The subjective effects of HY-770, a centrally acting muscle relaxant, were studied in 12 healthy volunteers under the double blind procedure, as an aid to assess psychic dependence potential of the drug in humans.
The dosages of HY-770 used were 50mg and 200mg. As the control drugs, 10mg of diazepam and placebo preparations were used. These drugs were orally administered as a single dosage.
As the result, no subjective effects were observed with 50mg of HY-770. With 200mg of HY-770, a mild “wellbeing” in one subject out of 12 and a mild “drunkenness” in two subjects were observed. With 10mg of diazepam, a mild “wellbeing” in one subject and a mild to moderate “drunkenness” in three subjects were observed. In addition, a mild to moderate “euphoria” in two subjects and a moderate “preference” in two subjects were observed only with diazepam.
These results may indicate that the subjective effects which may be relevant to psychic dependence potential are weaker with HY-770 than diazepam.

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The urinary excretion of metabolites of bifemelane hydrochloride (BFM) was studied in both young and elderly volunteers. BFM (50mg) was administered orally after breakfast to young healthy subjects (n=8) and elderly subjects (n=15). Urine was collected separately 0-8 and 8-24hr after administration, and the concentrations of metabolites including a new identified metabolite, M-2 sulfate, were determined. The excretion rate of M-2 sulfate within 24hr after administration, which was 27.55±3.25% of the dose in young and 20.88±1.56% of the dose in elderly subjects, was larger then that of any other metabolites. The excretion rate of total metabolites in the young for 8hr post-administration was 54.11±2.94% of the dose, which was significantly higher (P<0.01) than that in the elderly, 27.53±2.39%. On the other hand, the 8-24hr excretion rate of total metabolites in the elderly, 26.16±2.63% of the dose, was higher than in the young, 17.93±2.25% of the dose. The urinary excretion ratio of BFM metabolites in the elderly was less than that in the young, but the difference was not significant. The delay of urinary excretion of BFM metabolites in the elderly is considered to be mainly due to both the lower hepatic metabolic rate of BFM and renal excretion rate of its metabolites.

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Recent study of cyclosporine (CYA) therapeutic monitoring has reported an evaluation of area-under-the-curve (AUC) instead of trough level monitoring. In this paper, the prediction of AUC by a small number of blood samples from renal transplant recipients was investigated.
CYA (dose: 1.6-15.0mg/kg/day) was administered orally to the patients (18-52 years old) after renal transplantation every 12hr (8:00AM, 8:00PM). Blood specimens were collected at trough level, 1, 2, 3, 6, 8 and 12hr to determine the whole blood concentration of CYA. The prediction of AUC was calculated according to the multiple linear-regression analysis.
The coefficient of determination (r²) between CYA trough levels and AUC measured from a complete set of seven concentrations was 0.7108. In contrast, the predicted AUC calculated from three points (1hr, 3hr and 6hr) was well correlated with the measured AUC (r²=0.9880). The prediction error (%) between measured AUC and predicted AUC calculated from three time points (1hr, 3hr and 6hr) ranged within ±15%.
These results suggest that the prediction method by the three time points was very useful for monitoring of CYA therapy on the clinical practice.

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The genetically controlled isoniazid N-acetylation capacity was determined in 340 unrelated Japanese subjects residing in Japan. After an oral dose of 300 or 400mg of isoniazid, the “molar acetylation ratio” (INH/AcINH) in 8hr urine was measured by high-performance liquid chromatography. Bhattacharya's analysis was performed with the data obtained from INH/AcINH. The frequency distribution of the molar acetylation ratio showed an apparent trimodal pattern. Trimodal distributions were estimated to be 40 (rapid actylator: RA): 50 (intermediate: IM): 10 (slow acetylator: SA). These results suggested antimode of -0.85 and -0.325 (log INH/AcINH) discriminating trimodal distributions (RA>-0.85, -0.85<IM<-0.325, -0.325<SA). These 340 unrelated Japanese subjects were classified as RA (136 subjects), IM (170 subjects), or SA (34 subjects). This result was similar to previous studies. Although the present work was focused on isoniazid phenotyping, Bhattacharya's method may be applicable to other genetic polymorphic drugs such as dapsone, mephenytoin, and metoprolol.

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The pharmacokinetics of beta-methyldigoxin (β-MD) was investigated after a single oral administration (0.2mg) in 24 subjects with varying degrees of renal function. The subjects were assigned to four groups on the basis of predetermined 1-hour creatinine clearance (CL_CR; ml/min/1.48m²) [group I (hemodialysis), CL_CR<10; group II, 10≤CL_CR<50; group III, 50≤CL_CR<75; group IV, 75≤CL_CR]. Serum glycoside concentrations were measured by fluorescence polarization immunoassay. The mean peak concentration and the time to reach peak concentration were not different among the groups. The dependency of β-MD kinetics on renal function was demonstrated in the present study. Significant relationships were observed between CL_CR and pharmacokinetic parameters [total body clearance (r=0.446, P<0.05), AUC (r=-0.639, P<0.001), volume of distribution at steady state (r=0.738, P<0.001)]. The dosage of β-MD should be reduced by the same manner as digoxin dosage regimen in renal impairment.

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Bevantolol hydrochloride is a new β₁-selective β-adrenoceptor antagonist without intrinsic sympathomimetic activity. It has been also reported that bevantolol has α₁-blocking activity and calcium antagonistic action. The effects of bevantolol on hemodynamics in the resting state and during exercise loading were investigated in 7 patients with mild or moderate essential hypertension.
The treatment of bevantolol was started from 100mg twice a day. If an adequate antihypertensive effect was not obtained after 4 or more weeks of treatment, the dose of bevantolol was increased to 200mg twice a day. Before and after treatment for 16-26wk by bevantolol, the hemodynamics were measured in resting state and during exercise loading using a bicycle ergometer with the constant load of 1.25W/kg for 6min. Blood pressure, heart rate and cardiac output were measured and total peripheral resistance was calculated. In addition, plasma renin activity and concentration of aldosterone, norepinephrine and epinephrine in plasma were measured. One patient was excepted from the analysis because of lacking the measurement after the treatment. In the results, (1) bevantolol reduced blood pressure and heart rate in resting state. Cardiac output was invariable, and total peripheral resistance decreased after the treatment. (2) Bevantolol reduced the increase of blood pressure, heart rate and cardiac output during exercise loading. No significant change was found in the total peripheral resistance during exercise loading. (3) Plasma renin activity decreased after the treatment period. No changes were found in the plasma concentration of aldosterone, norepinephrine and epinephrine.
Based on the above, bevantolol is considered to reduce blood pressure without being accompanied by increase of total peripheral resistance. It is supposed that the result is caused by not only β₁-selective β-blocking action of bevantolol, but also the participation of its α₁-blocking action and calcium antagonistic action.
From these results, it is concluded that bevantolol, in spite of β-blockers, is useful in treating patients in hypertension without increase of total peripheral resistance in resting state and during exercise loading.

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