The metabolic fate and pituitary-adrenal cortex-supressibility of two injectable dexamethasone esters, 21-phosphate and 21-sulfate, were studied in ten healthy men. After i. v. injection in a dose of 20 mg free steroid alcohol, dexamethasone phosphate was efficiently hydrolyzed to free dexamethasone, reaching its peak plasma concentration within 5 minutes. 20-Dihydrodexamethasone, a metabolite of dexamethasone, reached its peak plasma concentration 2 hours after injection. About 6% of administered dose appeared in 24 hours urine as free dexamethasone. By contrast, virtually no free dexamethasone and 20-dihydrodexamethasone were found in plasma and urine after dexamethasone sulfate injection. Pharmacokinetic analysis showed that dexamethasone sulfate had shorter plasma half-life and greater metabolic clearance rate than did free dexamethasone. A large fraction (63%) of dexamethasone sulfate was quickly excreted unmetabolized in urine.
Plasma cortisol level was significantly supressed over 24 hours after dexamethasone phosphate, while the plasma cortisol profile after dexamethasone sulfate showed mere physiological circadian variations. When the steroid esters were injected after pretreatment with metyrapone, a definite supression of plasma ACTH was noted after dexamethasone phosphate. Here again, dexamethasone sulfate was ineffective.
The results cast a serious doubt on the clinical value of dexamethasone sulfate as an injectable glucocorticoid, and critical reevaluation on this preparation is needed.

View full abstract

Effects of 5-fluorouracil (5-FU), 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and 1-(n-hexylcarbamoyl)-5-fluorouracil (HCFU) on drug-metabolizing enzyme activities were studied with liver microsomes from male and female mice. Body and liver weights decreased significantly in male mice treated with 5-FU but not in FT-207-and HCFU-administered male mice. Contents of liver microsomal protein increased slightly in 5-FU-, HCFU-and FT-207-treated female mice and significantly diminished in HCFU-treated male mice. Serum GPT activities in these treated male mice remained unchanged. Cytochrome P-450 contents in 5-FU-and FT-207-treated mice of both sexes significantly increased, and aniline hydroxylase activities were slightly elevated in 5-FU-treated male mice, while they were significantly elevated in FT-207-treated female mice. A rise of aminopyrine Ndemethylase activities were found significantly in FT-207-treated female mice and slightly in 5-FU-and HCFU-treated female mice. The effect of FT-207 treatment on drug-metabolizing enzyme activities were generally greater in females than in males.
These observations indicate that these anticancer drugs may alter the biological activity of many other drugs which will be administered simultaneously.

View full abstract

Arteparon contains 50 mg mucopolysaccharide polysulfuric acid esters (MPS-L), i. e. polysulfuric acid esters of chondroitin sulfate extracted from bovine lung. Experimental and clinical studies suggest that the use of intra-articular injections of arteparon is effective in the treatment of osteoarthrosis. However, no doubleblind controlled studies have been performed yet. This report presents the results of a double-blind comparative study of intra-articular injection of arteparon in osteoarthrosis of the knee which was carried out in 26 orthopaedic clinics throughout Japan. A total of 120 patients were divided into groups ; One treated with 1 mg MPS-L (control group) and the other with 50 mg MPS-L (drug group). Five or more injections (average 9.3) were given at about weekly intervals (average 8.2 days). Score derived from knee scoring scale improved significantly in both groups, either after the 5 th and the 10 th injections. Score improved after the 10 th injection in drug group was statistically superior than that in the control (P<0.05), however, the difference in the two after the 5 th injection did not reach a level of any statistical significance. Doctors' assessment of the usefulness of the drug based on the balance of effects and side effects was obtained in 71.2% and 41.1% in drug group and the control, respectively. The difference was significant statistically (P<0.01). In conclusion, this study confirmed that intra-articular injection of 50 mg MPS-L was useful for osteoarthrosis of the knee although the clinical symptoms were improved gradually following the injections.

View full abstract

The drug arteparon (mucopolysaccharide polysulfuric acid esters) was developed in West Germany and its effects have been reported by Dettmer, Greiling, Greiling and Stuhlsatz, Platt, and Binzus and Holzer. To test this drug, a double-blind clinical study was conducted by authors using saline as the control (placebo). Although a total of 72 patients were studied, an evaluation of the effects was made on 27 patients in the arteparon group and on 31 patients in the placebo group.It was found that the arteparon group was significantly superior to the placebo group-in terms of total effectiveness and usefulness. Arteparon was more effective than the placebo especially for the alleviation of pain specific to arthropathy of the knee. However, no other significant difference between either group was observed regarding other symptoms. Although the only drug now available for intraarticular injection for arthrosis deformans of the knee is adrenocortical hormones, this hormone causes serious adverse reactions. This study indicates that arteparon can be a useful drug for the treatment of arthropathy of the knee.

View full abstract

In double blind tests, the results are usually expressed qualitively by physician's judgements. In order to express those results quantitatively and to avoid the personal deviation between physicians, the rate coefficient “b” is proposed under the assumption of exponential transition of clinical measurements, e. g., GOT, GPT, and etc. It is confirmed that “b” is distributed normally and its standard deviations are the same in tiopronin-group and placebo-group.Using “b”, tiopronin is judged significantly useful for outpatients, but not so useful for inpatients and the method for usefulness-judgement of drugs on Chronic Aggressive Hepatitis are proposed. These methods are checked by the data of previous double-blind test and its validity is recognized.

View full abstract

This study was carried out to investigate effects of trapidil on subjective symptoms, electrocardiograms and, especially, exercise tolerance of patients with angina pectoris. The material consisted of 8 male patients with angina of effort, aged from 46 to 73 years. Trapidil was administered in a dose of 100 mg, 3 times, namely, after each meal, daily for 2 to 13 weeks. The multistage treadmill exercise tests based on modified Bruce's protocol was performed before and after trapidil. The end-point of exercise was anginal pain. Beneficial effects on anginal attack, exercise-induced ST-T changes and exercise tolerance were obtained in 75.0%, 71.4% and 28.6% of the material, respectively. The duration of exercise after trapidil (mean value: 5.21 min.) was significantly (P<0.05) increased as compared with that before trapidil (mean value: 6.14 min.). No significant changes were observed in heart rates, arterial blood pressures and pressure rate products when those values before, during and after exercise were compared. Noside effects occurred in all cases. It was concluded that trapidil was effective inthe treatment of angina pectoris.

View full abstract

The diuretic effect and safety of piretanide injection were compared with that of furosemide injection in 66 patients with liver cirrhosis and 8 with other disease by means of a double blind intergroup comparison. The following conclusions were obtained.
1) No significant differences were observed in the degree of general improvement and usefulness in liver cirrhosis between the two groups, nor were there any significant differences between the two groups when all 74 cases were evaluated.
2) 0-4 Hour urine volume and urinary excretion of Na⁺ and Cl^- in the piretanide group showed significantly larger increases than the furosemide group.However there was no significant difference in the increase of K⁺ excretion.
3) Uric acid excretion on the 2nd day of treatment period and total uric acid excretion during the 3 days of the treatment period were both signicicantly larger in the piretanide group than in the furosemide group.

View full abstract

The authors have predicted the clinical effects of some anxiolytic drugs by analyses of changes in the averaged photopalpebral reflex (PPR) observed in healthy human adults administered these drugs. In the present study, effects of a new benzodiazepine derivative, ID-622, which possess a potent antagonistic action to pentetrazol-induced convulsions in mice, on PPR were investigated in 8 normal male subjects aged 32-45 years. One mg and 2mg of ID-662, 5 mg of diazepam and inert placebo were given to the subject 30 min after the lunch in a double-blind, cross-over design. PPR was recorded bipolarly from the electrodes placed on the right upper and lower palpebrae before and 0.5, 1, 1.5, 2, 3, 4 hr after drug ad-ministration. Two latencies, i. e., P₁ and P₂ latencies, and the amplitude of PPR were measured. They were also requested to fulfil the questionnaire for self-as-sessments of drug effects. Diazepam 5mg, ID-622 1mg and 2mg statistically significantly prolonged both the latencies as compared with placebo but failed to exhibit the significant alteration on the amplitude. Statistically significant pro-longations of P₁ and P₂ latencies were observed by diazepam 5 mg as compared with both doses of ID-622. All the subjective symptoms were slight, however, among them the drowsiness and vagueness induced by diazepam 5 mg were rela- tively potent. These results suggest that ID-622 possess an anxiolytic action, however, 5 mg of diazepam seems to be more potent than the used doses of ID-622 and it is considered to be not always suitable to determine the equipotent dose based on the anti-pentetrazol action in mice alone.

View full abstract

The efficacy, safety and utility of afloqualone on spastic paralysis were evalu-ated in comparison with tolperisone hydrochloride by a multi-center double-blind study in which 29 institutions participated throughout the country.
Afloqualone was given in a dose of 20 mg three times a day and tolperisone in a dose of 100 mg three times a day. A total number of 187 patients with cerebral and spinal spastic paralysis were treated with either drug for 4 weeks. Of them, 80 cases treated with afloqualone and 83 cases with tolperisone were evaluable for group comparison, totalling 163 cases, and 24 caseswere excluded from evaluation.
The drug efficacy was assessed both from neurological signs (neurological tests) and improvement in subjective symptoms before the start of and after 4 weeks of treatment. Overall safety rating (OSR) was judged on the basis of side effects and values of laboratory tests. Global utility rating (GUR) was evaluated by weighing both FGIR (final global improvement rating) and OSR. The results obtained were as follows:
1. There were no significant differences in background factors of patients.
2. Afloqualone was significantly superior to tolperisone HCl in terms of GUR and global improvement rating of subjective symptoms ata significant level of 5% as well as in FGIR and global improvement rating of neurological signs at a signi-ficant level of 10%.
3. By individual symptoms, improvements of “knee jerk reflex (2W) ”, “Achilles tendon reflex (2W & 4W) ”, “pathological reflex of lower extremities (4W) ”, and “gait (4W) ” were significantly better in afloqualone group than in tolperisone group at a significant level of 5%, and afloqualone was also significantly super-ior to tolperisone HCl at a significant level of 10% in improving “knee jerk reflex (4W) ”, “clonus in sitting position (2W) ” and “stiffness at exercise”.
4. Statistical analysis on stratified items of GUR showed significant differences in favour of afloqualone in the items of “cerebral” ofdiagnosis, “yes” of complications, “incomplete” of the degree of paralysis, “no” of previous drug therapy, “no” of past operation, “yes” of concomitant drugs, “no” of concomitant physical therapy, “more than 3 years” in the duration of illness, and “slight” in the degree of spastisity on passive movement. Multiple regression analysis revealed that the responsible factor for significant differences was only the test drugs of afloqualone and tolperisone HCl.
5. Side effects occurred in 18 cases of afloqualone group (23%) and in 22 cases of tolperisone group (27%). No serious adverse reaction was noted in both groups, but 5 cases of tolperisone group had to be discontinued treatment because of side effects. Laboratory tests disclosed no abnormal findings in either group.
The results obtained showed that afloqualone was a useful drug for the treatment of cerebral and spinal spastic paralysis.

View full abstract

The clinical effect of afloqualone (HQ-495) was evaluated by a double blind trial in comparison with tolperisone HCI in 79 patients with low back pain and 68 patients with neck-arm-shoulder syndrome. Afloqualone was given in a daily dose of 60 mg to 77 patients and tolperisone HCl in a daily dose of 300 mg to 70 patients, both divided into 3 doses, for a period of 2 weeks. The following results were obtained.
1) Among the patients who participated in the clinical trial, 71 cases treated with afloqualone and 66 cases treated with tolperisone HCl were evaluable for group comparison.
2) There were noted no significant differences in the backgrouds of patients between the two patient groups.
3) The rate of global improvement both in subjective and objective symptoms was 76.1% with afloqualone and 68.2% with tolperisone HCl. The difference in the rate of global improvement between the two drugs was not statistically significant, but the former seemed to be superior to the latter. There was noted almost no difference in improvement between low back pain and neck-arm-shoulder syndrome.
4) Adverse side-effects such as gastrointestinal disturbances occurred in 11 cases (14.1%) treated with afloqualone and 13 cases (17.6%) treated with tolperisone HCl. Laboratory examinations revealed no abnormal findings indicative of clinical significance.
5) The rate of usefulness which was assessed both from global improvement and adverse side-effects was 66.2% with afloqualone and 62.9% with tolperisone HCl. There was no statistically significant difference between the two drugs.
The results obtained suggested that afloqualone is equal to or otherwise superior to tolperisone HCl in the treatment of low back pain and neck-arm-shoulder syndrome.

View full abstract