The free fraction of drugs was measured with microultrafiltration devices: UltrafreeC3LGC (UFC; Nihon Millipore Ltd., Tokyo, Japan), Centricut W-10 (CCW; Kurabo Industries Ltd., Osaka, Japan), and MPS-1 (Amicon Corp., Danvers, MA). The drugs tested were phenytoin, carbamazepine, and valproic acid. A 200μl sample volume was used. For two of three drugs, the free fraction by CCW was significantly low, and those by UFC did not show constant values. The free fraction by MPS-1 using a small sample volume (200μl) tended to show high values. The variable values of free fraction of drugs obtained with several devices may be caused by protein leakage, adsorption to the device, etc. The accurate free fraction corrected for protein leakage and adsorption to the device was in good agreement in all devices. The results suggest that physicochemical properties of each drug should be noted when a new device is used to examine protein binding of drugs for routine therapeutic free drug monitoring, especially with a small sample volume. In addition, if needed, it is suggested that the free fraction obtained should be corrected for protein leakage and the adsorption to the device.

View full abstract

Effects of dosing time of trazodone hydrochloride, (KB-831), a new antidepressant drug, on the pharmacokinetics were investigated by a cross-over method using 6 healthy male volunteers administered 50mg of the drug orally after breakfast or after supper. There were some effects of dosing time on the pharmacokinetics of trazodone hydrochloride, showing significantly higher C_max and significantly larger AUC_0-24hr in the group administered in the morning than in the evening. Mild drowsiness, dizziness, and dry mouth observed after the administration of trazodone hydrochloride were relatively stronger in the group administered in the morning than in the evening. From these results, it could be presumed that a single oral administration of the drug before sleep might be better for the reduction of the side effects of the drug.

View full abstract

Hemodynamic effects of flosequinan (BTS 49 465), a new vasodilator, were studied in 29 patients with severe heart failure. During right heart catheterization by Swan-Ganz catheter, a single 100mg dose of flosequinan was orally administered, and pertinent hemodynamic parameters were obtained serially for 24hr after administration. Flosequinan produced significant increases in cardiac index and stroke index (16% and 12%, respectively, P<0.01 and P<0.05), and significant (P<0.001) decreases in pulmonary capillary wedge pressure (-7.7mmHg, 41%), mean pulmonary artery pressure (-7.2mmHg, 23%), and right atrial pressure (-3.2mmHg, 43%). Systemic vascular resistance was significantly (P<0.05) decreased by 13%. The hemodynamic changes were observed 30min after adminis tration and peaked at 2hr, persisting for 24hr. Blood pressure and heart rate showed minimal changes during the study period, although the changes were significant at 2hr after administration.
These results indicate that flosequinan exerts sustained beneficial hemodynamic effects on heart failure with once-a-day oral administration.

View full abstract

Efficacy of the hemodialysis and the hemoperfusion was studied for 2 patients (patient A and B) with acute intoxication by antiepileptics as phenobarbital and phenytoin. The serum concentrations of phenobarbital and phenytoin were determined and the values of elimination rate constants in each treatment state were estimated using the compartment model. In patient A, the values of elimination rate constant of phenobarbital during the conservative treatment, the hemodialysis and hemoperfusion were 0.021, 0.073 and 0.205hr^-1, respectively. The values of elimination rate constant of phenytoin during the conservative treatmant, the hemodialysis and hemoperfusion were 0.012, 0.024 and 0.123hr^-1, respectively. In patient B, the values of elimination rate constant during the conservative treatment and the hemodialysis were 0.0038 and 0.192hr^-1, respectively. The serum concentrations profiles of drugs could be predicted and simulated by using the computed each elimination rate constant.
The removed drugs amounts by the hemodialysis were related to the rate of protein binding of each drug, but those by the hemoperfusion were not related.
The hemodialysis and the hemoperfusion appears to be the rational and highly effective treatments of acute intoxication by antiepileptics.

View full abstract

Safety, tolerance and pharmacokinetics of pirmenol hydrochloride (pirmenol), a new antiarrhythmic agent, were investigated in 21 healthy male volunteers following single oral dose of 25, 50, 100, 200mg or placebo and in 5 subjects following multiple oral doses of 100mg b. i. d. for 7 days. At the same time, effect of food intake on the kinetics of pirmenol was determined in 5 subjects following a single 100mg dose at fasting and 30min after breakfast.
No remarkable change was observed in the blood pressure, body temperature and clinical laboratory data. As subjective symptoms, headache, heaviness in the head, chest discomfort etc. were observed after the drug and placebo administration, but were slight, transient and dose-independent.
Increase of the pulse rate and prolongation of QTc were noted following single and multiple doses. PR intervals and QRS duration were prolonged at the highest 200mg dose. Decrease in the ejection fraction and fractional shortening without obvious change in cardiac index was observed at a single 200mg dose.
The peak plasma concentration (C_max) and the area under the time-concentration curve (AUC) increased in a dose-dependent manner. C_max after 25, 50, 100 and 200mg dose occurred within 1.2 to 1.5hr and were 0.21, 0.35, 0.86 and 1.77μg/ml, respectively, and plasma half-life of the β-phase (t_1/2β) was the range of 7.4 to 13.8hr under fasting state. Twenty-four hr cumulative urinary excretion of unchanged pirmenol was 15-23%.
Administration of pirmenol with food slightly delayed the rate and decreased the extent of the absorption, but there was no significant difference between the fasted and fed states.
After the start of multiple dosing, steady-state plasma pirmenol concentrations were attained by Day 3 and C_max was 60% higher at the steady-state than on Day 1.
We concluded that these findings showed that oral pirmenol is well tolerated within the dose-range used in this study and can be expected to have clinical efficacy in patients with various cardiac arrhythmias.

View full abstract

The pharmacokinetics of pirmenol hydrochloride (pirmenol), a new antiarrhythmic agent, and its suppressive effects on ventricular premature contractions (VPC) were studied in 16 patients following single oral administration of 75mg, 100mg, and 150mg of the drug. In 8 of 16 patients, suppressive effects on VPC were also studied following multiple oral administration of pirmenol of 75mg b. i. d. or 100mg b. i. d. Blood samples were drawn before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48hr after single oral administration. In the multiple oral administration study, blood samples were collected before and 2hr after morning dose during the treatment period. Plasma and urine drug concentration were measured using high performance liquid chromatography (HPLC). Plasma protein binding of pirmenol was determined by an ultrafiltration method. A 48-hr continuous ECG and standard 12-lead ECGs were recorded to assess the effects of pirmenol on VPC and ECG parameters.
The C_max and AUC after single administration were 0.799μg/ml & 9.23μg·hr/ml in 75mg group (n=6), 0.784μg/ml & 11.23μg·hr/ml in 100mg group (n=6) and 1.156μg/ml & 15.70μg·hr/ml in 150mg group (n=4), respectively. The C_max and AUC increased in a dose-dependent manner. The T_max, t_1/2 β, urinary excretion rate and protein binding rate were independent of the dosage. The C_max and C_min at the steady state during multiple administration were 1.149 & 0.235μg/ml in 75mg b. i. d. group (n=2) and 1.472 & 0.598μg/ml in 100mg b. i, d, group (n=6). Suppressive effects of pirmenol on VPC were observed in 5 out of 12 patients with more than 3, 000VPC/day in the single administration study and also in 3 out of 4 patients in the multiple administration study. The minimum effective plasma concentration of pirmenol was 0.361±0.133μg/ml. The PQ & QT interval and QTc were prolonged significantly after single and multiple administration. Serious adverse events were not observed in any patients during the study.
We conclude that pirmenol is a useful antiarrhythmic agent for the treatment on VPC, and that 100mg b. i, d, is safe and suitable for chronic management of the patients with frequent VPC.

View full abstract

The Effects of the new non-sedating H₁-receptor antagonist, WAL 801 CL (Epinastine hydrochloride), was investigated in 12 healthy male volunteers by a randomized double-blind, cross-over design in comparison with d-chlorpheniramine and placebo on driving performance using on-the-road study of the most suitable method. The extent of sleepiness on driving was evaluated from continuously recorded electroencephalogram (EEG), eye movement and steering performance and the Stanford Sleepiness Scale (SSS).
As the results, the achieved duration of continuous driving, the alpha activity ratio in EEG, the frequency of slow blinking and the SSS were not significantly different between the WAL 801 CL group and the placebo group. In the d-chlorpheniramine group, on the other hand, 6 out of 12 subjects could not complete 120min continuous driving, and the other parameters all showed significantly higher values than those of the WAL 801 CL group and the placebo group, indicating the central nervous system depressant action of d-chlorpheniramine during driving.
This study suggests that WAL 801 CL is a new non-sedating H₁-receptor antagonist without any influence on the overall driving ability.

View full abstract

Phase I study of levofloxacin, an optically active isomer of ofloxacin, was conducted in 21 normal healthy male volunteers.
In the single-dose studies, levofloxacin was orally administered at doses of 50, 100, and 200mg after breakfast. The serum concentration of levofloxacin peaked at 0.92 to 2.41hr and reached 0.57, 1.22, and 2.04μg/ml, respectively, in a dose-dependent manner. The t_1/2 of serum levels were about 4 to 6hr. Approximately 85 to 92% of the dose was excreted unchanged into urine within 48hr and 3.9% into feces within 72hr. The absorption of levofloxacin tended to be more rapid under fasting condition than after meal, whereas the urinary recovery was not altered. The pharmacokinetic profiles of levofloxacin and ofloxacin, determined at a single dose of 200mg, were quite comparable, except for the significant difference in V_d and mean residence time. In the multiple-dose study, levofloxacin was not accumulated on the basis of serum concentrations and urinary recoveries. The salivary to serum concentration ratio of levofloxacin was about 0.7 until 10hr after administration. There was no obvious observation of chiral conversion of (S)-(-)-isomer, levofloxacin, to (R)-(+)-isomer in the body. Levofloxacin was well tolerated.

View full abstract

A fuzzy tolerable difference may be introduced in the statistical analysis for equivalence of response rate of test drug (T) with respect to that of standard drug (S) by formulating a membership function. When the membership function is expressed as a step function which indicates the degree of reluctance of accepting a seemingly less effective but much less toxic or more useful T, the procedure is not so complicated. This paper describes the application of this fuzzy equivalence with step function to the results of a double-masked randomized controlled trial in which the efficacy of intravenous drip of dopamine (S) and that of oral administration of docarpamine (T, TA-870) were compared in patients with circulatory failure.

View full abstract