1.A double bind group comparison study to ascertain the efficacy of piroxicam in the treatment of cervicobrachial syndrome and periathritis scapulohumeralis was conducted with indomethacin as control. Dosages used in the study were as follows: Piroxicam-20 mg once a day after supper. Indomethacin 75 mg a day, divided in to three doses to be taken after each meal.
Both drugs were administered daily for 14 consecutive days.
2. Total number of patients involved in the study was 313; those subjected to the analyses were 295 of which 149 were diagnosed as cervicobrachial syndrome (in the broad sense of the term) and 146 as stiff shoulder.
3. As for the background factors; very little differences were noted between both drugs as to their relations with other factors such as contraction period and seriousness of the ailment, although significant differences were found in both drugs in sex distinction for patients suffering from both ailments combined as well as those from periarthritis scapulohumeralis, and in ages for cervicobrachial syndrome. However, significant differences were not noted in either sex or age distinction analysis in the final stage of general improvement.
4. No significant difference was seen in both drugs in the final state of general improvement for cases of both ailments combined and for individual groups of cervicobrachial syndrome and periarthritis scapulohumeralis.
5. Occurrence rates of side effects were 14.3% for piroxicam administered group and 18.2% for the indomethacin group.Results of clinical and other tests indicated that piroxicam was safer than indomethacin.
6. On the basis of above mentioned facts, piroxicam was judged as being more effective in the treatment of the ailments associated with cervicobrachial syndrome and stiff shoulder, if dosage of 20 mg is administered once a day.

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The effect of azelastine, a new anti-allergic agent which possesses a variety of anti-allergic effects in addition to its H₁-blocking action, on the central nervous system was studied by observing the changes in EEG and behavioral state in unanesthetized rats. Certain H1-receptor antagonists such as promethazine, diphenhydramine, and homochlorcyclizine induced the drowsy pattern in EEGs at doses less than 5mg/kg. The pattern is characterized by high voltage and slow waves and is not interrupted by auditory stimulation. At 5mg/kg both promethazine and diphenhydramine blocked the EEG arousal response induced by electrical stimulation of the midbrain reticular formation (0.5 msec, 4V, 100 Hz for 5 sec). Diphenhydramine also diminished the photic driving responses significantly. Even at 10mg/kg (iv), azelastine had little EEG effect and did not prevent the EEG arousal responses provoked by both auditory and reticular stimulations. Further, the photic driving response was not inhibited at all by the same dosage of azelastine.

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Haemodynamic studies (using radiocardiography) were carried out in outpatients with essential hypertension, namely in 12 cases (av. 52 yrs) taking metolazone, in 15 patients (av. 41 yrs) taking trichlormethiazide and in 5 patients (av. 50 yrs) taking mefruside. After short-term (av. 6.7 wks) metolazone therapy, there were a significant decrease in mean blood pressure (MBP) (from 129±4 mmHg to 108 ±3mmHg, P<0.005), and a significant reduction in cardiac output (CI) (from 3.79±0.20 1/mm/m² to 3.33±0.24 1/min/m², P<0.05) without any change in total peripheral resistance index (TPRI). Short-term (av. 7.9 wks) trichlormethiazide treatement and short-term (av. 4.8 wks) mefruside treatment reduced MBP (trichlormethiazide, from 124±4 mmHg to 111±3 mmHg, P<0.005 ; mefruside, from 119±7 mmHg to 110±4 mmHg, ns). Both of these drugs induced similar haemodynamic changes to those observed with metolazone ; CI fell from 4.21±0.29 1/min/m² to 3.99±0.32 1/min/m² in the trichlormethiazide-treated group, and fell from 3.95±0.39 1/min/m² to 3.56±0.25 1/min/m2 in the mefruside-treated group, however, these changes were not significant.
In the long-term (av. 28.5 wks) metolazone therapy MBP fell from 130±4 to 101±3 mmHg (P<0.005), and CI fell from 3.74±0.22 1/min/m2 to 3.23±0.21 1/min/m² (P<0.05) as observed in the short-term metolazone therapy, while TPRI tended to decrease from 2, 858±197 dyne·sec·cm^-5·m² to 2, 573±158 dyne·sec·cm^-5Em² (ns).
Reduced cardiac output in the short-term metolazone therapy can be postulated to be due to reduced ECF and reauced venous return. However, many observations in the thiazide therapy indicate that cardiac output tended to return to the pretreatment values during continued treatment.
A possible mechanism of reduced CI in the long-term metolazone therapy may be partially attributed to a decrease in cardiopulmonary blood volume (CPBV), which may reflect venous return to the heart. Another mechansim seemed to be partially due to a decrease in CI/CPBV, while the decreases in the short- and long-term metolazone therapy were not so much those in the intravenous propranolol (0.4 mg/kg) and in the oral propranolol therapy.

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Flunitrazepam is a benzodiazepine drug which was developed by Hoffmann-La Roche & Co., Ltd. It has been shown that this drug not only produces hypnotic, sedative and muscle-relaxant effects but also potentiates analgesic agents. When flunitrazepam is administered intravenously in a dose of 1 to 2 mg as premedican or for the purpose of induction of anesthesia or sedation under local analgesia, sleep is induced in 1 to 2 minutes, and its effect continues for 20 to 40 minutes.
Clinical trials with flunitrazepam were carried out in 10 medical institutions in Japan in order to evaluate the usefulness of this drug in anesthesiological service and to establish the optimum clinical dosage and check for adverse reactions.
As a result, it has been revealed that this drug causes little vascular pain, induces sleep quick and does not disturb normal awakening. The results of the clinical trials suggest that the appropriate human doses of flunitrazepam for these purposes range from 0.015 to 0.03mg/kg.

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Based upon our preceeding studies which indicated the usefulness of oral administration of 5-fluorouracil, we studied on the anticancer efficacy and the toxicity of this particular usage, especially in the situation of long-term daily-dose schdule. This study is consisted of the animal experiments and the clinical trial for advanced breast cancer.
In the animal experiment, DMBA induced mammary tumor bearing S-D rats were used to assess the anti-tumor efficacy. The drug administration was made either through gastric catheter or through caudal vein. The obtained results were as follows:
1. Young S-D rats well tolerated daily oral dose 20mg/kg/day of 5-fluorouracil longer than 400 days. The body weight growth curve of this group of rat was not so much suppressed, comparing with that of control group.Among the rats which were given same dosage through intravenous route, marked growth suppression was observed.
2. The size of DMBA mammary tumors showed significant range of shrinkage, after 30 days of oral administration of 20mg/kg/day of 5-fluorouracil, comparing with that of non-treated group of DMBA tumor bearing rat.
3. There were no differences of drug distributions to the DMBA tumors between oral administration group and intravenous administration group.
4. The response rate (UICC, 1971) among the patients with advanced breast 38%. As to the side-effects in this schedule, nausea and anorexia were the common limiting factors, but the majority of the patients well tolerated more than 6 months of medication. Myelosuppression encountered during this trial were easily controlable. Neither hepatic nor renal impairment was experienced.

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A potent anti-cancer agent, 5-flurouracil has been generally given through parenteral routes. In the clinical practice of cancer chemotherapy, many cases are actually considered to be suitable as candidates of oral administration of this particular drug. To solve this practical problem, we studied on the absorption and the organ distribution of this agent, using S-D rats, comparing the two administration methods, namely oral and intravenous administration. Also, pharmacokinetic studies were performed on two patients with advanced breast cancer, to evaluate the above-mentioned two administration routes.
The rats were sacrificed 0.5, 1, 2, 4, 6 and 8 hours after oral or intravenous administration of 768×10^-6 mol of 5-fluorouracil or 5-fluorouridylic acid, to obtain organ tissue homogenates. The bioassay technique using staphylococcus aureus 209-p was employed to know the drug concentration levels. The following results were obtained:
1. Both intravenous and oral administration of 5-fluorouracil produced almost same level of organ distribution curve, except the mucous membrane of the stomach which showed markedly high level of the drug concentration approximately 12 hours following the oral administration.
2. The oral administration of 5-fluorouridylic acid showed extremely low organ distribution curve, comparing its intravenous administration.
3. Pharmacokinetic data obtained from the two volunteer patients showed significantly high bioavailability after the oral administration of 5-fiuorouracil, in comparison with the intravenous administration.

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The bioassay of 5-fluorouracil is an useful technique to obtain pharmacokinetic data in order to establish reasonable administration schedules of this particular drug. However, the growth-inhibition circle which is produced by this agent on the agar plate in this method has not been proved to be invited by whether solely original agent itself or together with some active metabolite of the drug.
We studied on this subject, employing an unique technique, the combination of paper-chromatography and bioassay, using the tissue homogenate from S-D rats. The following results were obtained:
1. Three biologically active substances which were designated “A”, “B” and “C” respectively contributed to produce bacterial growth inhibition circle on the agar plate.
2. These three substances were proved to be originated from administered 5-fluorouracil.
3. These substances were purified and were chemically identified that “A” is 5-fluorouracil, “B” is 5-fluorouridine, “C” is 5-fluorouridylic acid and 5-fluorouridine dishosphate.

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The phase one study was performed by the use of the single and multiple intravenous administration of newly developed synthetic antithrombin agent: (2 R, 4 R)-4-methyl-l- [N²- [(3-methyl-1, 2, 3, 4-tetrahydro-8-quinolinesulfonyl)-Larginyl] -2-piperidinecarboxylic acid monohydrate; MD-805]
As a single administration study, each one of groups consisting of six healthy volunteers was injected with one of 2.25mg, 4.5mg and 9mg of this agent by drip intravenous infusion taking 30 minutes and as a multiple administration study, 5 volunteers were injected with 9mg of the agent intravenously in three hours once a day for three days.
The clinicopharmacological reactions of this agent were evaluated with many parameter tests and clinical manifestations.
The evaluation from clinical symptom after the administration of this agent revealed no abnormality without spontaneous bleeding. However, the prolonga-tion of thrombin time, PTT and prothrombin time and the defect of platelet aggregation induced by thrombin were observed. These findings might be caused by main pharmacological action of this antithrombin agent.
On the other parameter tests, serum LDH level was slightly decreased on the cases of both single and multiple administration of this agent and A/G ratio was increased within normal range on single administration with this agent. All others of the safety parameters were within permitable changes in the clinical point of view.
On the basis of these results, we concluded that this agent can be applicable for phase two study.

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The effects of Lisuride hydrogen maleate (Eunal®, hereinafter called Lisuride) on EEG in patients with cerebral vascular impairments and mild senile dementia were studied by double blind technique using placebo as reference. The duration of treatment was at least 12 weeks or 16 weeks as far as possible. This study was conducted at 15 hospitals throughout Japan. All the EEG were read by EEG specialists. Cinnarizine was given to both groups as a basic drug.
1) Patients whose EEG was subjected to statistical analysis in Lisuride group (hereinafter called E group) and placebo group (hereinafter called P group) numbered 62 and 63, respectively. These patients demonstrated no significant difference in terms of background factors and EEG findings before treatment.
2) The global improvement rates of EEG at 12 weeks were 51% in E group and 39 % in P group, and aggravation rates were 12 % and 28 % respectively. Thus E group tended to be superior to P group.The improvement rates in local wave at 8 weeks were significantly (P<0.05) better in E group.
3) In E group, localized θ wave significantly (P<0.01) decreased at 8 weeks, α wave tended to be increased (P<0.10) at 12 weeks and dominant wave (α wave) was significantly larger than that in P group at 12 weeks.
4) With cerebral arteriosclerosis and cerebral infarction cumulated as ischemic cerebral disease, the improvement rates of EEG in E group was significantly (P<0.05) better at 12 weeks and the improvement rates of local wave also showed significant difference from that of P group.
5) In E group, the cases of a relatively long period of affection being more than 2 years and of the symptoms being stabilized showed good results in respects to global EEG improvement rates, improvement rates of local wave, etc. at 8, 12 and 16 weeks.
6) No significant correlation was observed between improvement of dementia test and EEG improvements.
7) By stochastically examining the various EEG factors which are associated with EEG improvements, the effects on the evaluation of the various factors which could be collectively considered unconsciously upon reading of EEG could be mathematically pointed out.
8) Incidence of side effects was 8.8 % in E group and 8.5% in P group.The side effects observed were all mild. The various clinical laboratory tests determined were within the normal range.
It is concluded from the above results that Lisuride is a useful and safe drug which enables to improve EEG in patients with cerebral vascular impairments and mild senile dementia.

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