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1)登録症例は16例で, 全例が適格例であった. 2)副作用は16例中8例に認められたが, 軽度で, 臨床上特に問題はなかった.乳房圧痛, 乳房腫脹等の副作用が50mg群で1例, 80mg群で3例及び100mg群で2例に認められた. 3)有効性に関しては, 各投与群の1例ないし2例において, PR以上の抗腫瘍効果が認められた.又, 排尿困難, 排尿痛, 夜間頻尿の改善がみられた. 4)血清中ホルモンでは, LH, FSH, testosterone及びestradiol濃度の上昇が認められた, A phase I study (open trial) of bicalutamide (Casodex), a non-steroidal antiandrogen, was conducted on 16 patients with prostatic cancer (stage C to D). The patients were given 10, 30, 50, 80 or 100 mg of bicalutamide orally daily for 12 weeks. Adverse reactions were observed in 8 out of 16 patients, but almost all were mild. Breast pain, gynecomastia and hot flushes were observed in 6 patients. Adverse reactions regarding liver function tests were observed in 3 patients. These were increased glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), alkaliphosphatase (AL-P) or gamma guanosine 5'-triphosphate (gamma-GTP). However, during or after the treatment period the elevated values were reversed to the pretreatment level. In terms of efficacy, anti-tumor effect was observed in 1 or 2 patients at each dose. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and estradiol increased during treatment. Plasma concentrations of the R (-) enantiomer, which has antiandrogenic activity, reached the steady state 6-8 weeks after the initiation of treatment; its apparent plasma elimination half-life observed following repeated administration was 8.4 +/- 1.1 days. In conclusion, bicalutamide (10-100 mg od) is considered to be tolerated well enough to be administered to patients with prostatic cancer and has shown evidence of anti-tumor effect.

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.

前立腺肥大症患者を対象としてTZP-4238 (TZP群)の性的機能に対する影響および自覚的排尿障害に対する有効性, 安全性, 有用性を酢酸クロルマジノン(CMA群)を対照薬にして, 二重盲検法により検討した。その結果, 性機能に与える影響はTZP 1.25mg/日投与群は45.1%, CMA 50mg/日投与群は71.4%と有意にTZP群が少ないこと, しかも排尿障害への臨床効果はTZP群45.9%, CMA群50.0%とほぼ同等であるという成績をえている。また他の副作用についても両薬剤間に差は認められなかった, Using chlormadinone acetate (CMA) as the control drug, a double-blind study was carried out to examine not only the effects of 17 alpha-acetoxy-6-chloro-2-oxa-4, 6-pregnadiene-3, 20-dione (TZP-4238;) on subjective urinary symptoms but also, especially, that on the sexual function in patients with benign prostatic hypertrophy (BPH). The clinical efficacy rate in relation to the subjective urinary symptoms was about the same in the two treatment groups; 45.9% in the TZP-4238 group and 50.0% in the CMA group. However, the incidence of adverse effects on the sexual function showed a marked difference between the two groups. The TZP-4238 group revealed a lower suppressive effect on the function than the CMA group (45.1% vs. 71.4%). In relation to their causation of other adverse effects, there were no differences between the two drugs. Accordingly, in consideration of the facts that TZP-4238 with less influence on the sexual function affords a superior quality of life to elderly patients, while achieving effective treatment by means of a convenient single daily administration, TZP-4238 was surmised to be a more useful drug than CMA as an antiandrogen for the treatment of BPH.

1)内分泌療法未治療の前立腺癌症例に対し, 375mg/日の用量で単独療法として使用しえる。この際, testosterone産生阻害療法に比し, 「生活の質」が保たれる。2)内分泌療法再燃例に対しても, ある程度その効果が期待できる。3)フルタミドと他の精巣性testosterone阻害剤との併用で, その併用効果が期待できる。4)また, LH-RHアナログの投与によるflare-up現象をフルタミドを併用することにより予防することが可能である, The phase II study of flutamide, a pure anti-androgen, was performed to estimate the clinical doses on 165 hormone untreated or treated patients with prostatic cancer. The hormone-untreated patients were given orally flutamide of 90, 375, 750 or 1, 125 mg/day in three divided doses daily for 12 weeks. Responses were not observed at the 90 mg/day dose except for improvement of clinical symptoms. However, an objective response rate of 48.8-46.7% was obtained at 375-1, 125 mg/day doses. In hormone-treated patients including cases refractory to the previous hormonal treatment, the objective response rates were 13.3 and 8.3% in 375 and 750 mg/day flutamide groups, respectively. Side effects such as gynecomastia, nausea, vomiting, diarrhea, and abnormal laboratory findings such as the elevation of hepatic transaminases were observed. The incidence increased dose-dependently. Determinations of serum hormone levels revealed an increase in testosterone levels by the use of flutamide. In conclusion 375 mg/day of flutamide is the optimal dose in monotherapy for hormone-untreated patients with prostatic cancer, where the quality of life can be maintained compared with therapies involving testosterone suppression. This dose is also expected to show some efficacy in cases refractory to hormone treatment.

The effects on renal scarring of bacterial pili and superoxide released by polymorphonuclear leukocytes (PMN) were examined using a rat experimental pyelonephritis model. Bacteria which possessed mannose-sensitive (MS) pili were found to promote renal scarring following their direct inoculation into the renal parenchyma. Treatment with cyclophosphamide to induce leukopenia, colchicine to modulate PMN migration, and superoxide dismutase or an experimental antioxidant to reduce PMN superoxide release suppressed renal scarring following infection with MS-piliated bacteria. In contrast, treatment with phorbol myristate acetate significantly enhanced renal scarring. In addition, the production of superoxide by PMN was significantly greater following stimulation by MS-piliated bacteria than after stimulation with either non-piliated or MR-piliated strains. These findings suggest that MS-piliated bacteria stimulate renal scarring more markedly than do non-piliated or MR-piliated bacteria, and that superoxide released from PMNs plays an important role in the development of renal scarring following infection by MS-piliated strains.

CPRは1回0.5 gまたは1.0 gを, CAZは1回1.0 gを1日2回, 点滴静注により5日間連続投与し, 臨床効果はUTI薬効評価基準により評価した.総投与症例530例中効果判定が可能であった症例はCPR 1日1 g投与群141例, CPR 1日2 g投与群136例, CAZ 1日2 g投与群140例であった.CPRは複雑性尿路感染症に対してCAZと同様に有用性の高い薬剤である, We carried out a randomized multi-center study comparing cefpirome (CPR) 0.5 g b.i.d. (1 g group), 1.0 g b.i.d. (2 g group) and ceftazidime (CAZ) 1.0 g b.i.d. (CAZ group) in the treatment of complicated urinary tract infections. Patients who were over 16 years old and had underlying urinary tract disease, with bacteriuria of more than 10(4) cells ml or more and pyuria of more than 5 WBCs/hpf (x 400) or more were randomly allocated to receive either 0.5 g of CPR, 1.0 g of CPR or 1.0 g of CAZ twice a day for 5 days by intravenous drip infusion. The overall clinical efficacy of the treatment was evaluated by the criteria of the Japanese UTI Committee as excellent, moderate or poor, on the basis of the changes in pyuria and bacteriuria. A total of 530 patients were treated. Of these, 141 patients in the 1 g group, 136 in the 2 g group, and 140 in the CAZ group were evaluable for clinical efficacy. No significant differences in background characteristics were observed among the treatment groups. The overall clinical efficacy rate of the 1 g group, the 2 g group and the CAZ group was 80.1%, 76.5% and 71.4%, respectively. The differences were not statistically significant. The overall bacteriological eradication rate of the 1 g group, the 2 g group and the CAZ group was 81.0%, 88.1% and 83.8%. The differences were not statistically significant either. Against the enterococcus group, however, eradication rates were higher significantly in the 1 g and 2 g groups than in the CAZ group. The incidence of adverse reactions was 2.2% in the 1 g group, 0.6% in the 2 g group and 2.9% in the CAZ group. Abnormal laboratory data after medication were observed in 10.8% of the 1 g group, 12.1% of the 2 g group and 10.2% of the CAZ group, the difference not being statistically significant. There were no serious untoward reactions to medication. From the results obtained in this study, we consider that CPR is at least as useful as CAZ in the treatment of complicated urinary tract infections.

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.

Male Sprague-Dawley rats were intravenously injected with 6.5 mg/kg of cisplatin combined with a subcutaneous methylprednisolone (MP) injection to study the prophylactic effects of steroid hormone on cisplatin-induced nephrotoxicity. In Expt. 1, the rats were injected twice with either 10, 20 or 50 mg/kg of MP 4 and 0 h prior to the cisplatin injection and in Expt. 2, they were given a single injection of 100 mg/kg of MP either 24, 4, 2 or 0 h prior to the cisplatin injection. In Expt. 1, elevations of the BUN and serum creatinine levels caused by the cisplatin were dose-dependently inhibited by the administration of MP. In the second experiment, BUN and serum creatinine levels in rats which were pretreated with MP 4 or 2 h prior to the cisplatin injection were significantly lower than those in rats which received cisplatin alone. Our preliminary results suggest that pretreatment with MP is an effective means of protection against cisplatin-induced nephrotoxicity.

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.

A phase I study (open trial) of bicalutamide (Casodex), a non-steroidal antiandrogen, was conducted on 16 patients with prostatic cancer (stage C to D). The patients were given 10, 30, 50, 80 or 100 mg of bicalutamide orally daily for 12 weeks. Adverse reactions were observed in 8 out of 16 patients, but almost all were mild. Breast pain, gynecomastia and hot flushes were observed in 6 patients. Adverse reactions regarding liver function tests were observed in 3 patients. These were increased glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), alkaliphosphatase (AL-P) or gamma guanosine 5'-triphosphate (gamma-GTP). However, during or after the treatment period the elevated values were reversed to the pretreatment level. In terms of efficacy, anti-tumor effect was observed in 1 or 2 patients at each dose. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and estradiol increased during treatment. Plasma concentrations of the R (-) enantiomer, which has antiandrogenic activity, reached the steady state 6-8 weeks after the initiation of treatment; its apparent plasma elimination half-life observed following repeated administration was 8.4 +/- 1.1 days. In conclusion, bicalutamide (10-100 mg od) is considered to be tolerated well enough to be administered to patients with prostatic cancer and has shown evidence of anti-tumor effect.

Using chlormadinone acetate (CMA) as the control drug, a double-blind study was carried out to examine not only the effects of 17 alpha-acetoxy-6-chloro-2-oxa-4, 6-pregnadiene-3, 20-dione (TZP-4238;) on subjective urinary symptoms but also, especially, that on the sexual function in patients with benign prostatic hypertrophy (BPH). The clinical efficacy rate in relation to the subjective urinary symptoms was about the same in the two treatment groups; 45.9% in the TZP-4238 group and 50.0% in the CMA group. However, the incidence of adverse effects on the sexual function showed a marked difference between the two groups. The TZP-4238 group revealed a lower suppressive effect on the function than the CMA group (45.1% vs. 71.4%). In relation to their causation of other adverse effects, there were no differences between the two drugs. Accordingly, in consideration of the facts that TZP-4238 with less influence on the sexual function affords a superior quality of life to elderly patients, while achieving effective treatment by means of a convenient single daily administration, TZP-4238 was surmised to be a more useful drug than CMA as an antiandrogen for the treatment of BPH.

The phase II study of flutamide, a pure anti-androgen, was performed to estimate the clinical doses on 165 hormone untreated or treated patients with prostatic cancer. The hormone-untreated patients were given orally flutamide of 90, 375, 750 or 1, 125 mg/day in three divided doses daily for 12 weeks. Responses were not observed at the 90 mg/day dose except for improvement of clinical symptoms. However, an objective response rate of 48.8-46.7% was obtained at 375-1, 125 mg/day doses. In hormone-treated patients including cases refractory to the previous hormonal treatment, the objective response rates were 13.3 and 8.3% in 375 and 750 mg/day flutamide groups, respectively. Side effects such as gynecomastia, nausea, vomiting, diarrhea, and abnormal laboratory findings such as the elevation of hepatic transaminases were observed. The incidence increased dose-dependently. Determinations of serum hormone levels revealed an increase in testosterone levels by the use of flutamide. In conclusion 375 mg/day of flutamide is the optimal dose in monotherapy for hormone-untreated patients with prostatic cancer, where the quality of life can be maintained compared with therapies involving testosterone suppression. This dose is also expected to show some efficacy in cases refractory to hormone treatment.

We carried out a randomized multi-center study comparing cefpirome (CPR) 0.5 g b.i.d. (1 g group), 1.0 g b.i.d. (2 g group) and ceftazidime (CAZ) 1.0 g b.i.d. (CAZ group) in the treatment of complicated urinary tract infections. Patients who were over 16 years old and had underlying urinary tract disease, with bacteriuria of more than 10(4) cells ml or more and pyuria of more than 5 WBCs/hpf (x 400) or more were randomly allocated to receive either 0.5 g of CPR, 1.0 g of CPR or 1.0 g of CAZ twice a day for 5 days by intravenous drip infusion. The overall clinical efficacy of the treatment was evaluated by the criteria of the Japanese UTI Committee as excellent, moderate or poor, on the basis of the changes in pyuria and bacteriuria. A total of 530 patients were treated. Of these, 141 patients in the 1 g group, 136 in the 2 g group, and 140 in the CAZ group were evaluable for clinical efficacy. No significant differences in background characteristics were observed among the treatment groups. The overall clinical efficacy rate of the 1 g group, the 2 g group and the CAZ group was 80.1%, 76.5% and 71.4%, respectively. The differences were not statistically significant. The overall bacteriological eradication rate of the 1 g group, the 2 g group and the CAZ group was 81.0%, 88.1% and 83.8%. The differences were not statistically significant either. Against the enterococcus group, however, eradication rates were higher significantly in the 1 g and 2 g groups than in the CAZ group. The incidence of adverse reactions was 2.2% in the 1 g group, 0.6% in the 2 g group and 2.9% in the CAZ group. Abnormal laboratory data after medication were observed in 10.8% of the 1 g group, 12.1% of the 2 g group and 10.2% of the CAZ group, the difference not being statistically significant. There were no serious untoward reactions to medication. From the results obtained in this study, we consider that CPR is at least as useful as CAZ in the treatment of complicated urinary tract infection

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 TA