1. A GC/MS method for quantitative determination of afloqualone in plasma was developed using deuterated afloqualone as internal standard. The method permits deermination of the drug in plasma above 5ng/ml.
2. A tablet containing 20mg of afloqualone was given orally to healthy men to study the time course of plasma drug concentrations. The mean plasma afloqualone concentration reached a peak of 37.9ng/ml at 1.29hr and thereafter declined with ahalf-life of 3.34 hr.
3. When a 20mg tablet was administered t. i. d. to healthy men daily for one week, there were neither abnormal laboratory test values attributable to the drug nor accom panying symptoms except for one subject who expressed a feeling of weakness.
4. The same dosage (20mg t. i. d.) was orally administered to healthy men for 2 successive weeks. The drug concentration in plasma was measured 1 and 24hr after single administration on the 1st, 8th, and 15th days. The drug levels on the 8th and 15th days were not significantly different from those on the 1st, proving that the drug was not accumulated. Neither untoward side-effects nor abnormal laboratory testitems were observed in these subject

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The effect of sodium nitroprusside on adrenaline-induced pulmonary edema was studied.
Pulmonary edema was induced in rabbits by intravenous infusion of adrenaline. The marked hemodynamic changes observed were: rise in systemic arterial pressure, reduction of left ventricular output, reduction of renal blood flow, elevation of left atrial pressure, and increase of pulmonary blood volume. When sodium nitroprusside was injected about 1 min after the start of the adrenaline infusion, the hemodynamic changes were suppressed or reversed, and pulmonary edema was prevented very effectively. However, maintenance of the renal blood flow was inadequate.

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Aprindine hydrochloride was administered orally to 10 patients with ventricular premature contractions in dosages of 10mg and/or 20mg at intervals of 8 hours. Plasma concentration was analyzed to clarify the process of reaching the steady state and the subsequent elimination state. The plasma concentration reached steady statewithin one to two weeks. There were very little diurnal and day-to-day variations in the plasma concentration, so a stable therapeutic level was maintained. Increased dosages from 30 to 60 mg per day resulted in threefold plasma concentration increase from 0.28 to 0.89μg/ml in steady state. The decline of aprindine hydrochloride after the last dose deviated from first-order kinetics, showing a convex decreasing curve on semilogarithmic graph paper.
These results demonstrate nonlinear pharmacokinetics for aprindine hydroch loride.

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The Pharmacokinetics of nipradilol (K-351: 3, 4-dihydro-8-(2-hydroxy-3-iso propylamino) propoxy-3-nitroxy-2H-1-benzopyran; NIP), a new potent antihyperten sive and antianginal agent, were investigated in healthy volunteers after single or repeated oral administration.
After administration at single doses of 1mg to 24mg, NIP was rapidly absorbed, reaching a maximum plasma concentration (C_max) at 2hr, and then eliminated with a plasma half-life (T_1/2) of 3.7 hr, irrespective of the dose. C_max and area under the plasma levels-time curve (AUC) of NIP, as well as the amounts of NIP and its metabolites excreted in the urine increased in proportion to the dose administered. The apparent volume of distribution, systemic availability, renal clearance, and plasma clearance were 5.621/kg, 35%, 0.181/min, and 1.041/min, respectively, independent of the dose.
Upon multiple oral administration of 6 mg two times daily for one or seven days, the experimental plasma concentrations of NIP and denitrated NIP coincided well with the simulation curves. Furthermore, T_1/2 values calculated from the plasma and urinary excretion rate did not differ significantly during repeated dosing, indicating no accumulation in the body.
The amount of parent drug excreted into the urine was 6.3%. The major urinary metabolites arose from three metabolic pathways, namely, denitration, hydroxylation of the ring system and glucuronidation of NIP. Degradation of the isopropylaminopropanol side chain was a minor route.

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A transdermal. therapeutic system (TTS) containing nitroglycerin (NTG) was applied to 12 healthy male volunteers for 24 hours and 48 hours.
Plasma NTG concentration was measured by capillary gas chromatography with electron capture detection using butane-1, 2, 4-triol-trinitrate as the internal standard.
The mean plasma concentration over the intervals of 1-24 hours and 1-48 hours after application maintained a steady level throughout the application. The mean plasma level in the steady-state phase for the 48-hour application was similar to that for 24 hours.
The notable subjective symptoms of TTS-NTG were generally reported as headache and/or heaviness of the head, but in the 48-hour application study, the incidence and intensity of these symptoms were reduced on the second day.
The local irritation was well acceptable. Several subjects showed mild rubef action at the margin of the covered area of skin, but there was no difference between the 24-hour and 48-hour applications in the local irritation index.
The residual amount of used system was analyzed by HPLC. The release rate of the system was 15.8±1.19μg/cm²·h (mean±S. E.) for the 24-hour, and 14.9±0.79μg/cm²·h (mean±S.E.) for the 48-hour application.

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The bioavailabilities of 6 theophylline slow-release preparations (E-0686) were compared using a crossover design with 16 healthy volunteers. The formulations used were 50% granule-1 (Gra-1), 50% granule-2 (Gra-2), a 50 mg tablet (T-50), a 100mg tablet (T-100), a 200mg tablet (T-200), a 300mg tablet (T-300), and a plain, uncoated aminophylline tablet (Neophylline^®, NT).
In experiment I of the two, 400mg equivalent doses of theophylline in the form of Gra-1, Gra-2, T-200 and NT were administered under the fasting condition, while in experiment II, T-20, T-100, T-200, and T-300 (T-300 was 300mg instead of 400mg) were used. All the E-0686 formulations found to have equivalent bioavailability. The relative extent of bioavailability of the E-0686 formulations were 91.3-98.1%, and C_max was significantly lower, while T_max and MRT were prolonged, compared with the values for NT.
Using % change as an index, the variation of serum concentrations after repeated administration of T-200 in experiments I and U was about 20% in the absorption phase and about 10% after the peak concentration.
Since all E-0686 formulations were well described by the one compartment open model with first order absorption and showed high reproducibility of serum levels, it was suggested that optimal adjustment of dosage regimen with these formulations will be easily applicable in around-the-clock therapy.

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The effects of carteolol, a β-blocking agent, on the incidence of ventricular arrhythmias and ventricular automaticity were studied in a canine acute myocardial infarction model. Carteolol (10 μ g/kg) was given intravenously 5∼ 30 minutes before balloon occlusion of the left anterior descending coronary artery in anesthetized, closed chest dogs (Group I). The total incidence of ventricular arrhythmias during the first 30 minutes of coronary occlusion was 91% (10/11) in group I, similar to control dogs without pretreatment of carteolol (Group II; 92%, 12/13, NS).
However, ventricular fibrillation or sustained ventricular tachycardia was not observed in Group I, compared to 2 cases in the Group II dogs.
Ventricular escape interval (VET), used as an index of ventricular automaticity, progressively shortened in the periods between 1 and 4 hours post-occlusion in both groups. However, the mean value of VET at 4 hours after coronary occlusion in Group I was significantly longer than.that of the Group II dogs (1549 ± 1259 msec vs 610 ± 224 msec, P<0.05).
It was suggested that carteolol prevented the occurrence of malignant ventricular arrhythmia in the acute phase (within 30 minutes) and suppressed the enhancement of ventricular automaticity in the delayed phase (4 hours) of myocardial infarction.

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Nipradilol (K-351) is a new type of beta-blocker with vasodilating action. In this paper, the hemodynamic effect of nipradilol was studied non-invasively using 10 hypertensive patients. Nipradilol was orally given to patients with mild or moderate essential hypertension for about 3 months, and blood pressure (BP), heart rate (HR), cardiac output (CO), and systolic time intervals (STI) were measured, respectively. As results in the responder patients, both BP and HR decreased significantly, CO remained unchanged, and the total peripheral resistance (TPR) tended to decrease. In STI, the ejection time (ET) prolonged, the preejection period (PEP) shortened slightly, and ET/PEP increased.
Accordingly, the hemodynamic effect of nipradilol was different from that of propranolol, probably due to the vasodilating action of nipradilol.

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The present study was designed to estimate the effect of KB-1712 (KB), a longacting preparation of nifedipine, on exercise tolerance in 9 stable effort angina patients with a mean age of 57 years. All patients participated in multistage treadmill exercise testing before, and 2, 4, and 7 hours after a single oral administration of placebo and KB 30mg. The exercise testing was symptomlimited according to the modified Bruce protocol.
The duration of the treadmill exercise was 300 ± 148 (mean ± SD), 323 ± 142, 316 ± 146, and 336 ± 160 seconds before, and 2, 4, and 7 hours after administration of placebo respectively, and 311 ± 138, 436 ± 155, 450 ± 148, and 461 ± 177 seconds before, and 2, 4, and 7 hours after administration of KB respectively. KB significantly prolonged the exercise duration at 2, 4, and 7 hours after administration. The analysis of nifedipine plasma concentration showed its peak at 4 hours. after KB administration and decreased gradually thereafte.
After KB, an increase in heart rate and a reduction in systolic blood pressure were observed at rest, and an increase in heart rate and an improvement of ST deviation were observed at peak exercise.
We concluded that KB improved the exercise tolerance in patients with stable effort angina pectoris up to 7 hours after a single oral administration and this effect seemed to be caused by reduced after-load due to dilatation of the systemic resistance vessels and probable coronary perfusion due to dilatation of the coronary artery.

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EST, a newly synthesized inhibitor specific for thiol protease, is developing as a candidate for muscular dystrophy therapy.
A single dose of EST was administered to adult patients with muscle diseases, and a single dose as well as single doses everyday for seven consecutive days was administered to children with Duchenne muscular dystrophy in order to confirm the safety of this drug and also to compare the pharmacokinetics between the patients and healthy adult males.
No side effect attributable to EST was observed in clinical signs or symptoms or in laboratory tests during administration.
EST was detected as E-64-c (effective form of EST) in the serum and urine after oral administration and there was no intrinsic difference between patients and healthy adult males in absorption and excretion of the drug.
Single dose and repeated dose administration did not produce different absorption and excretion patterns, with no accumulation of the drug being observed in either regimen.

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The effect of dosing time on salicylic acid (SA) kinetics after single oral administrations of two different aspirin formulations, a slow-release tablet (Veri^®) and enteric-coated granules (Minimax^®), was investigated in 15 healthy Japanese men. Eight subjects received slow-release tablets and the other seven subjects received enteric-coated granules. Each aspirin formulation was given in the morning (8: 30) or in the evening (20: 30) in a randomly assigned cross-over study. After the single dose study, the SA kinetics following repeated administration of the two different aspirin formulations, 2600 mg daily for five days, was investigated. Eight subjects received the slow-release tablets, and one subject received the enteric-coated granules. No time dependent changes were observed in SA kinetics after single and repeated administra tions of the two different formulations. In both dosing times, the mean peak SA concentrations in plasma were significantly higher in the enteric-coated granules, the mean elimination half-lives of plasma SA were significantly longer in the slow-release tablets, and the mean areas under the curves were significantly larger in the enteric coated granules. In repeated administration of the slow-release tablets, the mean SA concentrations were 47.4 ± 21.9 μ g/ml after administration at 20: 30 and 44.7 ± 24.4μ g/ml after dosing at 8: 30 on the day 5. The plateau SA concentrations in plasma were attained after day 3 to day 4, but after the day 5 SA concentrations in plasma tended to be decreased. This may be due to enzyme induction in the salicylate metabolism.

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