The association between acetylation genetic polymorphism and drug-induced lupus erythematosus with use of isoniazid as the pharmacogenetic probe was studied. Acetylator phenotype of isoniazid (INH) was studied in 129 unrelated pulmonary tuberculosis patients. Urine samples were collected over 8hr. INH and acetylisoniazid (AcINH) in urine were assayed by HPLC. From a frequency histogram and probit plot, the results of the log₁₀ of the metabolic ratios (molar acetylation ratio) indicated the existence of two modes. The frequency of slow acetylators was 10%. And the antinuclear antibody was determined by indirect immunofluorescence. Thirty-five of 129 patients (27%) had development of antinuclear antibodies (homogenous). Two cases out of the 35 (8.6%) were slow acetylators. The relationship between phenotype distribution and possible pathoetiologic factor is discussed.

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Pharmacokinetic and pharmacological effects and safety profile of eptazocine were investigated after an intravenous administration of eptazocine at doses of 60mg and 90mg under nitrous oxide, oxygen and enflurane anesthesia.
The pharmacokinetic data were well fitted to a three-compartment model. Its area under the curve (AUC) showed dose dependency (60mg:119.1μg·min/ml; 90mg:143.6μg·min/ml), although half-life (60mg:108.9min; 90mg:110.3min) and volume of distribution (60mg:76.6l; 90mg:70.1l) remained unchanged.
Blood pressure was slightly elevated after the administration of eptazocine. However, there were no clinically significant changes in pulse rate.
In recovery phase from the anesthesia, respiratory depression was not found. But at dose of 90mg, the time from the end of the anesthesia to the extubation was prolonged, being compared with at dose of 60mg, and the psychological status at the termination of anesthesia was drowsy at the doses of 60mg and 90mg.
From the above results, eptazocine at doses of 60mg and 90mg was confirmed to be safe under nitrous oxide, oxygen and enflurane anesthesia.
Furthermore, it was suggested that the property of eptazocine on the anesthetic effects of enflurane was additive.

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The comparison of pharmacokinetics of bifemelane hydrochloride (BFM) was studied in the young and the elderly. BFM (50mg) was administered orally after breakfast to young healthy subjects (male, N=8, mean age 21.1 years old, mean body weight 62.0kg) and to elderly patients (male N=8, female N=9, mean age 78.9 years old, mean body weight 44.4kg). Blood and urine samples were collected at 2, 4, 6, 8, 10, 12, 24hr and 0-8, 8-24hr, respectively to determine the plasma concentrations of BFM, M-2 (main metabolite of BFM) and the urinary concentrations of BFM, M-2, M-2 glucuronide. Plasma albumin (Alb) and α₁-acid glycoprotein (AAG) concentrations and creatinine clearance (CL_CR) were also determined in both groups. CL_CR in the elderly (52.9ml/min) was significantly low compared to the young (102.5ml/min). The lower concentration of Alb and higher concentration of AAG in the elderly were also observed. Plasma concentrations of BFM in the elderly were significantly higher (P<0.05-0.001) from 2 to 12hr after dosing. At 2 and 4hr, the t_max of BFM and the plasma concentrations of BFM (11.25, 9.18ng/ml) in the elderly were 3-4 fold higher than those (2.67, 3.11ng/ml) in the young. Plasma M-2 concentrations in the elderly were also higher than those in the young. BFM was not detected in urine in both groups; however, urinary excretion of M-2 and its glucuronide were shown to be delayed in the elderly. C_max of BFM in the elderly (13.41ng/ml) was about 4 times higher than that (3.21ng/ml) in the young. AUC of BFM in the elderly (74.26ng hr/ml) was significantly larger than that (20.24ng hr/ml) in the young. Prolonged t_1/2 of BFM in the elderly was shown. These results suggested that higher plasma concentrations of BFM or M-2 in the elderly might be mainly due to decreased hepatic metabolism (decreased first pass effect) of BFM.

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The electrophysiologic and hemodynamic effects and the pharmacokinetics of a single oral administration of pirmenol were evaluated in 20 patients with supraventricular tachycardia (SVT). Pirmenol, at 1hr after administration, significantly shortened sinus cycle length and sinoatrial conduction time. HV interval (46±10msec to 54±11msec, P<0.01), refractory period of the right atrium and the right ventricle were significantly prolonged. Furthermore, anterograde refractory period of accessory pathway and retrograde refractory period of AV node and accessory pathway were prolonged. Hemodynamic study revealed increased systemic and pulmonary vascular resistance and decreased stroke volume index. Induction of SVT was suppressed in 11 out of 16 patients. Among 5 patients who were not suppressed at 1hr, 2 patients resulted in noninducible at 2hr after administration. Plasma concentration of pirmenol at 1hr after administration was 1.0±0.4μg/ml in effective cases and was 0.4±0.5μg/ml in failed cases (P<0.05). Pharmacokinetics of single oral pirmenol were, t_max of 2.9hr, C_max of 1.4μg/ml, t_1/2 of 6.8hr and AUC of 18.7μg·hr/ml. In conclusion, a single oral administration of pirmenol was highly effective in suppression of induction of SVT with sufficient hemodynamic tolerance.

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The present study was undertaken to investigate the influence of food and gastric acidity on the pharmacokinetics of MPC-1304, a new calcium channel blocker, in two comparison studies.
Study I: A single oral dose of MPC-1304 (5mg) was given to six healthy male subjects with a crossover design during fasting and 30 minutes after meals. Study II: A single oral dose of MPC-1304 (5mg) was given to five subjects with normal gastric acidity and five subjects with low gastric acidity.
The area under plasma concentration curve (AUC_0-24hr), the maximum plasma concentration (C_max), the time to reach the maximum plasma concentration (t_max), the half-life (t_1/2) and the cumulative urinary excretion amount were compared by the analysis of variance. In addition, parameters by the moment analysis were calculated.
In study I, there were no significant differences between the values during fasting and those after meals. In study II, there were also no significant differences between the two groups though the interindividual variations were larger in the subjects with low gastric acidity than in the subjects with normal gastric acidity.
We conclude that the influence of food and gastric acidity on the pharmacokinetics of MPC-1304 was considered to be little.

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In this study, flecainide acetate (FLC) was orally administered by single dosage to twenty-five patients ventricular premature contractions and the FLC doses were 100 (n=5), 200 (n=13) and 300mg (n=7), respectively. The pharmacokinetics of FLC was analyzed by one compartment open model with lag time. The area under the plasma concentration-time curve (AUC) and the systemic clearance (Cl_sys) were calculated by means of the trapezoidal method. Good linear relationships between the maximum plasma concentration (C_max; mg/l) and dose (mg/kg), and between the AUC (mg·hr/l) and dose (mg) were seen (P<0.01). Moreover, the change in dose had no influence on the elimination half-life (t_1/2), the apparent volume of distribution, the Cl_sys, the lag time and the time of the C_max (12.8hr, 382l, 21.5l/hr, 0.69hr and 3.29hr, respectively). However, the t_1/2 values of three patients were longer than 25hr and the serum creatinine values in the patients were higher than 1.4mg/dl (normal range 0.7-1.4mg/dl). The kinetics of renal excretion of FLC was studied in the patients whose urine is able to be collected (n=8). The percentage of FLC excreted during 0-24hr or 0-48hr showed no significant difference between 200 and 300mg doses and the mean values were 19.8% for 0-24hr and 28.4% for 0-48hr. The renal and non-renal clearances were 6.28 and 13.93l/hr, respectively. However, the biggest renal clearance value was approximately 5.5 times bigger than the smallest ones. The FLC plasma concentrations at steady state after multiple dosing (200mg/12hr) were simulated using pharmacokinetic parameters obtained from the patients with the biggest, the mean and the smallest t_1/2 (1.729, 0.649 and 0.406mg/l, respectively). These results suggest that therapeutic drug monitoring of FLC is necessary since the average plasma concentration at steady state may be exceed toxic level in patients with hepatic or renal dysfunction.

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OPC-13340 is a dihydropyridine derivative calcium antagonist and was demonstrated to have a potent and long-lasting vasodilating effect.
The cardiohemodynamic effects of the drug before and during exercise were studied in ten patients with effort angina using a bicycle ergometer.
The patients received the drug at 4mg once daily after breakfast for one week. Cardiohemodynamic measurements were performed during exercise before and after administration of the drug.
OPC-13340 produced a significant improvement in ST depression and an improvement in subjective symptoms during exercise, significant decreases in systolic blood pressure, diastolic blood pressure and total peripheral resistance before and during exercise, no notable changes in heart rate before and during exercise, a significant increase in cardiac index during exercise with an insignificant change before exercise, a significant decrease in systolic, diastolic and mean pulmonary arterial pressures during exercise with insignificant changes before exercise, a significant increase in left ventricular ejection fraction (EF) before and during exercise and a significant suppression of decreased EF due to exercise load.
These results indicated that OPC-13340 has major hemodynamic effects featured by a decrease in afterload due to dilation of peripheral arteries and an anti-anginal effect due to coronary vasodilation. In addition, manifestation of an improvement in the EF during exercise suggests that the drug exerts an anti-anginal effect without decreasing cardiac function.
Thus, OPC-13340 produced electrocardiographic and hemodynamic improvements during exercise in effort angina patients and was therefore believed to be a useful drug in the treatment of ischemic heart diseases.

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