悦明 熊本’s scientific contributions

ビカルタミド1日1回50mg群,80mg及び100mgを12週間投与する3群比較の無作為化非盲検試験を実施した. 1)登録症例は124例で,適格例は122例であった. 2)総合効果における奏効率は50mg群,80mg群及び100mg群でそれぞれ50.5%, 61.0%及び53.7%であった. 3)PSAに対する奏効率は50mg群,80mg群及び100mg群でそれぞれ84.2%, 92.7%及び97.6%であった. 4)副作用発現率は3群ほぼ6割で副作用による中止例は80mg群の1例のみで,安全度において3群間に有意差はなかった.主な副作用は乳房腫脹,乳房圧痛等であった To investigate the efficacy and safety of bicalutamide (Casodex(R)) with its clinically recommended dose, the randomized early phase II study was performed in 124 patients with prostatic cancer (stage C, D). The patients were given 50, 80 or 100 mg of bicalutamide orally once a day in fixed doses for 12 weeks ; 122 patients were eligible for evaluation. The overall response rate was 50.0% (20/40); 61.0% (25/41) and 53.7% (22/41) in the 50 mg, 80 mg and 100 mg groups, respectively. The response rate in prostate lesion, bone and lymph node metastases was slightly higher in the 80 mg group than in the 50 mg and 100 mg groups. The proportion of patients showing a response with regard to serum PSA (CR and PR) was 84.2, 92.7 and 97.6% in the 50, 80 and 100 mg groups, respectively. The incidence of adverse reactions was 65.0, 61.0 and 61.0% in the 50, 80 and 100 mg groups, respectively, and there was no significant difference in overall safety rating in the three groups. Frequent adverse reactions were gynecomastia and breast pain. Only one patient in the 80 ing group was withdrawn due to shortness of breath. Serum concentrations of LH, testosterone and estradiol increased significantly after treatment. Bicalutamide was concluded to be effective and well tolerated in patients with prostatic cancer, and its recommended dose was 80 mg once daily.

Allylestrenol (ALE) and chlormadinone acetate (CMA) were administered to patients with prostatomegaly by the double-blind method, and the effects of these antiandrogens on their sexual function were objectively compared. Each agent was orally administered to 58 patients in a dosage of 50 mg/day for 12 consecutive weeks. For the objective evaluation of the sexual function, nocturnal penil tumescence (NPT) was measured using an erectometer. For the subjective evaluation the conventional interview method was employed. The levels of hormones relating to sexual function were also determined. A decrease in NPT was noted in both the ALE and CMA groups, but the degree of the decrease was significantly smaller in the ALE group than in the CMA group (p less than 0.001). The results of the interview, revealed a large between the two drug groups; in the CMA group, marked worsening for all items. In the determination of hormones, levels of luteinizing hormone, follicle stimulating hormone, testosterone and estradiol were decreased in both drug groups, while the prolactin level was increased in both groups. The changes in the testosterone, estradiol and prolactin levels in the CMA group were significantly dominant compared with those in the ALE group. In addition, drop-out cases due to a decrease in the sexual function numbered 7 (12.1%) in the CMA group, while there were no such drop-out cases in the ALE group; the difference in the drop-out rate was thus significant. In conclusion, ALE's effects on the sexual function were concluded to be smaller than those of CMA.

We have compared three treatments of congenital adrenal hyperplasia (CAH) for their effect on physical development. Thirteen girls and two boys with CAH due to 21-hydroxylase deficiency were treated with three different treatments, hydrocortisone (HC), dexamethasone (DXM) and cyproterone acetate (CA). The results showed that height growth was better with HC and CA than DXM, and bone excessive maturation was more suppressed with DXM and CA than HC. A dose-dependent relationship was revealed between body weight and dose of HC. Iatrogenic obesity was found in 42.9% and 38.1% of the patients treated with DXM and HC, but none of the patients treated with CA did became obese. Physical growth was better with CA treatment than HC or DXM treatment, but CA may have a suppressive effect on the pituitary-adrenal axis observed carefully, especially on prepubertal and pubertal cases.

We investigated how histopathological features, such as structural atypism (SAT), nuclear anaplasia (NAN) and Gleason's pattern, influence the prognosis of patients receiving endocrine therapy. Patients with SAT 3 or NAN 3 clearly had a lower survival rate and a shorter survival period than those with other grades of SAT or NAN and this tendency was more prominent in the high stage than low stage. Patients with a higher grade of SAT or NAN had a poorer prognosis as well, when only cancer-related death was considered in the calculation of survival and survival period. The results described above suggest that the grade of SAT and NAN is one of most influential factors for prognosis. In the analysis for the prognosis of patients according to grade of mean value of SAT + NAN, there were differences in prognosis among mean value of SAT + NAN 2-4, 5 and 6. This indicated that the combined grading system would provide more information to the prediction of prognosis. Patients with Gleason's primary (or secondary) pattern 1 and 2, or 3 and 4 had a better survival than those with pattern 5 in the analysis when only cancer-related death was considered. This was coincident with the result that the survival rate for each Gleason's sum 2-3, 4-5, 6, 7-8 and 9-10 was different. Consequently, Gleason's pattern influenced the rate of cancer-related deaths, and this pattern may be another important factor for predicting the prognosis.

The enzyme assay for acid phosphatase and even for L-tartrate labile acid phosphatase is not specific for that of the prostate origin. The radioimmunoassay has recently been developed to detect the enzyme more specific to the prostate. We carried out the investigations of the fundamental characters and clinical usefulness in three commercial kits (Eiken's kit, Clinical Assays' kit and Mallinckrodt's kit). The results were as followed. 1) The reproducibility of their standard curves using three kits showed the satisfactory results with the straight lines in them. Coefficients of variation within assay was minimum among three kits (2.1%-14.5%). Coefficient between assays was also minimum in them (6.2-14.3%). The dilution tests in them were satisfactory. The recovery tests in three kits revealed the recovered rate to be almost 100%. These results in this fundamental study showed that three kits were useful in clinical practice. 2) The correlation III three kits was investigated by the measurement of Eiken's standard sera with Clinical Assays' and Mallinckrodt's kit. This showed the good correlation in each instance. For the further investigation of their correlation, 41 samples which were below 3.0 ng/ml in Eiken's kit, were measured by Clinical Assays' and Mallinckrodt's kit. This, however, did not reveal the good correlation each other. While, comparing the ratio of samples within normal range in three kits, no significant difference was observed. With the same comparison between Eiken's 'and Clinical Assays' kit, and between Eiken's and Mallinckrodt's kit, these ratios were almost identical in the samples with B.P.H. and non-prostatic diseases. These results have led us to the conclusion that the low degree of correlation in low concentration samples in three kits have not always produced the serious problems in the clinical practice. Of course, the further fundamental investigations will be necessary in the selection of PAP sources and methods of PAP purification, which may be related to the differences of PAP level in three kits. 3) The correlation of PAP level measured by the radioimmunoassay and that by the enzyme assay was good on the whole (Eiken's kit: r=0.69, Clinical Assays' kit: r=0.85 and Mallinckrodt's kit: r=0.71), while this was not true in the low concentration samples. 4) PAP was measured by three kits in 427 samples from normal male and female adults, and those with various urological diseases (190 cases in Eiken's kit, 141 cases in Clinical Assays' kit and 96 cases in Mallinckrodt's kit). The normal values in each kit were determined as below 2.5 ng/ml in Eiken's kit, below 2.0 ng/ml in Clinical Assays' kit and 2.2 ng/ml in Mallinckrodt's kit. From the clinical point of view, PAP level below 2.5 to 3.0 ng/ml may be suitable for the normal value in three kits. 5) Other than the patients with prostatic carcinoma, there were three with B.P.H. whose PAP rose above the normal level in Eiken's kit. In Clinical Assays' kit such patients were observed in two with B.P.H. and one with nonprostatic diseases. There was only one patients with B.P.H. whose PAP rose above the normal level in Mallinckrodt's kit. In prostatic carcinoma, the positive rate of PAP were 28.6%, 37.5% and 84.2% in stage A+B, C and D, respectively in Eiken's kit; 10%, 45.5% and 81.3% in Clinical Assays' kit; 42.9%, 37.5% and 100% in Mallinckrodt's kit. The positive rate of PAP in relation to clinical stage could not be compared each other in three kits because these patients were not identical. Adding up the samples of all the tests the positive rate was 22.6% in stage A+B, 37.1 % in C and 85.4% in D. This value of stage A+B seems to be low. 6) The sensitivity and the specificity were 53.3% and 100%, respectively in PAP-RIA. In TAP-Enzyme assay these were 35.5% and 94.9%, respectively, in PAP-Enzyme assay the sensitivity was 48.6% and the specificity 75.9%. These results have led us to the conclusion that the radioimmunoassay for PAP has given more accurate information in clinical practice than the enzyme assay has done. Because of some advantage in the enzyme assay, however, the radioimmunoassay has been required to be further improved in its procedure. 7) The usefulness of radioimmunoassay for PAP in screening the patients with prostatic carcinoma in early stage has not been established. Our results agreed with this opinion. Not only more improvement of radioimmunoassay for PAP but also elucidation of the mechanism of PAP elevation in prostatic carcinoma will be necessary for the establishment of the clinical usefulness of PAP for screening of early prostatic cancer.

We studied the epidemiology of 109 cases of gonococcal infections (105 males with urethritis and 4 females with cervicitis), together with the basic and clinical effects of cefetamet pivoxil in the cases. The peak of age distribution of the male patients was in the younger half of their twenties, and all of the 4 female cases were between 20 and 39 years old. The major source of infections in the males younger than 25 years old was their girl friends or so-called pick-up friends, and that of the males older than 25 years old workers serving at an amusement center, for example, bars and so-called special massage parlor, which accounted for about three fourths of the male cases between 35 and 44 years old. The distribution of the MIC (inoculum size; 10(6) CFU/ml) of Cefetamet against beta-lactamase non penicillinase producing Neisseria gonorrhoeae (non-PPNG) ranged from 0.025 to 0.1 microgram/ml and that against beta-lactamase producing Neisseria gonorrhoeae ranged from 0.025 to 0.05 microgram/ml. The isolation rate of PPNG was 10.2% (9/88). In male patients with gonococcal urethritis, the efficacy rate was 100% on days 3 and 7 for 1,000 mg single dose and 7-day treatment and 500 mg single dose treatment. One of the cases treated with 250 mg single dose therapy was unchanged at 3, but the efficacy rate of the remaining cases was 100% at day 7. Complicated urethritis with C. trachomatis was noticed in 25.7% (5/105) of the male urethritis and in 25.0% (1/4) of the female cervicitis cases. The only side effect was diarrhea observed in 1 of the 124 case (0.8%).

A prostate mass screening was performed in 6 towns in Shiribeshi area in Hokkaido Prefecture on 384 males who were over 50 years old. The screening included digital palpation, uroflowmetry, blood sampling for tumor markers, questionnaire for voiding disturbances and transrectal sonography. Prostatic carcinoma was found in 9 (2.3%) of 384 males. An incidence of benign prostatic hypertrophy was 15.6% in 384 males. Atypical hyperplasia was found in 4 among 35 biopsied cases. Incidence of voiding disturbance such as retardation, prolongation and nocturia significantly increased with age as well as prostate size.

The criteria for clinical evaluation of the efficacy of antimicrobial agents on prostatitis were proposed. Nomenclatural definition, specifications of patients and criteria were as follows. Acute prostatitis: Target infection is acute bacterial prostatitis with no underlying condition in urinary tract. The findings of swelling and tenderness of prostate by rectal examination are essential. The patients are between 16 and 69 years old. They have fever greater than 37 degrees C and pain on micturition. Microscopic examination reveals white blood cells (WBCs) in VB1 or VB2 before treatment greater than or equal to 10 cells/hpf. Viable bacteria in VB1 or VB2 before treatment are greater than or equal to 10(4) bacteria/ml. Period of treatment is for 7 days. To evaluate clinical efficacy, 3 days after administration, changes of symptoms (fever and pain on micturition) are recorded. Seven days after administration, changes of symptoms, microscopic examinations and number of bacteria are recorded. The overall clinical efficacy is graded as "excellent", "moderate" or "poor" by combining changes in the above 3 parameters. Chronic prostatitis: Target infection is chronic bacterial prostatitis with no underlying condition in urinary tract. The patients are between 16 and 69 years old. Microscopic examination reveals WBC in EPS or VB3 before treatment greater than or equal to 10 cells/hpf. Viable bacteria before treatment are greater than or equal to 10(3)/ml (GNR) or greater than or equal to 10(4)/ml (GPC). Treatment period is for 14 days. To evaluate clinical efficacy, after 14 days of administration, changes of symptoms, microscopic examinations and number of bacteria are recorded. The overall clinical efficacy is graded as "excellent", "moderate", or "poor" by combining the changes in the 2 parameters, microscopic examination and number of bacteria.

女性急性単純性膀胱炎(AUC)の再発判定基準につき9種の経口抗菌薬(計270余症例)の治療後経過観察所見について臨床的に解析を加え,下記の基準決定案を作成した.1)対象患者:投薬前に急性単純性膀胱炎におけるUTI薬効評価基準の患者条件を満足し,規定された投薬期間投薬後に著効であった患者とする.2)投薬期間:薬効評価(3日分投薬)に使用した薬剤を同量で4日分追加し,計7日分とする.3)休薬期間:7日間とする.4)再発判定:膿尿および細菌尿を指標とし,膿尿10個/hpf未満かつ細菌尿104個/ml未満を再発なし,膿尿10個/hpf以上かつ細菌尿104個/ml以上を再発ありとし,それらの中間のものはどちらとも規定しない.5)再発判定時期:7日分投薬後著効であることを確認し,7日間の休薬後に判定する.ただし,休薬期間中に再発が認められる場合はその時点で判定する.6)採尿法:本判定にかかわる(すなわち7日分投薬終了時以降)尿検査は中間尿で行い,陽性所見が出ればカテーテル尿で再検査する.中間尿の採用方法は外陰部清拭(クロールヘキシジン綿)の通常の方法で行う The recurrence of female acute uncomplicated cystitis was investigated clinically. The criteria for the evaluation of recurrences were proposed, as follows; Patients: Target infection is acute uncomplicated cystitis (AUC) which had satisfied the specifications of AUC Criteria by the UTI Committee of Japan and showed the excellent effects of an antimicrobial agent after a definite period of administration. Treatment period: Seven days; after 3 days' administration to evaluate the drug efficacy, patients shall take an additional 4 days' treatment. Interval of follow up proposed was 7 days. Evaluation of recurrence: Parameters of criteria are pyuria and bacteriuria. Recurrence: Pyuria greater than or equal to 10 WBCs/hpf and bacteriuria greater than or equal to 10(4)/ml. Evaluation of the day of recurrence: Evaluation should be made 14 days after the start of treatment. Urine sampling: After 7 days of treatment, midstream urine is collected and in cases with positive findings, catheterized urine should then be collected. Using these criteria it will be possible to evaluate and compare the ability of various antimicrobial agents to cure acute uncomplicated cystitis.

TAP-144-SRの前立腺癌に対する比較対照試験をリン酸ジエチルスチルベストロールを対照薬として行った.有効性では,前立腺癌の判定基準の適格例で,TAP群54.5%(36/66),対照群47.1%(32/68)のPR例が得られ,両群間に有意差はみられなかった.病巣別効果や自他覚症状に対する効果でも両群間に差はみられなかった.PAPなど腫瘍マーカーに対して対照群の方が有意に優れる効果を示した.内分泌効果では両群とも全例で血清testosteroneがcastration levelに低下した.安全性については,副作用発現率はTAP群64.1%(41/64)に対し,対照群は95.4%(62/65)と有意に高く,対照群で4例が副作用のため試験が中止された.主治医判定による全般安全度では"問題あり"と判定された症例はTAP群6.3%(4/64),対照群36.9%(24/65)であった.主治医判定による有用度では"有用"以上でみると,TAP群65.6%(42/64),対照群52.3%(34/65)であった A randomized controlled phase III clinical trial comparing TAP-144-SR (TAP) and diethylstilbestrol diphosphate was conducted for patients with prostatic cancer. Patients with Stage B, C, or D disease, who were previously untreated, were enrolled. TAP-144-SR 3.75 mg was administered subcutaneously at 4-week intervals for 12 weeks (a total of 3 injections) in the TAP-144-SR group, while 100 mg of diethylstilbestrol diphosphate was administered orally three times a day (before meals) for 12 weeks in the control group. A total of 141 patients were enrolled using a centralized telephone registration system. Four of these patients were ineligible, and there were 3 drop-outs who never received drugs because they withdrew their consents to participate in the trial. These 7 were excluded from the evaluation, and as a result, 134 patients (66 in the TAP group and 68 in the control group) were evaluable in safety and efficacy. Between the two groups, there were no significant differences in patient characteristics, except the age distribution. Clinical response rates (CR+PR) in evaluable patients according to the criteria of Japanese Prostatic Cancer Study Group were 54.5% in the TAP group and 47.1% in the control group. In addition, the rates according to the criteria for Evaluating the Direct Response to Chemotherapy in Solid Carcinomas and NPCP criteria were 7.6% in the TAP group and 8.8% in the control group and 18.2% in the TAP group and 20.6% in the control group, respectively. Using any of the three criteria, there were no significant differences in response rate between the two groups. The incidence of side effects was 64.1% in the TAP group and 95.4% in the control group; the incidence being significantly higher in the control group (p less than 0.001; chi 2-test). Therefore, the overall safety was significantly greater in the TAP group than in the control group (p less than 0.001; chi 2-test). On the basis of the efficacy and safety the clinical usefulness rate of TAP-144-SR was significantly higher than that of diethylstilbestrol diphosphate (p = 0.038; U-test). In conclusion, TAP-144-SR was confirmed to be more useful than diethylstilbestrol diphosphate as a standard drug for hormonal therapy of prostatic cancer.