In an attempt to establish a better cancer chemotherapy, the metabolism of fluoropyrimidines was investigated in cancer patients.
Both uridine phosphorylase (UrdPase) and thymidine phosphorylase (dThdPase) activity were estimated, using resected stomach or breast cancer specimens as mate rial. Autopsy specimens were also used to determine the whole body distribution of the enzymes in patients with gastric cancer.
As a result, it was demonstrated that dThdPase activity was dominant compared to that of UrdPase. Accordingly, it was considered that 5-fluorouracil (FUra) wasmainly activated, via 5-fluoro-2-deoxyuridine (FdUrd), to produce 5-fluoro-2-deoxy - uridine 5-monophosphate (FdUMP), an active form of FUra. Further, it was also observed that both 1-(2-tetrahydrofurany1)-5-fluorouracil (FT) and 5'-deoxy-5-fluorouridine (5'-DFUR) were activated by dThdPase to form FUra. It was empha sized that this dThdPase activity was over 5-fold higher in tumor tissues than in nor-mal tissues. This observation would indicate that the compounds would exert a tumor-selective toxicity in cancer patients.

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A Phase Istudy on cisapride (R 51 619), a new gastrointestinal prokinetic agent, was conducted in 12 healthy Japanese male volunteers. The safety and pharmacokinetics of the drug were studied in single oral doses of 2. 5, 5, 10, 20 and 40 mg.
The six men of group 1 received 2.5, 10 and 40 mg doses at intervals of five to sixweeks. The remaining six individuals (group 2) were given doses of 5 and 20 mg. Thedoses were increased step by step after the safety of the compound was confirmed.
No pronounced change was noted in vital signs, ECGs or laboratory tests. As tosubjective symptoms, borborygmi, which appear to be a pharmacological effect, were observed at the 20 and 40 mg dose levels. Reports of flushing, headache and feeling of heavy-headedness occurred after intake in the 40 mg group.However, these subjective symptoms were mild and transient.
Peak plasma levels were found about 1.3 hours after the administration and the biological half life of the β phase was about 8.5 hours.

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A Phase I study on cisapride (R 51 619), a new gastrointestinal prokinetic agent, was conducted in 12 healthy Japanese male volunteers. The safety and pharmacokinetics of the drug were studied in repeated oral doses of 15 mg/day and 30 mg/day.
The volunteers were randomly divided into two groups (group 1 and group 2). The six men of group 1 received 15 mg/day t.i.d. for 5 days and the remaining six individuals (group 2) were given 30 mg/day t.i.d. for 7 days.
No abnormalities were observed in the vital signs, ECGs or laboratory tests. Among subjective symptoms, one individual in each group complained of a slight feeling of heavyheadedness and headache on the first day of administration.
The measured plasma levels of unchanged cisapride in this study almost coincided with the simulation curves which were defined based on the parameters obtained in the single oral dosing study. Moreover, the plasma levels reached steady states on the 3 rd or 4 th day of administration.
The serum levels of prolactin rose temporarily within the normal range on the first day of administration and normalized after repeated dosing.
The above results confirmed the safety of cisapride in repeated oral dosing in healthy male volunteers.

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A Phase l study on cisapride (R 51 619), a new gastrointestinal prokineti cagent, was conducted in 7 healthy Japanese male volunteers.The safety and phafmacokinetics of the drug were studied in single intravenous doses of 2 and 4 mg.
The 2 men of group 1 received 2 mg, and the remaining 5 men (group2) were given 4 mg.
There were no complaints about subjective symptoms.No abnormalities were seen in ECGs or laboratory tests.Among vital signs, a rise of pulse rate was observed after the 4 mg dosing.
The time-concentration curves of cisapride could be fitted into a three compartment open model.The half-life of the unchanged drug in the π-phase, the α-phase, and the β-phase rate was 0.032, 0.90 and 6.4 hours respectively.
The above results confirmed the safety of cisapride in single intravenous dosing in healthy male vorunteers.

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rimoprostil (Ro 21-6937), an analog of PGE₂, was previously evaluated to assess its inhibitory effect in stimulated gastric secretion, and was found to be active when administrated orally. The purpose of this study was to determine the safety, tolerance and pharmacokinetic profile of trimoprostil following single oral administration (250, 500 and 1, 000 μg) and multiple dosing regimen (500 μg 4 times a day for 7 days) in healthy volunteers and also, to determine the pharmacokinetic profile of trimoprostil (500 μg 4 times a day) 30 min after every meal. Plasma concentrations of this compound were determined by enzyme immunoassay and GC-MS methods. Administra tion of trimoprostil in single or multiple dose regimen had no significant effects on vital signs (blood pressure, pulse rate, respiration rate, body temperature), subjective symptoms, ECG, or clinical laboratory test data in this study. Dose-related plasma concentration time curves were obtained following single dose. The rate of absorption was diminished following postprandial administration. Because of the rapid elimination of trimoprostil from blood, there was no accumulation of drug in the blood even in a 7-day multiple dose reginem. These results indicate no significant dose-related intorelance which would prohibit the continuation of clinical trials of this compound.

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EST is a specific thiol protease inhibitor newly synthesized as a drug for muscular dystrophy.
Following the first Phase I study of EST single dose (First report), the second Phase I study on EST continuous administration was performed in healthy adult male volunteers to investigate its safety and pharmacokinetics.
In the first stage, 100mg was administered 3 times a day after meals for 1 day, and in the next stage, 100 mg was administered 3 times a day after meals for 7 consecutive days.
No change due to EST was found from the observation of the subjective and objective symptoms and clinical tests.
EST was detected as E-64-c (effective form of EST) in serum and urine after oral administration. No accumulation of EST was observed after continuous administration, and approximately 30% of total EST was collected in urine.

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The clinical utility of TY-0032 (sustained-release capsule containing 3mg of dihydroergotoxine mesylate) was compared with that of dihydroergotoxine mesylate tablet in 330 patients with cerebrovascular disorders by means of multi-center (57 hospitals) double-blind clinical trial. No significant difference in patient's characteris tics was noted between TY-0032 group (TY group) and dihydroergotoxine mesylate tablet group (DE group), except for significant existence of previous history and tendency of more frequent ischemic heart disease noted in TY group.
As for final global improvement rating (GIR), TY group was significantly superior to DE group (P<0.05).Overall safety rating of TY group was the same as that of DE group, As for stratification analyses of the final GIR and final global utility rating by patient's background characteristics, TY group was significantly superior to DE group in many items, and no reverse findings were noted.
The incidence of side-effects was5% in both groups, and these side-effects were mild in most cases.
No significant abnormal laboratory findings were noted in both groups.
It was concluded that a single medication of TY-0032 a day would be more recommendable than 3-times medication of 1 mg dihydroergotoxine mesylate tablet a day for the treatment of cerebrovascular disorders.

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E-0687 is a newly developed agent which has protective action against cerebral hypoxia by improving cerebral monoamine metabolism according to animal experi ments.
We studied the effects of E-0687 on regional cerebral blood flow (rCBF) in patients of chronic ischemic. cerebrovascular diseases by oral administration (150 mg/day) for a period of 8-14 weeks.
Nine patients with mild cerebral infarction and one patient with carotid TIA, mean age 63 years, were studied. The control group consisted of twelve subjects, mean age 54years. rCBF was measured by the Xe 133 inhalation method using a NOVO cerebrograph, and F₁ value was calculated by Fourier Analysis used as gray matter flow. The interval of rCBF measurements was 8-14 weeks in the treated group.
There were no significant changes in mean arterial blood pressure (MABP), Ht, and PCO₂ before and after the treatment. Mean rCBF significantly increased (10.5%) in the treated group in contrast to the change in the control group (-2.3±7.5%, mean± SD). The rCBF showed a tendency to increase in all regions. Fig. 6 showed a typical case of improved rCBF by long-term administration of E-0687.
The subjective symptoms in this case were also improved after treatment.
E-0687 significantly improved rCBF in chronic ischemic cerebrovascular diseases by oral administration for 8-14 weeks. This effect on cerebral circulation might be a secondary effect stemming from improvement of the brain metabolism.

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The antihypertensive effect of a calcium entry blocker, diltiazem (Herbesse®), was evaluated in different age groups by using a double-blind group comparison method. In a monotherapy study, 57 patients were divided into a group of 25 younger patients aged less than 59 years (50.4 years on the average) and a group of 32 older patients aged more than 60 years (66.3 years on the average). In a study of combined therapy with diuretics, 119 patients were divided into three groups ; 40 younger patients in their thirties and forties (average age 41. 7 years), 45 middle-aged patients in their fifties (average age 54. 3 years) and 34 older patients aged more than 60 years (average age 64. 1 years). Diltiazem 90 to 180 mg per day was used for 12 weeks in both studies.
Antihypertensive effects (blood pressure falling 20/10 mmHg or more) were ob served in 83.3 % of the younger patients and 66.7% of the older patients in monotherapy, showing significant difference (P<0.05). In combined therapy, antihypertensive effects were observed in 81.1% of the younger patients, in 76. 3% of the middle-aged patients, and in 71. 9% of the older patients, showing no significant ifference in each age group.Blood pressure decreased from 176. 3/102. 7 mmHg to 149.1/85.0 mmHg in the younger patients, and from 174.8/97.7 mmHg to 157. 7/86.2 mmHg in the older patients on monotherapy. In the combined therapy, blood pressure decreased from 169.8/108.5 mmHg to 145.2/93. 4 mmHg in the younger patients, from 173.3/102.5 mmHg to 147.4/89.1 mmHg in the middle-aged patients, and from 175.4/101.5 mmHg to 149.7/88.9 mmHg in the older patients. The decrease in blood pressure was not significantly different in each age group.Heart rate was lowered slightly in the younger patients, but did not change in the older patients in either monotherapy or combined therapy.
The incidence of side effects was 12.0% in the younger patients and 15. 6% in the older patients on monotherapy, while the incidence for combined therapy was 14.0% in the younger patients, 10.9% in the middle-aged patients and 11.0% in the older patients. Laboratory data revealed no significant changes in either monotherapy or combined therapy in each age group.
The results indicated that the Ca entry blocker, diltiazem, has usefulness (useful or above) at 80. 0% in the younger patients and 76.3% in the older patients on monotherapy, while the rates for combined therapy were 81.1% in the younger patients, 76.3% in the middle-aged patients, and 71.9% in the older patients. There was also no significant difference between age groups in either therapy. The Ca entry blocker, diltiazem, seemed to be equally useful for the treatment of both older and younger patients with essential hypertension.

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Acetylsalicylic acid (ASA) and salicylic acid (SA) concentrations in plasma were determined by high-pressure liquid chromatography in 14 healthy male Japanese volunteers after single oral administrations of two different aspirin formulations, enteric-coated granules (Minimax®) and a slow-release tablet (Verin®). Seven subjects received 650 mg and the other seven subjects received 1300 mg of each formulation in a randomly assigned cross-over study. Mean peak SA concentrations in the plasma were significantly higher with the enteric-coated granules than with the slow-release tablets (P<0.001 with both 650 mg and 1300 mg doses), although the times to peak SA concentration in the plasma were not different between the two formulations. Plasma ASA concentrations were detected only following administration of the enteric-coated granules. Mean elimination half-lives (t1/2) of plasma SA were significantly longer with the slow-release tablets at both doses (P<0.05 at 650 mg and P<0.01 at 1300 mg) and the mean areas under the curves (AUC^∞₀) were significatly greater with the enteric-coated granules at both doses (P<0.001 at 650 mg and P<0.05 at 1300 mg). Racial differences in SA kinetics between the Japanese and the American subjects were suggested by the results of the study.

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Twenty-nine patients with various tachyarrhythmias were treated with intravenous aprindine, a new antiarrhythmic drug. Three patients also exhibited Wolff-Parkinson-White syndrome.
Aprindine was significantly effective on ventricular premature beats (7/10) and paroxismal supraventricular tachycardia (5/6), but not effective on ventricular tachy cardia (1/4), atrial fibrillation (0/7), and atrial flutter (0/2). In all patients with WolffParkfnson-White syndrome, delta waves disappeared with aprindine injection. Electrophysiological study revealed that aprindine lengthened the conduction time significantly, but no significant prolongation of the effective refractory period was observed. The average half-life of elimination for 2 mg/kg intravenous aprindine was about 17. 5 hrs and was much longer in the patients with liver dysfunction. No severeside effects were observed.
In conclusion, intravenous aprindine showed efficacy on ventricular premature beats and paroxysmal supraventiruclar tachycardia, and proved safe for use under the conditions tested.

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A single dose Phase I study was performed on the newly developed antirheumatic, N (2-mercapto-2-methylpropionyl)-L-cysteine (SA 96)
Five healthy volunteers were administered 200 mg and 400 mg of SA 96 in a singledose after breakfast, after which the safety and pharmacokinetics of the drug were studied with the following results.
1) No remarkable subjective complaints were registered except for belching.
1) No significant anomaly was noted in clinical signs or laboratory examination values.
3) The average concentration of SA 96 in the blood reached highest concentration by about 1 hour after administration and repidly disappeared thereafter . About 40% of the SA96 was excreted into the urine in 24 hours.
Based on the above results, we plan to proceed to a multiple dose study in order to further evaluate the safety of SA96.

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The multiple dose Phase I study was performed on SA96 in 5 healthy volunteers.300 mg/day and 600 mg/day of SA96 were administered t. i. d. after meals for 6 days consecutively after 2 weeks washout.
The following results were obtained.
1) No remarkable subjective complaint was registered except for belching.
2) No significant anomaly was noted in clinical symptoms or laboratory values.
3) The changes in blood concentration of SA96 followed the same pattern as the single dose study, that is the drug was rapidly absorbed in the blood and rapidly excreted without accumulation.
4) Little difference was noted in urinary excretion pattern between day 1 and day 6, and 39-46% of the amount administered was excreted into the urine by 24 hours after the first administration on each day. SA96 was not detected in the urine on the day after finishing the administration, but trace amou ts of SA679 was found for 2 days thereafter.
Since the Phase I studies confirmed the safety of SA96 in the range of single doses at 200 mg and 6 consecutive days of doses at 600 mg/day, it is adjudged possible to proceed to a Phase II study to evaluate the effectiveness, safety, and usefulness of the drug on rheumatoid arthritis.

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In order to investigate the effect of isosorbide 5mononitrate (5-ISMN) on exercise tolerance, a controlled study was carried out in 11 patients with effort angina pectoris. Multistage treadmill exercise testing was performed before, and 2, 4, and 7 hours after a single oral dose of placebo at 9: 30 to 10 o'clock in the morning. Two to seven days later, the test was again performed with the test drug (TY-10368) containing 20 mg of 5-ISMN according to the identical test protocol. It was terminated at moderate anginal pain.
Before administration, there were no significant differences in treadmill exercise duration, pressure-rate product (PRP), and ST deviation between TY-10368 and placebo.
At 2, 4, and 7 hours after the administration, the exercise duration was significantly longer after TY-10368 than after placebo (P<0.01).
At 2 hours after the administration, peak PRP was significantly greater after TY-10368 than after placebo (P<0.05). ST deviation at peak exercise showed no significant difference between TY-10368 and placebo. PRP and ST deviation at the same exercise time were significantly smaller or tended to be smaller after TY-10368 than placebo.
There was a significant linear correlation between plasma 5-ISMN concentration and Δ ExD (exercise duration after administration minus that before administration) (r=0.42, P<0.05).
At 7 hours after a single oral administration of TY-10368, the mean plasma level of 5-ISMN was sustained above 200 ng/ml, which was regarded as the minimum effective plasma concentration of the compound for effort angina in the present study.
These results showed that TY-10368 significantly increased exercise tolerance in patients with effort angina pectoris even at 7 hours after a single oral dose, and was considered to be a clinically useful oral antianginal agent.

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