The antihypertensive effects of once daily dosing with atenolol were assessed in 10 inpatients with essential hypertension (WHO I -III). In the pre-treatment period, indirect measurements of blood pressure and heart rate were prformed 15 times every hour form 07: 00 to 21: 00. The same measurements were taken during the treatment period, when atenolol was given for 7 days, 100 mg/day orally administered at 11. 30 a. m. Aten. olol as a hypotensive agent was effective in eight of the 10 patients and induced the overall reduction of blood pressure. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) in the 10 patients were reduced as average values of the recording taken one hour after atenolol therapy, although the decrease in DBP was statistically insignifi cant by 18: 00 hours. These results suggest that once daily dosing with atenolol maintained the therapeutic effect in essential hypertension over 24 hours.
Haemodynamic studies (using radiocardiography) were carried out in 13 outpatients with essential hypertension (51±3yrs., WHO I-II) taking atenolol 100 mg once daily for 5 weeks, and in 15 patients taking metoprolol ay . 195 mg (120-240mg) daily in three divided doses for 5 weeks. Both atenolol and metoprolol reduced SBP (atenolol, from 177±6 mmHg to 153±mmHg, p<0.005 ; metoprolol, from 177±6mmHg to 153±6 mmHg, p<0.005), and reduced DBP (atenolol, from 103±3 mmHg to 89±3 mmHg, p<0.005 ; metoprolol, from 119±6 mmHg to 95±4mmHg, p<0.005) with a concomitant decrease in heart rate . Atenolol induced similar haemodynamic changes to those observed with metoprolol ; cardiac index (CI) fell from 3.95±0.34 l/min/m² to 3.35±0.19 l/min/m² (p<0.05) in the atenolol-treated group, and fell form 4.10±0.24 l/min/m² to 3.30±0.22 l/min/m² (p<0.05) in the metoprolol-treated group without any change in the total peripheral resistance (TPRI). However, in the total of 28 patients treated with atenolol or metoprolol, the decrease in mean blood pressure (MBP) did not correlate with the derease in CI, but correlated with the decrease in TPRI.
This correlation between MBP and TPRI corresponds to that observed in pindolol therapy in our previous study. These results suggest that the antihypertensive effects of beta-adrenergic blockade depend mainly on the reduction of peripheral resistance, although the pharmacological properties of these beta-blockers are not uniform.

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It is well known that the administration of dextran sulphate (DS) enhances the fibrinolytic activity of the circulating blood. Furthermore, it has been shown that concomitant administration of urokinase (UK) and DS enhanced the fibrinolytic activity of UK alone. Nevertheless, the mechanism of enhancement of fibrinolytic activity by the administration of DS is not yet fully understood.
In order to clarify the enhancing mechanism, the interaction between UK, DS and dog serum was studied using gel chromatography.
The results obtained may be summarized as follows.
1) On gel filtration of a mixture of DS and UK, it was found that DS did not interact with UK and did not enhance the fibrinolytic activity of UK in vitro.
2) On gel filtration of a mixture of serum inhibitor and DS, it was found that the carbohydrate content in the DS fractions decreased and the carbohydrate content in the inhibitor fractions increased. Furthermore, the inhibitory activity against UK of the inhibitor decreased.
Based on these results, it is suggested as a mechanism for the enhancement of fibrinolytic activity by DS, that DS combined with the inhibitor and the inhibitor'sactivity against UK therefore decreased.

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An open study was carried out on the oral effect of perhexiline maleate on angina pectoris. After 2 weeks observation period, during which a placebo was given, a daily dose of 300 mg, divided in 3 times after each meal, administered for 4 weeks in 79 cases of angina pectoris. Beneficial effect was obtained in 77.9% of the cases at the end of 2 weeks administration and in 80.0% at the end of 4 weeks administration, compared with preceding observation period. Two weeks after discontinuation of the drug, the effectiveness reduced to 51.6%, significantly lower than the active treatment period (p<0.001). Number of attacks and the consumption of nitroglycerin tablets showed also significant reduction as compared with the observation period. No remarkable changes were observed in arterial blood pressure, heart rate and cardiothoracic ratio. Side effects occurred in 17 cases. Most frequent one was gastrointestinal disturbance. The drug was required to discontinue in only 2 cases: hemorrhagic stomatitis and skin rash. In conclusion, perhexiline maleate was evaluated as a promising antianginal agent.

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The hypotensive effect of metoprolol at doses from 60 to 120 mg/day was studied in 10 patients with mild to moderate essential hypertension (4 males and 6 females, the average 55.6±9.7 years old). The effects of metoprolol on hemodynamics (9 cases) and plasma renin activity (7 cases) were simultaneously studied in these patients. The hypotensive effect of metoprolol was rapid, and was more marked in diastolic than in systolic. Metoprolol decreased the diastolic blood pressure significantly from 103.7±8.8 mmHg (Mean±S. D.) in supine position before administration to 97.6±8.8 mmHg in the second week. The hypotensive effect continued for some time afterwards, and even in the 10 th week the diastolic blood pressure recorded 92.0±11.1 mmHg.
Metoprolol caused significant decrease in the pulse rate. Dose of metoprolol was increased in 3 cases, in one of which the hypotensive effect tended to increase further. In 2 cases with chronic obstructive airway disease, the administration of metoprolol did not aggravate the symptoms. In 3 out of 9 cases, metoprolol induced marked decrease in cardiac output, but did not cause any reduction in blood pressure. In 2 cases, a remarkable reduction in total peripheral resistance was observed after the administration of metoprolol, and in these cases the hypotensive effect was remarkable.
There is a significant positive correlation between the, change in the diastolic blood pressure and that in the total peripheral resistance. Metoprolol gave variable influence on the change in plasma renin activity, and there was no correlation between the change in plasma renin activity and that in the blood pressure. Metoprolol could be used safely and effectively for the patients with essential hypertension including those with chronic obstructive airway disease. Its hypotensive effect is thought to mainly be due to the decrease in peripheral vascular resistance.

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The antihypertensive effectiveness, influence on laboratory parameters and adverse reaction of FR 3068 (tienilic acid, FR), a new nonthiazide diuretic developed by Albert Rolland Co. of France with uricosuric properties, were evaluated by double-blind parallel group comparison with methyclothiazide (MCTZ).
Placebo was initially administered for a period of at least 2 weeks. Patients with systolic blood pressure of≥150 mHg and diastolic blood pressure of≥90 mmHg at the termination of the placebo control period were enrolled as subjects .
FR and MCTZ were administered in fixed dosages of 250 mg/day and 5 mg/day respectively. The duration of treatmentwas 8 weeks.
Blood pressure significantly decreased in both groups in 2 weeks. In MCTZ group, blood pressure showed a continuous, gradual decrease until Week 8. In FR group, a mild reduction in blood pressure was seen from Week 2 onwards, at Week 8 there being a further decrease.
Comparison of laboratory data before and after treatment revealed increase in BUN and serum Na⁺ in FR group.In MCTZ group, increase in some hematological indexes and serum creatinine value and decrease in serum Na⁺, K⁺ and Cl^- were seen. Severe liver function disturbance was noted in one patient of FR group.
Serum uric acid increased in MCTZ group.In contrast, it decreased in FR demonstrating a distinct uricosuric effect.
Symptoms appearing during the treatment period which did not occur during the control period consisted of those of central nervous, autonomic nervous and gastrointestinal systems. These symptoms occurred in 15 of 50 patients in the FR group and 7 of 46 patients in the MCTZ group.
The usefulness of both drugs was globally assessed based on symptomatic change, antihypertensive effectiveness, adverse reaction, laboratory data abnormalities, etc. There was no significant intergroup difference at 5% level.

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This paper describes a possibility that a metabolite of orally administered gefarnate (GF), an antiulcerative agent, is an acting substance, instead of GF.
When GF was orally administered in rabbits or rats, its metabolites, farnesylacetic acid (FAA), geraniol etc. were clearly detected in portal or lymphatic flow, while mother compound GF was not detectable. FAA revealed about 100 times potent increase in the O₂ consumption of mitochondria of rat liver than that of GF. When FAA (4 mg/kg) was intraperitoneally administered in rats, it showed a potent inhibitory effect on the stress ulcer, while oral administrations (1-260mg/ kg) were inactive or slightly adverse.
These findings may be related to the assumption that FAA, a main metabolite, acts as a main pharmacologically active substance, but when it was directly applied to the surface of gastric mucosa with higher concentrations, it may inhibit the cellular respiration.

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The particle-size effect of acemetacin on oral absorption was evaluated in three normal male subjects with standardized breakfast. Two sieved particle-size formulations were used: one with crystals with mean equivalent spherical diameter of 27.6μm and the other with crystals with mean equivalent spherical diameter of 3.8μm.
Plasma acemetacin and indomethacin concentrations and urinary drug excretion were used to determine the relative absorption of the two formulations. Particle-size had a dramatic effect on oral absorption of the drug. The smaller crystals produced higher plasma indomethacin concentrations and more rapid peak concentration attainment.
The pharmacokinetics of acemetacin was compared with indomethacin after a single oral dosing in three normal male subjects with standardized breakfast. Mean absorption parameters for 30 mg acemetacin, 25 mg indomethacin of conventional capsule and 25 mg indomethacin of timed-release capsule were as follows. Mean C_max of plasma indomethacin concentrations were 481, 754 and 684 ng/ml and t_max. were 3, 2 and 4 hr after dosing, respectively. With acemetacin t1/2 (α) of plasma indomethacin concentrations was 0.6 hr and t1/2 (β) was 3 hr. Aceme tacin was mainly metabolized to indomethacin and, in part, to deschlorobenzoylacemetacin and desmethylacemetacin in man. The possibility that the characteri stics of acemetacin kinetics may be related to the decrease of indomethacininduced side effects in clinical situation was discussed.

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Alprazolam kinetics were studied in 6 healthy male volunteers after a single oral 0.8 mg dose of the drug. A linear 2-compartment model with elimination from the central compartment was proposed to describe the drug kinetics. In the fasting state, T_max was 1.5 hr and C_max was 16.1 ng/ml. Alprazolam disappeared from plasma with a terminal half-life (t1/2 β) of about 16 hr.
Alprazolam produced shorter-lasting sedative effects and longer-lasting anxiolytic effects in these subjects.

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