hr after administration. It also significantly prolonged the latter parameter at 7 hr after administration. It significantly reduced systolic and diastolic blood pressure and the pressure rate product (PRP), both at rest in the standing position and at peak exercise at 7 hr after administration. Carvedilol significantly reduced heart rate during exercise at 24 hr after administration. There were no significant differences between carvedilol and placebo, in the ST deviation at peak exercise, PRP at onset of the ST-segment depression ≥0.1 mV, or the ST/HR slope at 2, 7, and 24 hr after administration.
These results indicate that carvedilol significantly increases exercise tolerance in patients with stable effort angina pectoris after a single oral administration of 10 mg. It is concluded that carvedilol is a clinically useful antianginal agent.

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1. The “Adverse Drug Reaction Monitoring System” has been developed by the Japanese Ministry of Health and Welfare. From 700 to 900 adverse reactions are reported annually. They are not, however, used clinically, since an appropriate computer system has not been established.
2. We have been entering 12, 241 adverse reactions reported in the past 8 years into a personal computer in order to create an adverse drug effects database.
3. The database has enabled fast, accurate retrieval and analysis.
4. There were 2, 863 adverse effects associated with antibiotics. Classification by the chemical structure is more appropriate than by the sensitivity to microorganisms, which was used by the Japanese Ministry of Health and Welfare.
5. In order to compile the database, it was necessary to standardize and classify the drug names and adverse reactions in an appropriate manner.
6. The present goal is to make this database widely available for clinical use.

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1. Using information from the Ministry of Health and Welfare's “Adverse Drug Reaction (ADR) Monitoring System, ” we previously compiled an 8-year database of 12, 241 adverse reactions that were reported between April 1980 and March 1988. We have analyzed these data.
2. The most frequently reported drugs were co-trimoxazole (206 adverse reactions), amoxicillin (185), cephalexin (182), mefenamic acid (170), and indomethacin (156).
3. The most frequently reported ADRs were dermatologic (4, 211), whole body (1, 517), digestive (1, 423), cardiovascular (1, 004), and hemic and lymphatic (993) disorders. The most -frequently reported drugs were classified as antibiotic (2, 863), central nervous system (including NSAIDs) (2, 793), dermatologic (1, 116), and cardiac (1, 033) drugs.
4. Deaths (246) were associated mainly with antibiotics (89), central nervous system drugs (66), and diagnostic drugs (17).
5. Associations between drugs and adverse effects were analyzed in the database. But the patient's age, sex, drug dose, concomitantdrugs, the duration of therapy, and the outcome of ADRs are not available in this “Adverse Drug Reaction Monitoring System.” These items must be available for each reaction to make this monitoring system more useful.

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Phase I study of propiverine hydrochloride (P-4), a new anticholinergic and antispasmodic drug, was performed in healthy adult male volunteers to investigate its safety and pharmacokinetics. P-4 was administered orally in single doses of 5, 10, 15, and 20 mg (six volunteers in each group). The doses were increased step by step after the safety of the compound was confirmed. No pronounced changes were noted in vital signs, ECGs, or laboratory tests. Subjective symptoms were observed at the 15 and 20 mg dose levels. But they were very mild and transient.
P-4 and its metabolites were detected in plasma and urine after oral administration. Peak plasma levels of P-4 were found about 1-2 hr.
Dose-dependency was observed in the plasma concentration (C_max, AUC).

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Phase I study of propiverine hydrochloride (P-4), a new antispasmodic and anticholinergic drug, was performed in healthy adult male volunteers to investigate its safety and pharmacokinetics. P-4 was administered orally in repeated doses of 20, 30, and 40 mg twice daily after meals for 5 or 7 days (five volunteers in each group). The study was a doubleblind trial and placebo was administered to two or three volunteers as control. The doses were increased step by step after the safety of the compound was confirmed.
No apparent changes were noted in vital signs, ECGs or laboratory tests. As to subjective symptoms, anticholinergic-like subjective symptoms were observed at the 40 mg/day dose levels. They were, however, very mild and transient.
P-4 and its metabolites were detected in plasma and urine after continuous administration.
The measured plasma levels reached steady states on the 4th day of administration.

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The time-dependence in diazepam kinetics after a single oral dose and after repeated oral doses was investigated in 5 healthy volunteers. Subjects took a single oral 5 mg dose of diazepam on two occasions, in the morning (09: 30) or in the evening (21: 30). Then they took repeated oral 5 mg doses once a day for 8 days every morning or every evening. After repeated oral doses as well as after a single oral dose, the mean peak total diazepam concentration in plasma (C_max) tended to be higher in the morning trial. However, no difference was found in the mean elimination half-life.(t_1/2), the area under the plasma concentration time-curve (AUC), the volume of distribution (Vd), or the total plasma clearance (CL) after repeated diazepam doses between morning and evening. The results found in the single dose study were essentially identical to the findings reported previously by our group.The time-dependence in diazepam kinetics was also found after repeated administrations. The mechanism of this time-dependency in the drug seems to be explained by the time-dependent variations in the rate of absorption from the gastro-intestinal tract and the rate of distribution of the drug. The plasma diazepam clearance significantly increased after repeated doses.

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We intended to determine the concentrations of antiepileptic agents in saliva, as a substitute of serum, by the fluorescence polarization immunoassy technique, using the TDx analyzer (Dainabot). It had been considered that it would be difficult to handle a very small amount of saliva samples (2-10 μl) with the TDx analyzer because of its high viscosity. However, the drug concentrations in saliva could be determined by the analyzer after the saliva sample was diluted with an equal volume of saline. Using the salivary concentrations determined by this technique, we could obtain the simple and practical equations, which correlate the total concentrations of drugs in serum (Ct) with those in saliva (Cs) without taking the salivary pH into consideration as follows: 1) phenytoin (PHT): Ct=9. 422 Cs, r=0. 965, n=5; 2) phenobarbital (PB): Ct=4.261 Cs, r = 0.883, n=27; 3) carbamazepine (CBZ): Ct=3. 200 Cs, r= 0.734, n=10.
As for sodium valproate (VPA), we could predict the maximal saturated concentration of the bound drug (Cb) with serum protein as 102 μg/ml from double-reciprocal plot between the bound and free (Cf) concentrations in serum as follows: 4) sodium valproate: Cb^-1=0.0575 Cf^-1 +0.00981, r= 0.850, n=38. And this maximal value of Cb would indirectly support the upper therapeutic range (about 100 μg/ml) of VPA in Japanese. However, the above equations must be reconstructed in each laboratory, because they were obtained from a small population.

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The relationship between the negative inotropic effect and the effect on maximal upstroke velocity of action potentials (V_max) induced by class 1 antiarrhythmic drugs [aprindine (A); cibenzoline (C); disopyramide (D); lidocaine (L); pirmenol (P); quinidine (Q)] was evaluated in the guinea-pig myocardium using electrophysiological techniques. Each drug reduced the force of contraction (Fc) and V_max of fast action potentials dose-dependently. Tetrodotoxin and verapamil also decreased Fc in a dose-dependent manner. Class 1 an-tiarrhythmic drugs also reduced V_max of the Ca-dependent slow response together with Fc. These drugs might be divided into three types according to the regression patterns of Fc. Type 1: The reduction of Fc was mainly due to Na channel blockade, resembling the pattern of tetrodotoxin (A). Drugs of this type show weaker negative inotropic than antiarrhythmic properties compared with drugs of types 2 and 3. Type 2: The reduction of Fc was predominantly due to Ca channel blockade, resembling the pattern of verapamil (Q). Type 3: Other type (C, D, L, P). This classification of class 1 antiarrhythmic drugs seems to be clinically useful in choice of drugs considering the patient's condition, such as cardiac function, and possible mechanism of arrhythmia.

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The platelet aggregation inhibitory activity of antithrombotic agents, dipyridamole, limaprost (α-cyclodextrin clathrate), cilostazol, and ticlopidine was tested on ten healthy human volunteers.
Dipyridamole (at the dose of 300 mg/day), limaplost (30 μg/day), cilostazol (200 mg/day), and ticlopidine (300 mg/day) were orally administrated for 7 days. The post-drug platelet aggregation was compared with pre-drug control to determine antiplatelet activity of each drug. The concentrations of β-thromboglobulin (β-TG) and platelet factor 4 (PF-4) were also determined to evaluate drug effect on the blood coagulation system.
Platelet aggregation was induced by ADP, collagen, epinephrine, and arachidonic acid. To obtain the optimal concentration and personal baseline, blood platelet aggregation response by the 4 inducers on each volunteer were predetermined. Plasma samples were prepared to uniformly contain platelets at a concentration of 3 × 10⁵/μl.In a comparison of the area under the aggregation response curve during an early phase of testing, dipiridamole and limaprost did not exhibit the antiplatelet effect against any of the 4 inducers. In contrast, cilostazol inhibited significantly the aggregation due to ADP (P<0.05), and arachidonic acid (P<0.01), and ticlopidine also inhibited the aggregation by ADP (P<0.01), collagen (P<0.01), and epinephrine (P<0.05). Similar results were obtained by a comparison of the maximum aggregation rates.
β-TG and PF-4 concentrations did not indicate any specific changes in their time profiles.

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A phase I study of E-1020, a newly synthesized selective phosphodiesterase inhibitor that possesses both positive inotropic and vasodilatory properties, was carried out in healthy Japanese male volunteers.
E-1020 was administered by intravenous infusion to evaluate its safety, and to establish its pharmacokinetic and pharmacodynamic profiles, at doses of 1. 25 μg/kg to 50 μg/kg with 5-min infusion (Step 1 to Step 7) and at doses of 61. 25 μg/kg to 163. 75 μg/kg with a combination of 15-min loading dose and following 165-min maintenance dose (Step 8 to Step 10).
E-1020 was generally well tolerated by all subjects at each dose level, except for episodes of mild hyperemia in the eyes, a warm feeling in the face and/or the earlobes, and palpitation. These symptoms disappeared within a few hours after dosing, and seemed to be attributable to the pharmacological effects of the drug. Significant increments of heart rate were observed at the dose of 50 μg/kg (Step 7) and 61. 25 μg/kg to 163. 75 μg/kg (Step 8 to Step 10). However, no clinically significant changes in blood pressure, electrocardiograms, or clinical laboratory test values were noted.
A significant increase in the mean values of the fractional shortening as assessed by echocardiography was observed after administration of the higher doses of E-1020.
The plasma pharmacokinetics of E-1020 could be best described by an open linear two-compartment kinetic model. The half life in the β-phase was about 1 hr in all steps. The urinary excretion was about 80% of the dose, and mostly unchanged form.
We conclude that the drug posesses a good tolerance and no clinically significant adverse effect as demonstrated in the present dose range of E-1020. Thus it is suitable for further clinical studies.

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A Phase I study of E-1020, a new positive inotropic agent, was performed on normal healthy volunteers to define its pharmacological characteristics, safety, and tolerance. The study evaluated both single (0.5, 1.0, 2.5, 5.0, 10.0, and 20.0 mg, n=4 for each) and repeated (5 and 10 mg t. i. d. for 7 days, n=6 for each) oral administration of E-1020. In all studies, subjects were evaluated by physical examination, blood pressure measurement, heart rate measurement, plasma concentration of E-1020, clinical laboratory tests, ECG and echocardiography during the administration of the drug and for varying periods thereafter.
1) Conjunctival hyperemia, flushing, and headache secondary to vasodilatory action, and palpitations due to positive inotropic and/or chronotropic action were observed in some cases. However, all symptoms were short-lived and of a mild nature, resulting in no clinically serious problems.
2) Both single and repeated dosing resulted in dose-related increases in plasma E-1020 C_max and AUC with a t_1/2 of 2 hr and urinary recovery of 40-50%.
3) The heart rate increased at higher doses, but blood pressure remained unchanged. An increase in fractional shortening, and cardiac output as assessed by M-mode echocar-diography indicated positive inotropic action.
We conclude that E-1020 is a potent positive inotrope with vasodilator properties and that it is well tolerated. There were no clinically significant adverse effects. The drug can be effective as an oral agent in patients with heart failure.

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Celiprolol is a selective β1-antagonist with intrinsic sympathomimetic activity. The effects of celiprolol on 24-hr ambulatory blood pressure during daily activity and its hemodynamic effects at rest were investigated in 11 patients with mild to moderate essential hypertension. Patients were treated with celiprolol 200 mg once a day for 4 to 6 wks, followed by an increased dose of 400 mg for 12 to 14 wks. The 24-hr ambulatory blood pressure was monitored using a portable automatic noninvasive device during the control and treatment periods. For the hemodynamic effect, cardiac output was measured by the dye dilution method during the two periods to calculate total peripheral resistance.(1) As a result, both blood pressure at visit to the hospital and 24-hr ambulatory blood pressure were reduced significantly during the treatment period. Regarding 24-hr ambulatory blood pressure, blood pressure significantly decreased when patients were awake but not when they were asleep.There was no apparent difference between the control and treatment periods in the variability of 24-hr ambulatory blood pressure as expressed by the standard deviation of average values. Heart rate decreased when patients were awake but increased during sleep.(2) Concerning hemodynamic effects, there was significant change in total peripheral resistance but none in cardiac output.
Celiprolol reduced blood pressure in the waking state rather than during sleep, and did not obviously affect the variability of 24-hr ambulatory blood pressure. Celiprolol showed hypotensive effects by reducing total peripheral resistance without decreasing cardiac output. Therefore, it can be concluded that celiprolol is a useful antihypertensive drug.

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For the treatment of hepatocellular carcinoma by intra-hepatic arterial injection, CDDP-Lipiodol emulsion (CPLEM) was prepared.
CPLEM was in a water-in-oil state, and showed moderate retaining and releasing of CDDP.
Clinically, 9 patients with advanced hepatocellular carcinoma underwent the transarterial chemo-embolization by CPLEM. Partial response was observed in 2 cases, and minor response 1 case. AFP decreased considerably, and side effects were slight.
Serum platinum concentrations after administration were low. Deconvolution of the present data was demonstrated, and leakage of CDDP from liver was supposed to be gradual.
In conclusion, CPLEM was considered to be useful for mild chemo-embolization in a treatment of hepatocellular carcinoma.

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Hemodynamic effects of lisinopril, a new angiotensin converting enzyme inhibitor, and betaxolol, a new β₁-selective β-blocking agent, were evaluated in 21 outpatients with essential hypertension (WHO I / II stage) introducing them orally for six wks. Lisinopril (mean dose, 13.5 ±2.2 (SEM) mg/day) and betaxolol (8.4 ± 1.9 mg/day) reduced blood pressure (lisinopril, 176/103 ± 7/2 to 154/88±6/3 mmHg, P<0. 01; betaxolol, 171/107 ± 5/2 to 152/92±5/2 5/2 mmHg, P< 0.005) with different effects on heart rate ; betaxolol reduced heart rate significantly (66 ± 2 to 61 ± 3 bpm, P< 0.01) but lisinopril did not (71 ± 3 to 71 ± 3 bpm). These two drugs did not induce any significant change in circulating blood volume (measured using ¹³¹I-labeled human serum albumin) (lisinopril, 2. 95 ± 0. 17 to 2. 93 ± 0.15 l/m² ; betaxolol, 2.80± 0.08 to 2.77± 0.09 l/m2) and cardiac output (measured using ^99mTc in vivo labeled red cells) (lisinopril, 3.19 ± 0.20 to 3. 19 ±0.19 l/min/m2 ; betaxolol, 3.23 ± 0.09 to 3.19 ±0.16 l/min/m2). Both of them induced a slight and insignificant increase in left ventricular ejection fraction (LVEF) and reduced total peripheral resistance index (lisinopril, 3, 302 ± 196 to 2, 828 ± 150 dyn·sec·cm^-5·m², P<0.01; betaxolol, 3, 179 ± 75 to 2, 856 ± 167 dyn·sec·cm^-5·m²), though the decrease in the betaxolol group was not significant.
These effects in the lisinopril-treated group may be attributable to angiotensin converting enzyme inhibiting activity mainly in vascular beds. As β₁-selective β-blocking agents without vasodilating properties, such as atenolol and metoprolol, were reported to reduce cardiac pump function without decrease in peripheral resistance, and celiprolol, one with vasodilating properties, was reported to reduce peripheral resistance in essential hypertension, these results obtained in the betaxolol-treated group warrant a further investigation on its vasodilating properties.

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