Alpha-1-acid glycoprotein (AAG) concentration and protein binding of disopyramide (DSP) in serum were measured in patients with heart disease. An increase in AAG (121±45mg/dl, mean±SD) was fbund in padents with heart failure as compared with healthy controls (73±14) and with cardiac patients without heart failure (78±12). The free fraction of DSP (0.35±0.12) was decreased in patients with heart failure as compared with control (0.56±0.11) and with patients without heart failure (0.47±0.15). The values of the heart failure patients returned to the level of cardiac patients with out heart failure (89±23 mg/dl and 0.48±0.07) with recovery from the decompensated stage. These findings suggest that the free concentration of DSP should be monitored frequently in cardiac patients, especially in patients with congestive heart failure.

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The pharmacokinetics of valproate (VPA) following single and multiple administration of a sustained-release preparation (KW-6066 N) were investigated in healthy human volunteers.
VPA was absorbed slowly, showing maximum plasma concentration (C_max) at 8.4 to 9.8h after administration. The C_max were 21.0 and 62.2μg/ml following administration of 400 and 1200 mg, respectively. After the peak time the plasma concentration declined monophasically. The elimination half-lives were 15.8 to 16.3h.
Linearity was observed in the pharmacokinetics of VPA in the range of 400 to 1200 mg of administered KW-6066 N.
While it has been reported that the change in protein binding at higher concentrations causes non-linear pharmacokinetics, no difference was found in the protein binding of the C_max samples (13.6-79.6μg/ml).
We then investigated the change in the plasma concentration-time profile during and after multiple administration (600mg×2/day for 15 times and 1200 mg×1/day 8 times).
The values simulated from the preceding single administration coincided well with the observed plasma concentrations during and after the multiple administration. It is therefore thought that no significant change in pharmacokinetics is likely to occur during and after multiple administration of KW-6066 N in humans.
The sustained-release preparation (KW-6066 N) will enable safer and more effective therapy for VPA because the differences between the peak and trough at steady state were much smaller than those with a typical VPA tablet.

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It has been reported that the free radical is the major couse of reperfusion arrhythmias and that captopril, an angiotensin-converting enzyme inhibitor (ACE-I) with an SH radical, is useful in preventing reperfusion arrhythmias. However, recently it has been suggested that not only ACE-I with an SH radical, but also ACE-I without an SH radical has a preventative effect on reperfusion arrhythmias, and that these effects might be due to a decrease of the after load or the suppression of sympathetic tones. On the other hand, the role of hypertensive cardiac hypertrophy on reperfusion arrhythmia is not clear yet. In the present study, we attempted to determine the effect of enalapril, an ACE-I without an SH radical, on reperfusion arrhythmias in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) considering changes in blood pressure (BP), and also the effect of nitroglycerin (NTG) on the decreasing effect of pre- and after loads on reperfusion arrhythmias.
Method: The coronary arteries of the rats under anesthesia by ether respiration were ligated by the Selye method. The rats were monitored by limb leads ECGs. Five minutes later, coronary arteries were united and reperfused. The reperfusion arrhythmias were compared between the SHRs and WKYs. Then the effects of two doses (0. 4 mg and 4. 0 mg) of enalapril, and a dose of NTG (0. 5 mg) were investigated in the SHRs. The changes of the active potential and activation time with enalapril were compared with nitroglycerin insections of the SHRs left ventricular papillar muscle in Tyrode solution saturated by oxygen.
Results: The duration per rat of the total continuous ventricular tachycardia (VT) was: 1) 23. 3, 2) 179. 1, 3) 46. 3, 4) 57. 3 and 5) 38. 8 seconds in 1) WKY without any drugs, 2) SHR without any drugs, 3) SHR with NTG, 4) SHR with enalapril of 4. 4 mg and 5) SHR with enalapril of 4. 0 mg, respectively. The duration per rat of the total continuous ventricular fibrillation (VF) was 1) 0.5, 2) 61. 3, 3) 48, 4) 1. 3, 5) 5. 6 seconds, respectively. The effect of these drugs on BP were 40 mmHg in SHR with enalapril of 0.4 mg; 29 mmHg (poor responder) in SHR with enalapril of 4.0 mg; 75 mmHg (good responder) in SHR with enalapril of 4.0 mg; 15 mmHg in WKY; 19 mmHg in SHR with NTG.
Enalapril at 4.0 mg had the effect of both decreasing BP and suppressing VT and VF after reperfusion. However, enalapril at 0. 4 mg showed only a slight suppression of BP, VT and VF. This is more remarkable in the SHR than in the WKY. The active potential duration of 70% with enalapril extended from 42 to 48 seconds, respectively, but there was no extension with nitroglycerin.
Conclusion: 1) Frequency and duration of VT and VF in the SHR were more frequent longer than those in the WKY. 2) Enalapril of a larger dose (4.0 mg) produced a decrease in BP and a suppression of VT and VF, especially, in the SHR. 3) Smaller dosesenalapril (0.4 mg) had little effect on BP and arrhythmias. 4) NTG produced a decrease BP and a suppression of VT. 5) NTG did not extend APD 70, but enalapril did. 6) From these observation, it is suggested that the after load is one of the mechanisms of reperfusion VT and the chemical change is one of the mechanisms of reperfusion VF.

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We administered single oral doses of 100, 200, 300 and 400 mg of EN-313 and repeated oral doses of 300 mg t.i.d., for 1 and 7 days to healthy adult men to confirm the safety and pharmacokinetics of this agent and to elucidate the effect of meals on the pharmacokinetics at a dose of 300 mg. At single doses of 100 and 200 mg, there were subjective symptoms of dizziness and nausea, but these were slight, and were regarded to have no relation to the test agent. No objective symptom was observed. And there was no abnormal finding in blood pressure, pulse rate, body temperature, or the results of laboratory tests. There was no significant change in the ECG parameters or in the hemodynamic parameters obtained by echocardiogram. After oral administration, EN-313 was rapidly absorbed, and reached C_max in 0.77-1.17 hrs. EN-313 disappeared in two phases, and its T_1/2 was 2. 21 to 3.08hrs. EN-313 showed a linear increase in C_max and AUC concomitant with the dose increase. The T_max of EN-313 was prolonged from 0.97 to 1. 45 hrs when administered after breakfast. The rates of excretion of the compounds in the urine were less than 1% (EN-313, 0.04%; INX-5575, 0. 51%; INS-9673, 0. 206%), even at the dose of 400mg.
In the repeat-dose study, subjective/objective symptom, blood pressure, body temperature and laboratory test data indicate no abnormal change considered to be caused by EN-313.
However, in the seven-day test, a significant increase in pulse rate was observed from day 4 of administration. ECGs revealed shortened RR on QT intervals and a prolonged PQ interval, but no significant change was observed QRS width or in QTc. No significant change was observed in hemodynamic parameters.
In the one-day test, the T_max of EN-313 after the first administration was 1.5 hrs and the C_max was 0.728 μg/ml. After the second administration, T_max doubled and C_max was 0.482 μg/ml. C_max after the third administration was lower than after the second. Twelve hrs after the third administration, the concentration of EN-313 was only approximately 0.05 μg/ml, with no drug accumulation.
And in the seven-day test, the C_max of EN-313 was 0.465μg/ml on day 1, and was at a similar level on day 4, but on day 7 it was decreased to 0.288μg/ml. The AUC of EN-313 was 1.48μg/ml on day l and 1.519μg/ml on day 4, then on day 7 it fell to 0.893μg/ml, but the difference between the day 1 and 7 values was not statistically significant. T_max for EN-313 were 3. 17, 1. 83 and 3. 67 hrs on days 1, 4 and 7, respectively. No accumulation of EN-313 was seen throughout the 7- day oral administration. The total excreted amount of EN-313, INX-5575 and INX-9673 was less than 1%.
The above results demonstrate the safety of EN-313 for clinical use; no problems have arisen during a 7-day period of multiple-dose administration.

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We performed a pharmacoepidemiological study of the response to norfloxacin (duration of treatment and total dose prescribed) in order to determine whether norfloxacin in combination with metal cation containing preparations has an effect on the outcome of treatment. The treatment duration and total dose prescribed were significantly greater (p<0.005; Mann-Whitney test) in the patients given norfloxacin in combination with metal cation containing agents than in these of monotherapy.

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An investigation of the current situation and practice in undergraduate and postgraduate education for clinical pharmacology was performed by mailing questionnaires to 85 departments of basic pharmacology, schools of medicine, universities or medical colleges with no department of clinical pharmacology. Questionnaires were returned by 54 of 85 departments (63. 5%). Major findings were:
1. Undergraduate education for clinical pharmacology was established in 48 of 54 universities or colleges (89%), and the main person responsible was a teacher of basic pharmacology in 45 of 48 universities or colleges (94%).
2. Postgraduate education was established in only 17 of 54 universities or colleges (32%), and the main person responsible was a teacher in a clinical department in 12 of 17 universities or colleges (70%).
3. The course curriculum for clinical pharmacology was lecture and practical exercise for undergraduate students in 46 of 54 universities or colleges, while lecture, practical exercise and seminar was the curriculum for postgraduate education in 9 of 54 universities or colleges.
4. Difficult issues for clinical pharmacology education (total plural number of answers was 61) were lack of specialists (21), incompletely established curriculum (16), and lack of specific department (11), etc.
5. Needs for the future of clinical pharmacology (number of answers: 56) were the cooperation of clinical departments and the tie-up of basic and clinical departments (16), the institution of a department of clinical pharmacology (15), development of specialists (9), and fuller curriculum (7), etc.
Results showed that the undergraduate education for clinical pharmacology was not completely but appropriately established, while for postgraduate it was insufficiently established.

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