Zomepirac sodium is a new non-narcotic analgesic antiphlogistic developed by McNeil Laboratories, U. S. A., particularly noted for its strong analgesic effect upon oral administration.
As reported in this paper, a comparative study of the analgesic effect of zomepirac sodium was conducted in comparison with aspirin and a placebo based on pain meter measurements.
The pain meter used was the Nakahama-type NYT-model 5 which is an improved version of the original pain meter developed by Hardy et al.
Two methods were used in recording pain: The intensity method in which the duration of the stimulus was set at a fixed standard and the amount of radiant energy was measured and the time method in which the amount of radiant energy was set at a fixed standard and the duration of the pain was measured.
The subjects were 9 healthy male volunteers who were divided into three groups, namely the 200 mg zomepirac group, the 500 mg aspirin group and the placebo group.Measurements were taken on the hand, leg, and breast.
The results obtained indicate that it is impossible to detect any significant difference between zomepirac sodium, aspirin and the placebo in either the time or intensity methods.
It is said that in general such non-narcotic analgesics as zomepirac sodium do not respond well to mechanical stimuli such as used during this experiment and our results support this conclusion. This analgesic exhibits quite different characteristics in comparison with CNS analgesics such as pentazocine.

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The bioavailability of methyldopa was assessed in 9 normal male subjects in a cross-over study following single doses of 500 mg of methyldopa fine granules and 500 mg tablets. The following results were obtained:
1 . Methyldopa fine granules and tablets were shown to be bioequivalent, with no statistically significant difference in plasma concentration at each time and pharmacokinetic parameters including Cmax, Tmax, [AUC], t_1/2 and clr.
2. No significant difference in the 24 hour urinary excretion was observed between two forms.
3. No significant difference in normal blood pressure and pulse rate was detected between two forms.
4. Peripheral blood counts, blood chemistry and urine tests showed no abnormali-ties.

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Either single (50mg) or multiple (25mg/day × 4 days) dose of etretinate was administered orally into 5 healthy volunteers once a day 30 minutes after breakfast.After the administration with a single dose of 50mg or the initial dose of 25mg, the AUC (Area Under the Curve) of the blood level of unchanged etretinate was 1, 305 ng · Ehr/ml with 50mg and 267 ng · Ehr /ml with 25mg. The approximate half-life was 2 hr with 25 mg and 3.6 hr with 50mg. The AUC of the main metabolite, Ro 10-1670, was 2.7 times as large as that of unchanged etretinate with the first dose of 25 mg, but the AUC with 50mg was merely 1.5 times as large as that with the first dose of 25mg.
On the 4 th day of the administration with 25 mg/day, the AUC of unchanged etretinate became 1.6 times as large as the 1st day, but the AUC of the main metabolite was decreased on the 4 th day down to 61% of the level on the 1st day. The amount equivalent to 49% (28.0-66.%) of the dose was excreted into feces. Fecal excretion rate was 3.3%for the main metabolite. No changed etretinate nor its main metabolite was detected in the urine. Main adverse reactions attributable to etretinate were itching of the skin, dryness, headache and desquamation. These results suggest that etretinate was not absorbed well but metabolized rapidly after absorbed and the metabolism would be saturated and the hepatic metabolic capacity for etretinate in maximum seemed to be 30 to 40mg. That is, the pharmacokinetic process of etretinate was considered to take place not in the first order kinetics but zero order kinetics.

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The present experiment was undertaken to elucidate the simultaneous effect of clonidine on ambulatory activity and water drinking behavior in spontaneously hypertensive rats (SHR). An attempt was also made to determine the role of sympathetic nerve activity in the mechanism of clonidine-induced sedation in SHR. The sensitive method developed by Tadokoro et al. for simultaneous determination of ambulatory activity and drinking behavio in rats was used. Clonidine (150μ Eg/kg, po twice daily) produced a significant decrease in ambulatory activity and water drinking behavior at the beginning of the dark phase in twenty week old male SHR of Wistar Okamoto strain. Clonidine produced an increase in water drinking behavior in the light phase which was not observed in the control period. Under the same experimental conditions, the lowering of brain stem norepinephrine content produced by diethyl dithiocarbamate appeared to be inhibited in clonidine-treated SHR in the dark phase. Clonidine significantly decreased urinary norepinephrine content in the dark phase. On the other hand, clonidine (30μ g/kg, iv) produced a decrease in efferent nerve discharges of splanchnic nerve and sympathetic adrenal nerve in SHR. These findings suggest that decreased sympathetic nerve activity via a centrally mediated mechanism is at least in part associated with the decreased ambulatory activity induced by clonidine.

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The pharmacokinetics of ranitidine, a new H₂-receptor blocking agent, and its effects on tetragastrin-induced gastric acid serection were studied in five healthy volunteers. The ranitidine concentrations in plasma and urine were determined by HPLC.
After single oral administration of ranitidine (100 mg or 150 mg tablet), the peak plasma concentration of the drug was attained in 2-2.5 hrs and the elimination half-life was 2-2.5 hrs when they were obtained from the 24-hr plasma concentration-time curve. After the administration of 100 mg and 150 mg, the maximum plasma levels were in the ratio of 1: 1.57 and the AUCs were, 1: 1.53 which were roughly coincident with the dose ratio. Recovery of unmetabolized ranitidine from urine over a 24-hr period accounted for 40-45% of the administered drug.
In the multiple oral doses of ranitidine (150mg b. i d., for 14 days), the actually measured plasma concentrations of the drug were nearly in agreement with the simulation curves obtained from the single dose.
A single dose of ranitidine (150mg/10ml) significantly reduced gastric volume rate and the output concentration of the acid induced by tetragastrin.
No abnormality attributable to ranitidine was noted in physical findings, clinical laboratory findings or subjective symptoms.

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Influence of liver disease on metabolism and pharmacokinetics of cephalothin (CET) was studied. CET was given 1g bolus intravenously to 7 patients with liver cirrhosis, 7 patients with hepatitis (3 cases of acute hepatitis and 4 of chronic active hepatitis) and 7 patients with normal liver function. Serum consentration of CET and deacetyl CET was measured by High Performance Liquid Chromatography.
Ratio of deacetyl CET to CET was less in cirrhosis compared to that in hepatitis or control group, demonstrating impaired metabolism of CET to deacetyl CET in cirrhosis. Deacetyl CET/CET ratio was correlated to such liver function test as BSP retention rate, prothrombin time or serum γ -globulin level which were characteristic in chronic liver disease, while not correlated to GP T, GOT, γ -GTP, total bilirubin which are characteristic in acute hepatic parenchymal disorders.
Pharmacokinetic parameters calculated as two compartment open model were not statistically different among three groups.
These results show that severe chronic liver disease impairs the biotransformation of CET to deacetyl CET, but does not affect pharmacokinetics of CET.

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The influence of penbutolol on hypertension and its diurnal variation wereinvestigated in 12 inpatients with essential hypertension. The study extended for 14 days. Placebo was administered b.i.d., i.e., after breakfast (8 a.m.) and dinner (5 p.m.) for the first 7 days (pretreatment period). Penbutolol 40 mg was administered in the same manner for the latter 7 days (treatment period). Blood pressure and pulse weremeasured 3 times, i.e., at arising in the morning (5 a.m.), after lunch (1 p.m.) and before going to bed (7 p.m.), daily for the 14 days. On the 7 th day of each period, these parameters were measured not only at the above 3 points of time but also at 7 a.m., 9 a.m., 11 a.m., 3 p.m. and 5 p.m..
The following results were obtained:
1) Blood pressure and pulse were significantly reduced in 8 and 9 patients, respectively.
2) An analysis of measurements made 3 times daily showed that systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse were significantly decreased at all given times on the 3 rd to 7 th days of the treatment. Diurnal variations of both SBP and DBP were also significantly reduced.
3) An analysis of measurements made 8 times on the 7th day showed that a significantly decrease was observed in SBP at 5a.m., 11a.m., 1p.m., 3p.m. and 7p.m.; DBP at the last 5 points of time; and, pulse at all points of time. Only SBP showed a significantly reduction in diurnal variation.

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Serum concentrations, urinary excretion and diuretic effect of piretanide werestudied in 9 subjects (3 healthy volumteers, 3 patients with chronic renal failure and 3 patients with liver cirrhosis) after a single 6mg oral dose. The following results were obtained:
(1) Peak serum concentrations of piretanide were attained within 2 hours after treatment in all subjects. Peak serum concentrations and the AUC of the serum concentration curve did not indicate any marked inter-subject variations in absorption.
(2) The disappearance of piretanide from the serum was prolonged in patients with reduced renal function. After 24 hours, however, no appreciable amounts of piretanide were detected, even in patients with chronic renal failure.
(3) Urinary piretanide excretion was generally completed within 24 hours after treatment in all three groups. The excretion in the renal failure group was, however, lower than in the other two groups.
(4) 24-hour urine volumes were comparable in all three groups. Electrolyte (Na⁺, K⁺, Cl^-), creatinine and uric acid excretion was lower in the renal failure group.
(5) In the healthy volunteer and liver cirrhosis groups, serum concentrations and urinary excretion of piretanide both closely reflected diuretic effect. In the renal failure group, diuretic activity was only correlated with urinary excretion of piretanide and not with serum concentrations of drug.

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Anti-anginal effect of nicorandil was evaluated by a double blind trial incomparison with propranolol in 80 patients with angina pectoris. Nicorandil was given in a daily dose of 15-45 mg to 36 patients and propranolol in a daily dose of 30-90mg to 44 patients, both divided into three doses, for a period of 3 weeks. Inactive placebo was given in the 1st and 2nd weeks, either 15 mg nicorandil or 30mg propranolol was given in the 3rd week, either 30mg nicorandil or 60mg propranolol was given in the 4th week, and variable doses (the same dose as that used in the 4th week or 50% increase ordecrease of the dose used in the 4th week) were given in the 5th week, and the following results were obtained:
1. There was no significant difference in background between nicorandil and propranolol groups.
2. Decrease in number of anginal attacks/week in the 4th and 5th weeks in nicorandil group was significantly larger than that in propranolol group.Reduction of nitroglycerin consumption in the former group, however, was not significantly larger than that in the latter group.
3. The rate of grobal improvement was 94. 4% with nicorandil and 77. 3%with propranolol. The difference in rate of improvement was statistically significant (z=2. 4785, U-test).
4. Improvement in ischemic ST change was observed in 45. 8% in nicorandil group and in 56.0% in propranolol group.However, the difference in rate of improvement was not significant.
5. Adverse side-effects such as headache and gastrointestinal disturbance were observed in 13.5% of nicorandil group, and those such as general malaise and gastrointestinal disturbance in 16.7% of propranolol group.The difference in rate of side-effects between two groups, however, was not significant. Laboratory examinations revealed no abnormal findings indicative of clinical significance in both groups.
6. The rate of usefullness assessed from grobal improvement and adverse side-effects was 91.7% with nicorandil and 77.3% with propranolol. The difference in usefulness between these two groups was statistically significant (z= 2. 1777, U-test).
The results indicate that anti-anginal effect of nicorandil is superior to propranolol.

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Labetalol which has the combined α - and β -adrenoceptor blocking actions was administered in doses of 300 to 600mg/day for one month to a patient with essential hypertension to observe endocrine homeostatic action.
Antihypertensive effect was noted from the first day of administration and the effect became more marked with dose-dependency with neither any side effect nor remarkablechange in the laboratory findings as the dose was increased from 300mg/day to 400mg and 600mg/day. Marked suppressions on PRA, secretion of aldosterone and manifestation of borderline diabetic data in glucose tolerance test were noted after labetalol. No difference in THS levels between before and after the administration, but lowering of the prolactin level and increase in LH and FSH responses were noted.

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