Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.

This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site-specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective.

Prostatic penetration of meropenem in humans, and dosage considerations for prostatitis based on a site-specific pharmacokinetic/pharmacodynamic evaluation.

The aims of this study were to investigate the penetration of meropenem (MER) into human prostate tissue and to assess MER regimens for prostatitis by performing a site-specific pharmacokinetic/pharmacodynamic evaluation. Patients with prostatic hypertrophy (n=49) prophylactically received a 0.5-h infusion of MER (250 mg or 500 mg) before transurethral resection of the prostate. MER concentrations in plasma (0.5-5h) and prostate tissue (0.5-1.5h) were measured chromatographically. Concentration data were analysed pharmacokinetically with a three-compartment model and were used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24h) in prostate tissue, an indicator for antibacterial effects at the site of action. The prostate tissue/plasma ratio was 16.6% for the maximum drug concentration and 17.7% for the area under the drug concentration-time curve, irrespective of the dose. Against MIC distributions for clinical isolates of Escherichia coli, Klebsiella spp. and Proteus spp., 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue. However, against the Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability of attaining the bacteriostatic or bactericidal targets.

Intravesical administration of pirarubicin against superficial bladder cancer: Relationship between tumor tissue concentration and exposure time in the bladder or therapeutic effect.

The aim of this study was to investigate the relationship between tissue concentrations and exposure times or therapeutic effect of an anthracycline anticancer drug, pirarubicin, in bladder cancer tissue after single intravesical administration against superficial bladder cancer. The concentrations of pirarubicin in tumor tissues and serum were measured at designated collection times after a single intravesical administration of pirarubicin (30 mg) in 22 patients with superficial bladder cancer. A wide range of concentrations of pirarubicin in bladder cancer tissue was observed (2.3-125 µg/g of tissue), although serum pirarubicin concentrations were not detected in any of the patients. Recurrence of superficial bladder cancer after transurethral resection of the bladder tumor (TUR-BT) was observed in 2 patients (9%). The concentration of pirarubicin in the tumor tissue tended to be higher as the exposure time increased. There was a weak relationship between the pirarubicin tissue concentration and tumor size. However, no significant relationship between tissue pirarubicin concentrations and the prophylactic effect against intravesical recurrence of bladder cancer after TUR-BT was observed. All patients had no adverse events, such as bladder irritation and local toxicity, caused by the treatment with pirarubicin. These findings suggest that prior to single intravesical administration of pirarubicin to patients with superficial bladder cancer the exposure time and tumor size should be considered.

Potential of molecular targeted therapy of HER-2 and Cox-2 for invasive transitional cell carcinoma of the urinary bladder.

Expression of HER-2 and COX-2 was determined to assess the potential of molecular-targeted therapy against human epidermal growth factor receptor-2 (HER-2) and cyclooxygenase-2 (COX-2) for the treatment of invasive bladder cancer. The subjects were 46 patients who attended Aichi Medical University Hospital between January 2001 and August 2008, underwent total cystectomy with a diagnosis of M0 bladder cancer, and received a pathological diagnosis of invasive transitional cell carcinoma of the urinary bladder (pT2-pT4). Expression of HER-2 and COX-2 was determined by immunohistochemical staining, and the results were interpreted by two pathologists by classifying HER-2 expression into four grades, and considering COX-2 positive when 10% or more of the tumor cells were stained. In HER-2 immunostaining, 10 subjects (21.7%) were positive, all of whom had a Grade 3 tumor. Staging classification identified 2 subjects (2/22, 9.1%) with pT2 stage, 3 (3/16, 18.8%) pT3 stage, and 5 (5/8, 62.5%) pT4 stage. There was a correlation between HER-2 positivity and tumor stage (P=0.007). Lymph node metastasis was detected in 13 subjects, 3 of them (3/8, 37.5%) with pN2 metastasis were HER-2 positive. The 5-year cause-specific survival rate was 51.4% for HER-2-positive subjects and 83.4% for HER-2-negative subjects. The outcome was poorer in HER-2-positive subjects, but the difference in survival rate was not statistically significant (P=0.218). In COX-2 immunostaining, 27 subjects (58.7%) were found to be positive. Three (3/4, 75.0%) showed a Grade 2 tumor and 24 (24/42, 57.1%) a Grade 3 tumor. Staging classification identified 13 subjects (13/22, 59.1%) with pT2 stage, 9 (9/16, 56.3%) pT3 stage, and 5 (5/8, 62.5%) pT4 stage. There was no correlation between COX-2 positivity and tumor grade or stage (P=0.488 and 0.089, respectively). Classification by the extent of lymph node metastasis revealed that 6 subjects (6/8, 75.0%) with pN2 were COX-2 positive. There was a correlation between COX-2 positivity and the extent (pN1 or pN2) of lymph node metastasis (P=0.008). The 5-year cause-specific survival rate was 84.0% for COX-2-positive subjects and 71.7% for COX-2-negative subjects. However, the difference in survival rate was not significant (P=0.407). Seven subjects (7/46, 15.2%) were positive for both HER-2 and COX-2, and there was no statistically significant correlation between the status of HER-2 expression and that of COX-2 expression (P=0.2195). The present study failed to show any association between HER-2 or COX-2 positivity and outcome in subjects with invasive bladder cancer. However, HER-2-positive subjects tended to have a poorer outcome. This finding suggests that molecular-targeted therapy against HER-2 could be an effective therapy. Further studies involving a larger number of subjects are required.

Penetration of doripenem into prostatic tissue following intravenous administration in prostatectomy patients.

This study examined the prostatic penetration of doripenem in prostatectomy patients. Doripenem 500 mg was administered by a 0.5-h infusion and venous blood and prostatic tissue samples were obtained up to 5h afterwards. Drug concentrations in plasma and prostatic tissue were measured chromatographically. The observed maximum concentration (C(max)) (mean+/-standard deviation; n=9) was 27.5+/-5.1 microg/mL in plasma and 5.09+/-1.94 microg/g in prostate tissue and the prostate/plasma C(max) ratio was 0.189+/-0.078. The area under the drug concentration-time curve (AUC) was 49.7+/-6.9 microg h/mL in plasma and 3.93+/-1.89 microg h/g in prostate tissue and the prostate/plasma AUC ratio was 0.081+/-0.047. Based on a three-compartment pharmacokinetic analysis, average drug exposure times above 0.25 microg/mL (the minimum inhibitory concentration for isolates of common pathogens) in the prostate were 23.2% for 500 mg once daily, 46.2% for 500 mg twice daily and 69.9% for 500 mg three times daily. The 500-mg regimens all achieved the drug exposure time target (bacteriostatic 20% or bactericidal 40%) in the prostate, despite the relatively low penetrability of doripenem.

Percutaneous ureteral incision with a small-caliber flexible ureteroscope.

OBJECTIVES: We reviewed the results of percutaneous ureteral incisions for ureteroenteroanastomotic stricture using the holmium laser. METHODS: We performed this procedure through a 6.9-F flexible ureteroscope on 3 ureters in 3 patients. Balloon dilation was not necessary prior to insertion of the ureteroscope. The stricture was incised with the holmium laser with a 200-microm fiber through the working channel of the ureteroscope. After completion of the incision, a 12-F double-J ureteral stent was left in situ for 6 weeks. Thereafter, patients were followed with repeated renal scans, ultrasound, or both, and excretory urography at 3- to 6-month intervals. RESULTS: The stricture resolved completely in all cases at an average follow-up of 25.3 months (16 to 32 months). CONCLUSIONS: Although the number of treated patients was small, percutaneous ureteral incision for ureteroenteroanastomotic stricture using the holmium laser was associated with a good outcome. We recommend this procedure be considered initially because it is less invasive and has a favorable outcome.

Further investigation of the epitope recognized by the new monoclonal antibody 2C9.

OBJECTIVE: We established a new monoclonal antibody (2C9) that reacted with prostate tissue. The immunohistochemical reactivity of this antibody is similar to anti-prostate-specific membrane antigen (PSMA). Herein, we report the antigenic determinant of 2C9 antibody. METHODS: The reactivity of the antibody was characterized by immunohistochemical staining and the antigen target was characterized by amino acid sequencing after immuno-affinity purification from an LNCaP cell lysate and cloning of a cDNA using a mammalian expression cDNA cloning system. RESULTS: The amino acid and nucleotide sequences for the antigen molecule recognized with 2C9 monoclonal antibody demonstrated identity with PSMA. CONCLUSION: The target molecule of the 2C9 monoclonal antibody is PSMA, pointing to future diagnostic and therapeutic applications.

Clinical experience of ureteroscopic treatment for ureteral transitional cell carcinoma using the Holmium:YAG laser.

The standard operative method for ureteral transitional cell carcinoma is nephrouterectomy with partial bladder excision of the ureteral orifice of the affected bladder. However, a conservative kidney operation and endoscopy are now being performed for low grade, low stage cases. We performed an operation using a Holmium: YAG laser, and examined its safety and efficacy. The patients were four men, and 1 woman aged from 68 to 87 (mean 78) years. There were 2 imperative cases (1 solitary kidney case, and 1 high-risk case), and 3 elective cases. The tumor size ranged from 8 to 25 (mean 14) mm. Urinary cytology was negative in all cases, and the tumors were pathologically diagnosed as grade 1 atypism on biopsy. A VersaPulse Select 80 laser generator, a 365 micro m SlimLine laser fiber, and an 8F rigid ureteroscope were used. A 6F double J catheter was indwelt for three weeks after the surgery. The pulse energy setting was 0.5-1.0 J, and the frequency was 10 Hz. The total amount of energy was 1.02-11.22 (mean 3.56) kJ, and the operation time was 20-97 (mean 50) min including the time for indwelling a ureteral stent. Neither urinary tract perforation nor ureteral stricture caused by the laser irradiation were observed. The patients have been followed by examining urine cytology once a month, and cystoscopy, retrograde pyelography, and urethroscopy once every 3 months. No recurrence has been observed as of 4-20 (mean 10) months postoperatively. Transurethral endoscopic resection using a Holmium: YAG laser is a safe and effective therapy for ureteral transitional cell carcinoma while preserving kidney and a good treatment outcome can be expected even in elective cases.

Vesicourethral anastomotic suture placement during radical prostatectomy using Maniceps.

INTRODUCTION: A new method of using a semiautomatic device (Maniceps) for precise vesicourethral anastomosis during radical retropubic prostatectomy is described. METHODS: A total of 15 patients underwent radical retropubic prostatectomy with this technique. The follow-up period ranged from 6 to 16 months. The retrograde urethrocystography was performed at 2 weeks. Patients were evaluated specifically for anastomotic time, anastomotic obstruction and urinary continence. RESULTS: The average anastomotic time was 8.1 (range 5-12) min. The catheter of all patients could be removed at 2 weeks. Anastomotic obstruction occurred in 1 patient (6.7%), and 14 patients (93.3%) were completely continent of urine. CONCLUSION: Maniceps is a useful procedure to carry out vesicourethral anastomosis safely, easily and surely, and it has provided good surgical results in our experience.

Clinical features of renal cell carcinoma less than 25 millimeters in diameter.

BACKGROUND: We retrospectively investigated the clinicopathological features and prognosis of patients who underwent surgical treatment at our department for renal cell carcinoma (RCC) less than 25 mm in diameter. METHODS: Of the 158 patients who underwent surgical treatment between April 1975 and April 1998, 16 (17 kidney, 10.1%) were included in this study. The study included 11 men and 5 women (ratio: 2.2). The age range was 35-76 years (average: age 53). The right kidney was involved in 9, left kidney in 6 and bilateral kidneys in 1 patient. The follow-up period was 26-157 months (mean: 86 months). RESULTS: Thirteen tumors (81.2%) were incidental carcinomas. No patients had a tumor of rapid growing type. Radical nephrectomy was performed for 12 kidneys (70.6%), simple nephrectomy for 2 (11.8%) and partial nephrectomy for 3 (17.8%). Seven patients (43.7%) received interferon-alpha as postoperative adjuvant therapy. All tumors were pathologically classified as expansive type; 11 (64.8%) as clear cell carcinoma; 3 (17.6%) cyst-associated, and 3 (17.6%) papillary. Nine (52.9%) tumors were grade 1, and 8 (47.1%) were grade 2. Fourteen patients were pNo and V(-). The 5- and 10-year survival rates were excellent (100%). CONCLUSION: The features of small RCCs less than 25 mm were as follows: many tumors were incidental to clear cell carcinomas; all tumors were low grade, low stage and expansive type; no tumors showed acute phase reactants; and few tumors were of the solid type. Thus, the prognosis seemed to be excellent.

Ammonium acid urate urinary stone caused by a low-caloric diet: a case report.

A 32-year-old woman complained of right back pain and pyuria. The plain radiograph (KUB) and drip infusion pyelography (DIP) demonstrated a right renal stone and hydronephrosis. The stone was successfully treated using extracorporeal shock wave lithotripsy. Infrared spectrophotometry revealed that the stone was composed of pure ammonium acid urate. The patient had a 3-year history of excessive anorexia. The low-caloric diet was considered to have caused the disease.

[A case of self-mutilation of testis].

A 22-year old man was admitted to the emergency room of our hospital with bleeding from scrotal wound. He had resected his own scrotum and both testes by himself with a small knife, since he thought that his testes had developed necrosis. He had thrown his scrotal skin and both testes away in a lavatory. We closed the wide wound surface and the surrounding skin after ligation of the spermatic cord. The post-operative course was uneventful. The patient was referred to the psychiatric department of our hospital and received supportive psychotherapy under diagnosis of schizophrenia. This is the 23rd case to be reported as self-injury of the external genitalia and the 7th case limited to testis in the Japanese literature.

Retrograde ureteroscopic endopyelotomy using the holmium:YAG laser.

BACKGROUND: We report our experience of retrograde ureteroscopic endopyelotomy using the holmium laser for ureteropelvic junction (UPJ) obstruction not associated with upper tract stones. METHODS: We carried out this procedure on five patients through an 8-Fr semirigid ureteroscope. The ureter was not stented before the procedure and balloon dilation was not necessary before retrograde insertion of the ureteroscope. The obstruction was incised with the holmium laser using a 200 microm fiber in a linear fashion. After completion of the incision, a 12-Fr double-J ureteral stent was left for 6 weeks. Thereafter, patients were monitored with renal scan and/or ultrasound and excretory urography at 3-6 month intervals. RESULTS: Hydronephrosis was obviously improved in four cases (80%) at an average follow up of 12.8 months (4-23 months). Although the number of treated patients was small, retrograde ureteroscopic endopyelotomy for UPJ obstruction using the holmium laser achieved good results. CONCLUSIONS: We recommend that this procedure be used initially because it is less invasive and has a favorable outcome.

Effective treatment of bladder tumor-bearing mice by direct delivery of bleomycin using electrochemotherapy.

We investigated the cytotoxicity on the combination of bleomycin (BLM) with electric pulses against transplanted bladder tumors in nude mice. Loading with high-voltage electric pulse after injection of BLM was associated with a decrease in tumor size; tumor size became smaller and disappeared 8 days after the treatment. Such complete regression was achieved with one treatment using BLM of one-tenth the lethal dose (LD(50)) combined with electric pulses. On day 20, regrowth was observed at a much slower rate than at lower concentrations of BLM. Pathological examinations of the tumor tissues after treatment revealed disruption of the nucleus in the exposed tissues on day 2. Furthermore, a decrease in number of the stained nuclei and cytoplasmic lysis were observed on day 4. These results showed that electric pulses was an effective tool to deliver drugs into bladder tumor cells and an effective treatment method for bladder tumors.