Drug interactions between tacrolimus and phenytoin in Japanese heart transplant recipients: 2 case reports.

OBJECTIVE: The purpose of the study was to demonstrate how the interaction between phenytoin and tacrolimus (FK 506) can be managed clinically and to characterize the change in FK 506 levels after discontinuation of phenytoin in two Japanese heart transplant recipients with different dosing periods ofphenytoin. METHODS: A drug interaction between phenytoin and FK 506 was investigated in 2 patients. The concentration-dose ratios (CDR: trough blood FK 506 level (ng/ml)/FK 506 dose (mg/day) on the previous day) were calculated as an index of the induction of the CYP3A4 enzyme during and after phenytoin therapy. RESULTS: About 2- to 3-fold dosages of FK 506 were required to maintain the required blood level when phenytoin was used concomitantly in the two cases examined. The FK 506 dose was constant within 21 days after discontinuing phenytoin in Patient 1 who had 36 days of phenytoin therapy. In Patient 2 with 21-day phenytoin therapy, the FK 506 doses and CDR varied for 10 days after discontinuing phenytoin, and expected FK 506 C0 levels were achieved within 11 days. CONCLUSIONS: The persistence of CYP induction after discontinuing phenytoin is dependent on the history of administration and, perhaps, on the dosing period in particular.

Genetic variations and haplotype structures of the ABCB1 gene in a Japanese population: an expanded haplotype block covering the distal promoter region, and associated ethnic differences.

As functional ABCB1 haplotypes were recently reported in the promoter region of the gene, we resequenced the ABCB1 distal promoter region, along with other regions (the enhancer and proximal promoter regions, and all 28 exons), in a total of 533 Japanese subjects. Linkage disequilibrium (LD) analysis based on 92 genetic variations revealed 4 LD blocks with the same make up as previously described (Blocks -1, 1, 2 and 3), except that Block 1 was expanded to include the distal promoter region, and that a new linkage between polymorphisms -1,789G>A in the distal promoter region and IVS5 + 123A>G in intron 5 was identified. We re-assigned Block 1 haplotypes, and added novel haplotypes to the other 3 blocks. The reported promoter haplotypes were further classified into several types according to tagging variations within Block 1 coding or intronic regions. Our current data reconfirm the haplotype profiles of the other three blocks, add more detailed information on functionally-important haplotypes in Block 1 and 2 in the Japanese population, and identified differences in haplotype profiles between ethnic groups. Our updated analysis of ABCB1 haplotype blocks will assist pharmacogenetic and disease-association studies carried out using Asian subjects.

Serum amiodarone and desethylamiodarone concentrations following nasogastric versus oral administration.

OBJECTIVE: Hospitalized patients unable to ingest anything by mouth require nutritional support by enteral feeding and administration of drugs through a nasogastric tube inserted into the digestive tract. Nasogastric administration of amiodarone may not always be equivalent to oral administration of amiodarone. METHODS: We collected 162 observations of serum amiodarone and desethylamiodarone metabolite concentrations from 93 patients within 60 days of starting treatment with amiodarone. Eight patients were given the drug nasogastrically and 85 patients, orally. The two groups, were compared in terms of their serum concentration/(dose/weight) (C/D) value. A ratio of serum amiodarone concentration to serum desethylamiodarone concentration (AMD/DEA) was calculated for each sample. In addition, the percentage drug recovery after nasogastric administration of amiodarone was analysed. RESULTS: Significant differences were observed in C/D values of amiodarone and desethylamiodarone and in AMD/DEA values of patients given amiodarone orally when compared with those given the drug nasogastrically. The C/D values of patients who received their medication nasogastrically were approximately 30% of the C/D values of patients who received their medication orally. Approximately 70% of the drug was recovered after it had passed through the nasogastric tube. CONCLUSIONS: To achieve similar concentrations, an approximately 3-fold increase in dosage of amiodarone was required when patients were given the drug nasogastrically rather than orally. This suggests that the absorption of amiodarone following nasogastric administration is poor when compared with oral administration. Therapeutic drug monitoring is necessary to optimize dose particularly during the early stages of amiodarone therapy.

Haplotype structures of the UGT1A gene complex in a Japanese population.

Genetic polymorphisms of UDP-glucuronosyltransferases (UGTs) are involved in individual and ethnic differences in drug metabolism. To reveal co-occurrence of the UGT1A polymorphisms, we first analyzed haplotype structures of the entire UGT1A gene complex using the polymorphisms from 196 Japanese subjects. Based on strong linkage disequilibrium between UGT1A8 and 1A10, among 1A9, 1A7, and 1A6, and between 1A3 and 1A1, the complex was divided into five blocks, Block 8/10, Block 9/6, Block 4, Block 3/1, and Block C, and the haplotypes for each block were subsequently determined/inferred. Second, using pyrosequencing or direct sequencing, additional 105 subjects were genotyped for 41 functionally tagged polymorphisms. The data from 301 subjects confirmed the robustness of block partitioning, but several linkages among the haplotypes with functional changes were found across the blocks. Thus, important haplotypes and their linkages were identified among the UGT1A gene blocks (and segments), which should be considered in pharmacogenetic studies.

Appropriate dosing regimen of allopurinol in Japanese patients.

OBJECTIVE: Approved dosage regimens for prescription drug products are developed with a view to obtaining a favourable therapeutic index in the overall exposed population. The purpose of this study was to examine differences between the approved dosage regimen and the clinically prescribed doses of allopurinol in major hospitals in Japan. METHODS: The prescribing records for allopurinol were scrutinized at five national hospitals in Japan. Prescription information, including mean dose and the distribution of doses, was extracted for each hospital and the data compared with the dosage recommended in the approved labelling for the product. In addition, therapeutic drug monitoring (TDM) data were examined to evaluate relationships between dose administered, serum concentration of oxypurinol, and clinical efficacy. RESULTS: The mean dose of allopurinol prescribed in the five institutions, 131.7 mg/day, was lower than the approved dosage of 200-300 mg/day. There were no differences in the mean dose between the hospitals, and similar dose distributions were seen among the hospitals. Approximately 60-70% of patients were treated with 100 mg/day and 20-30% with 200 mg/day of allopurinol. The most frequent dosage of allopurinol used in clinical practice was 100 mg/day. In the TDM study, the mean trough serum concentrations of oxypurinol were 9.5+/-3.6 microg/mL (50 mg/day), 13.0+/-6.8 microg/mL (100 mg/day), 19.8+/-12.9 microg/mL (200 mg/day) and 15.7+/-7.3 microg/mL (300 mg/day). The mean values of creatinine clearance were 17.0+/-16.4 mL/min (50 mg/day), 33.5+/-32.8 mL/min (100 mg/day), 57.8+/-33.8 mL/min (200 mg/day) and 94.3+/-35.8 mL/min (300 mg/day, in patients with normal renal function), and showed a downward trend together with a reduction of dosage of allopurinol. Allopurinol was given to 91% (91/100) of patients at a daily dose of 100-200 mg, and the oxypurinol trough serum concentration attained (>4.6 microg/mL) was sufficient to maintain a therapeutic effect in 92.3% (84/91) of these patients. A daily dose of 100-200 mg may be enough to obtain therapeutic serum oxypurinol concentrations in most Japanese patients. CONCLUSIONS: Dose of 100-300 mg/day was an effective and commonly used dosing regimen for allopurinol in Japanese patients. The approved dosage range (200-300 mg/day) may be too high for patients with renal dysfunction, suggesting the recommended dosing regimen for allopurinol should be revised to include the lower doses.

Appropriate dosing of antiarrhythmic drugs in Japan requires therapeutic drug monitoring.

OBJECTIVE: In general, drugs are used in accordance with an approved dosage regimen in expectation of an appropriate balance between efficacy and toxicity. However, dose control of drugs with a narrow therapeutic range and marked intersubject variability in pharmacokinetics should be established through individualization of dosing based on therapeutic drug monitoring (TDM). The purpose of this study was to examine differences between the approved dosage regimen and the doses of antiarrhythmic drugs and digoxin used in clinical practice and to examine the influence of TDM on dosing. METHODS: Prescription research of antiarrhythmic drugs was performed at five national hospitals in Japan. Prescriptions for antiarrhythmic drugs (cibenzoline, disopyramide, pirmenol, mexiletine, aprindine, flecainide, pilsicainide, amiodarone and digoxin) were counted for the study period. The mean dose and dose distribution of the drugs were determined in each hospital. Comparisons were made of mean dose obtained in the study with the dosage approved by the authority. In addition, the percentage of patients that received TDM was determined. RESULTS: A difference was seen between the approved dosage and the actual dose. For all drugs except flecainide, the mean dose was smaller than the approved dosage. For all drugs except digoxin, remarkable variations were seen in the dose distribution among the hospitals. Digoxin showed a similar dose distribution among the five hospitals. Overall, the percentage of patients that received TDM was low except for Hospital A. However, TDM of digoxin was relatively common at four of the hospitals. CONCLUSIONS: It is concluded that, with the exception of digoxin, the appropriate dosing regimen for antiarrhythmic drugs is not yet established. The establishment of appropriate dosing regimens for antiarrhythmic drugs requires the more widespread adoption of TDM.

Comparison of T1c versus T2 prostate cancers in Japanese patients undergoing radical prostatectomy.

In order to examine the characteristics of patients with nonpalpable prostate cancer (T1c cancer) in Japan, patients treated with radical prostatectomy were compared with those with palpable (T2) cancer. Prostate-specific antigen (PSA) level in patients with T2b disease was significantly higher than those with T1c and T2a tumors. At the time of radical prostatectomy, 78%, 71% and 31% of patients with T1c, T2a, and T2b, respectively, had organ-confined disease. When insignificant cancer was defined as volume 0.5 ml or less and Gleason score less than 5, only 2 of 34 (5.9%) with clinical T1c disease were clinically insignificant. T1c cancers were clinically significant and clinicopathological features of Tlc tumors were similar to T2a tumors. PSA measurement could detect potentially curable prostate cancer.

[A case of adult Wilms' tumor].

Wilms' tumor is very rarely found in adults and there are no established treatment guidelines for such tumors in adults. A 56-year-old woman was referred to our hospital for further examination of macroscopic hematuria. Computed tomography scan revealed a large right renal mass with enlarged lymph nodes. Angiography showed a hypovascular tumor. She underwent right nephrectomy and resection of lymph node metastasis with a diagnosis of malignant renal tumor. Histopathological examination revealed nephroblastoma with lymph node metastasis. The disease was classified as stage III according to the National Wilms' Tumor Study classification. The patient received adjuvant chemotherapy consisting of ifosfamide, cisplatin, and etoposide. This protocol was selected because of the published poor results with the standard Wilms' tumor chemotherapeutic agents when used in adults. She remained without tumor recurrence as of six months after surgery. Development of better therapeutic approaches to adult Wilms' tumor is awaited.

[Clinical effects of a 3-month formulation LH-RH agonist (Zoladex LA 10.8 mg depot) in patients with prostate cancer].

Pharmacodynamics (PD), anti-tumor effects, safety and pharmacokinetics of a 3-month formulation of goserelin (Zoladex LA 10.8 mg depot: "10.8 mg depot") were investigated in a collaborative multicenter study. Study participants were 40 Japanese patients with prostate cancer comprising 20 untreated patients and 20 switch patients who had been receiving Zoladex 3.6 mg depot for 3 months or longer. Serum testosterone levels, serum LH levels, prostate-specific antigen (PSA) levels and drug concentrations were measured until 12 weeks after a single subcutaneous dose of 10.8 mg depot. Anti-tumor effects were evaluated by means of changes in the tumor lesions and the PSA levels at 12 weeks. After administration to the untreated patients, 10.8 mg depot reduced serum testosterone to the castrate range within 4 weeks and the reduction was maintained for up to 12 weeks. In the switch patients, serum testosterone suppression that had been produced by previous treatment with Zoladex 3.6 mg depot was maintained for up to 12 weeks following 10.8 mg depot administration. The anti-tumor effect at 12 weeks was 90.0% including partial response cases. The ratio of PSA normalization at 12 weeks was 75.0%. Fifty-seven adverse reactions were observed in 27 of the 40 patients (67.5%), but none were clinically significant. Although a disease flare presented as urinary retention in 1 of the untreated patients, all patients completed the study. Serum goserelin was detected up to 12 weeks after the administration of 10.8 mg depot. In conclusion a single dose of 10.8 mg depot showed a satisfactory PD-effect and brought about clinical efficacy persisting for at least 12 weeks and was well tolerated in patients with prostate cancer.

Arthroscopic osteochondral autograft transplantation for chondral lesion of the tibial plateau of the knee.

Arthroscopic osteochondral autograft transplantation is often used to treat chondral/osteochondral lesions of the femoral condyle of the knee. However, arthroscopic autologous osteochondral grafting to the tibial plateau has not been reported. We report the surgical technique and the clinical course of a patient who underwent engraftment by this method. A 26-year-old man developed symptoms of pain and catching in his knee. Arthroscopy revealed a deep chondral lesion, 10 x 15 mm in size, down to the subchondral bone on the posterocentral area of the lateral tibial plateau. The injured cartilage was debrided using a curette and an abrader until normal healthy cartilage bordered the debrided defect. An osteochondral plug, 10 mm in diameter and 20 mm long, the chondral surface of which was orientated 25 degrees obliquely, was harvested from the most peripheral and proximal part of the lateral patellar groove. A bony hole was created in the center of the defect through the tibia using a core reamer. The osteochondral plug was inserted from the tibial window through the bony hole. To enhance the stability of the osteochondral fragment, bioactive ceramic fillers were used to fill the space below the plug. A second-look arthroscopy 10 months after surgery showed that the grafted osteochondral plug was well adapted and integrated into the surrounding cartilage on the lateral tibial plateau.

Prostate-specific antigen density adjusted for the transition zone for staging clinically localized prostate cancer in Japanese patients with intermediate serum prostate-specific antigen levels.

The prostate-specific antigen (PSA) density of the transition zone (PSATZ) in 45 prostate cancer patients who received radical prostatectomy with a PSA value of 4.1-10 ng/ml was determined to see whether PSATZ was useful in the prediction of extracapsular invasion of prostate cancer. The value of PSATZ for the detection of extracapsular invasion was compared with that of PSA and PSA density (PSAD). Thirty-one patients (68.9%) had pathologically organ confined cancer while 14 (31.1%) had extracapsular disease. Patients with organ confined tumor had significantly lower PSAD and PSATZ than those with non-organ confined tumor. PSATZ was superior to PSA when analyzed by receiver operating characteristics curves. In those patients with a cut-off value of 1.0 ng/ml per ml of transition zone volume, the PSATZ had a sensitivity of 43% and a specificity of 90% for prediction of extracapsular extension. The present study demonstrated that PSATZ was superior to PSA as a predictor of extracapsular invasion in intermediate PSA levels. Measurement of PSATZ may be of additional value to indicate the need for radical prostatectomy.

[A case of clinically multifocal renal cell carcinoma].

A 61-year-old woman was diagnosed with a renal tumor of the left kidney by ultrasound sonography during a health check-up. Computerized tomography (CT) and colored Doppler ultrasound sonography demonstrated two hypervascular tumors as typical renal cell carcinomas. A radically nephrectomized specimen was step-sectioned. Four tumor nodules were detected macroscopically, and 47 small nodules were detected microscopically, showing the clear cell type and alveolar growth pattern. Then all nodules including the 47 small nodules were diagnosed renal cell carcinoma.

Prostate-specific antigen, prostate volume and transition zone volume in Japanese patients with histologically proven benign prostatic hyperplasia.

The relationship among age, prostate-specific antigen (PSA) level and prostate volume in Japanese patients with lower urinary tract symptoms (LUTS) and histologically proven benign prostatic hyperplasia (BPH) was examined in order to assess the utility of PSA as a predictor of prostate volume. Two hundred eighteen patients with LUTS were confirmed to have BPH by histological examination for the reason of elevated PSA and/or abnormal digital rectal examination finding. Correlation among PSA, prostate volume and transition zone volume were analyzed in patients classified into age-stratified groups. Prostate volume increased with age. Mean serum PSA increased with age, and the correlation of PSA and prostate volume was determined to be statistically significant in each cohort of age. A correlation coefficient ranged from 0.315 to 0.439. In patients with LUTS and clinical BPH, serum PSA increased with age and was related to prostate volume. PSA might be useful for therapeutic decision making for patients with symptomatic BPH.

Auxin-induced elongation growth and expressions of cell wall-bound exo- and endo-beta-glucanases in barley coleoptiles.

When auxin stimulates rapid cell elongation growth of cereal coleoptiles, it causes a degradation of 1,3:1,4-beta-glucan in hemicellulosic polysaccharides. We examined gene expressions of endo-1,3:1,4-beta-glucanase (EI) and exo-beta-glucanase (ExoII), of which optimum pH are about 5, and molecular distribution of hemicellulosic polysaccharides in barley (Hordeum vulgare L.) coleoptile segments treated with or without IAA. IAA (10(-5) M) stimulated the gene expression of EI, while it did not affect that of ExoII. IAA induced gene expression of EI after 4 h and increased wall-bound glucanase activity after 8 h. The molecular weight distribution of hemicellulosic polysaccharides from coleoptile cell walls was shifted to lower molecular weight region by 2 h of IAA treatment. Fusicoccin (10(-6) M) mimicked IAA-induced elongation growth and the decrease in molecular weight of hemicellulosic 1,3:1,4-beta-glucan of coleoptiles in the first 4 h, but it did not promote elongation growth thereafter. These facts suggest that acidification of barley cell walls by IAA action enhances pre-existing cell wall-bound glucanase activity in the early first phase of IAA-induced growth and the late second phase involves the gene expression of EI by IAA.

A dose-escalation and pharmacokinetic study of subcutaneously administered recombinant human interleukin 12 and its biological effects in Japanese patients with advanced malignancies.

A pilot dose-escalation study of recombinant human interleukin 12 (rhIL-12) was conducted in Japanese patients with advanced malignancies. Cohorts of three patients received escalating doses of rhIL-12 that increased from 50 to 300 ng/kg/day s.c. three times a week for 2 weeks followed by 1-week rest. The same dosage and schedule was repeated for two additional courses. Sixteen previously treated patients were registered, and 15 were evaluated. Common toxicities were fever and leukopenia; the abnormality of laboratory tests included elevations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, C-reactive protein, and beta2-microglobin. Dose-limiting toxicity was the grade 3 elevation of aminotransferases, and was observed in two of six patients at the 300-ng/kg dose level after the first course in one patient and after the third course in the other. Leukopenia was observed at all of the dose levels; two of six patients at 300 ng/kg experienced grade 3 leukopenia. Thus, 300 ng/kg was determined to be the maximum acceptable dose. Peak plasma levels of rhIL-12 decreased in the second courses, but the areas under the curve were almost the same in the first and second courses. Biological effects included increases of plasma levels of IFN-gamma, tumor necrosis factor-alpha, IL-6, IL-10, and neopterin. In two patients with renal cell carcinoma, complete response and partial response of metastatic tumors were observed with 50 and 300 ng/kg; the responses lasted for 5 and 3.5 months, respectively. Although immunological response to rhIL-12 varies depending on administration route and schedule and on patients' physiological conditions, the recommended dose for Phase II studies is 300 ng/kg s.c. three times a week for 2 weeks followed by 1-week rest.

[Preventive effect of chlormadinone acetate on flare-up phenomenon in advanced prostate cancer administered with a luteinizing hormone-releasing hormone analogue].

To investigate whether chlormadinone acetate (CMA) could prevent the flare-up phenomenon induced by a luteinizing hormone-releasing hormone analogue (LH-RHa), we treated 4 cases of stage C and 17 cases of stage D prostate cancer with CMA for 4 weeks and CMA plus monthly injection of LH-RHa for following 24 weeks. Serum LH, testosterone, and prostate-specific antigen (PSA) levels were closely monitored before and 3 days, 1-, 2-, and 4-weeks after LH-RHa injection. Subjective and objective responses were also investigated. Serum LH and testosterone levels significantly elevated 3 days after the initial injection of LH-RHa. However, they resumed 1 week after LH-RHa injection with fluctuation under the normal range. Out of 21 cases, 3 cases (14%) consisting of 2 poorly and 1 moderately differentiated adenocarcinoma showed increased serum PSA levels 1 week after LH-RHa injection in spite of suppressed serum testosterone levels. The objective response of these 2 poorly differentiated cases was progressive disease at 24 weeks. No cases indicated worsening of clinical symptoms concerning flare-up phenomenon. CMA seemed to be capable of preventing flare-up phenomenon in advanced prostate cancer.

Incidence rate of satellite tumors in renal cell carcinoma.

BACKGROUND: Nephron-sparing surgery for incidentally detected small renal tumors has been performed. The main objection to such surgery concerns the incidence rate of satellite renal tumors. In this study, the authors analyzed the rate of incidence and proliferative potential of satellite renal tumors. METHODS: The tumors of 124 renal cell carcinoma patients with a clinically identified unilateral and single tumor measuring

[Late phase II clinical study for bropirimine (U-54461S) in situ carcinoma of the bladder: follow-up investigation. Bropirimine Study Group].

A follow-up investigation was conducted on a Late Phase II clinical study of bropirimine for carcinoma in situ (CIS) of the bladder. We previously reported that 48 patients were enrolled and 17 patients achieved complete remission (CR) in the Late Phase II study. Of the 17 CR patients, 5 had recurrence, but 9 were recurrence free for a year and 5 have remained so for more than 2 years (median follow-up: 29.1 +/- 4.2 months). The 1-year and 2-year recurrence-free rates calculated using the Kaplan-Meier method were 70.3% and 61.5% respectively. Of all the 47 bropirimine-treated patients, 11 underwent total cystectomy (median follow-up: 31.8 +/- 5.2 months). The rates of bladder preservation after 1 year, 2 years, and 3 years calculated using the Kaplan-Meier method were 87.2%, 80.7%, and 74.0% respectively. Of the 39 patients who did not respond to bropirimine or suffered from recurrence after bropirimine treatment, 19 received subsequent intravesical bacillus Calmette-Guerin (BCG) therapy and 13 achieved CR (68.4%). This suggests that bropirimine does not decrease the efficacy of BCG therapy. In the present study, the prognosis was confirmed to be favorable after bropirimine therapy. Bropirimine would thus seem to be a useful oral anticancer agent for bladder CIS.