Labetalol, a newly developed α, β-blocking agent, was orally administered to 5male healthy volunteers and its pharmacokinetics and pharmacodynamics wereinvestigated.
Serum and urine concentration of labetalol was determined by fluorometry. The time course of the serum concentration was able to be fitted to the two compartment open model. The time to the maximum serum concentration was 1-1.5 hours, and the maximum serum concentration was 21.8 ng/ml after 50 mg dose, 59.7ng/ml after 100 mg dose, and 163.3 ng/ml after 200 mg dose. The elimination half-life was 8.62-17.65 hours. The fraction of drug excreted in unchanged form into 0-24 hours' urine was about 2%.
Both systolic and diastolic blood pressures were significantly decreased by single oral dose of 50 mg, 100 mg and 200 mg in the supine, sitting and standing positions. The reduction of the blood pressure was bigger in standing position than in the supine and sitting positions. Exercise-induced elevation of systolic blood pressure and tachycardia were attenuated by the administration of labetalol. The percent reduction of exercise-induced tachycardia was significantly correlated with the logarithm of the serum concentration of labetalol.
In some subjects, scalp tingling, tiredness of the lower legs during exercise, drowsiness, nausea and postural dizziness were complained above the dose of 100mg in this study.

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To test the clinical usefulness of new drugs, the efficacy of the new drugs are often compared with that of the standard drugs. The criterion to adopt the test drug is generally accepted to be that “the efficacy of the test drug is egual to or higher than that of the standard drug.”
However, the statistical interpretation of the above criterion is not so clear, for it is not possible to test the equality of efficacy by statistical methods.
In this paper, based on the fiducial argument, a method to make a decision in above situations is proposed and the procedure is illustrated by examples.

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We carried out a phase I study of zomepirac sodium in healthy Japanese volun-teers and studied the safety and pharmacokinetics of the drug.
The volunteers were divided into 5 groups (A-E) of 3 volunteers each and the following dosages were tested: single doses of 50 mg, 100 mg and 200 mg, a divided daily dose of 450 mg (150mg×3) and finally a 3 day continuous administration test of 300 mg (100mg×3) per day.
Absolutely no abnormality was observed in either subjective or objective symp-toms. No remarkable change was seen in the blood pressure, pulse rate, respiratory rate, body temperature or ECG.
In the blood chemistry tests and urinalysis, no abnormalities were observed except that the BUN and the blood creatinine exhibited a tendency to rise. In regard to blood coagulation factors, no definite tendency was observed.
The peak time of blood concentration for a single dose was between 0.5 to 1.5 hours and for the continuous administration at 2 hours.
Urinary excretion was rapid and the main metabolite, glucuronic acid conjugate was excreted at a rate of approximately 50-60%.
During the continuous administration test no increase was observed in either the blood concentration or the excretion rate.
The above results confirm the safety of zomepirac sodium in healthy Japanese volunteers.

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The practical usefulness of oral administration of 5-fluorouracil has been shown in our previous reports, in terms of organ-distribution, anti-tumor efficacies and toxicities, experimentally as well as clinically, in comparing with its parenteral usage. However, these results have urged us to study further on the ideal dosage schedules of this particular mode of administration of this agent. Seeking the most appropriate dosage to be given at each administration and the most reasonable medication interval, we made some experimental study using transplantable animal tumor. Following the results obtained in this fundamental study, we engaged in clinical trials to confirm the antitumor effects and toxicities of several dosage schedules of oral administration of 5-fluorouracil, on the patients in advanced stage of breast cancer. The results obtained in these experimental and clinical studies are asfollows:
1. Animal experiments
Using Walker-carcinosarcoma 256 implanted to SD-JCL female rats, Yoshidasarcoma (solid) implanted to Donryu male rats and Sarcoma 180 implanted to dd male mice, the tumor shrinkage effects of orally administered 5-fluorouracil were evaluated according to specially designed many dosage schedules.
Regarding the drug dosage given at each administration, those transplantable animal tumors required different amounts of the drug respectively, as minimum threshold level of dosage, to achievesignificant tumor shrinkage. However, the dosage above these threshold levels could not produce any better responses.
As to the administration interval, even when large amounts of the agent were given, the cyclic administration within 2 day period was required to produce significant tumor regressions.
Concerning the administration routes of 5-fluorouracil, both oral and intraperitoneal administration showed almost identical tumor regressions, at each dosage schedule.
2. Clinical trials
During ten year period from 1970 to 1979, at the Breast Service Unit of National Nagoya Hospital, 106 patients with measurable lesions of advanced breast cancer were treated with oral administration of 5-fluorouracil, either as a sole anti-cancer agent or combined together with other agents. The standard dosage schedule was 250 mg/body/day, given as a water mixture at 3 o'clock p.m. every day. This schedule rarely invited severe toxicities, accordingly majority of the patients tolerated the long-term continuous chemotherapy.
The response rate according to UICC criteria was 29% (6/21) among the patients treated wih 5-fluorouracil solely, and was 48% (15/31) among the patients given 5-fluorouracil together with cyclophosphamide.

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