RESUMO
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.
Assuntos
Anticonvulsivantes/farmacologia , Transplante de Coração , Imunossupressores/farmacocinética , Fenitoína/farmacologia , Tacrolimo/farmacocinética , Adulto , Anticonvulsivantes/administração & dosagem , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos , Feminino , Humanos , Imunossupressores/administração & dosagem , Japão , Fenitoína/administração & dosagem , Tacrolimo/administração & dosagemRESUMO
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.
Assuntos
Etnicidade/genética , Variação Genética , Haplótipos , Transportadores de Ânions Orgânicos/genética , Regiões Promotoras Genéticas , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Humanos , Japão , Desequilíbrio de Ligação/genética , Neoplasias/epidemiologia , Neoplasias/genética , Taquicardia Ventricular/epidemiologia , Taquicardia Ventricular/genéticaRESUMO
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.
Assuntos
Amiodarona/análogos & derivados , Amiodarona/administração & dosagem , Amiodarona/farmacocinética , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Amiodarona/sangue , Antiarrítmicos/sangue , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Meia-Vida , Humanos , Intubação Gastrointestinal , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Povo Asiático/genética , Glucuronosiltransferase/genética , Haplótipos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , HumanosRESUMO
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.
Assuntos
Alopurinol/administração & dosagem , Alopurinol/uso terapêutico , Antimetabólitos/administração & dosagem , Antimetabólitos/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Administração Oral , Idoso , Alopurinol/farmacocinética , Antimetabólitos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Antiarrítmicos/uso terapêutico , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Antiarrítmicos/administração & dosagem , Relação Dose-Resposta a Droga , Prescrições de Medicamentos/estatística & dados numéricos , Revisão de Uso de Medicamentos/métodos , Registros Hospitalares , Humanos , Japão , Padrões de Prática MédicaRESUMO
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.
Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Antígeno Prostático Específico/análise , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Adenocarcinoma/mortalidade , Idoso , Análise de Variância , Biomarcadores Tumorais/análise , Biópsia por Agulha , Estudos de Coortes , Humanos , Imuno-Histoquímica , Japão , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Palpação , Probabilidade , Prognóstico , Neoplasias da Próstata/mortalidade , Estudos de Amostragem , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
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.
Assuntos
Neoplasias Renais/terapia , Tumor de Wilms/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Excisão de Linfonodo , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nefrectomia , Resultado do Tratamento , Tumor de Wilms/diagnóstico , Tumor de Wilms/patologiaRESUMO
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.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Gosserrelina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacocinética , Preparações de Ação Retardada , Esquema de Medicação , Gosserrelina/administração & dosagem , Gosserrelina/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/metabolismo , Testosterona/sangueAssuntos
Adenocarcinoma/sangue , Adenocarcinoma/secundário , Neoplasias Ósseas/sangue , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Ósseas/cirurgia , Reações Falso-Negativas , Evolução Fatal , Humanos , Masculino , Antígeno Prostático Específico/análise , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Radioimunoensaio , Medição de RiscoRESUMO
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.
Assuntos
Artroscopia , Cartilagem Articular/lesões , Cartilagem Articular/transplante , Futebol Americano/lesões , Traumatismos do Joelho/cirurgia , Tíbia/lesões , Adulto , Humanos , Traumatismos do Joelho/diagnóstico , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Meniscos Tibiais/cirurgia , Radiografia , Amplitude de Movimento Articular , Reoperação , Lesões do Menisco Tibial , Transplante AutólogoRESUMO
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.
Assuntos
Adenocarcinoma/sangue , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Adenocarcinoma/fisiopatologia , Adenocarcinoma/cirurgia , Humanos , Japão , Masculino , Invasividade Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Neoplasias da Próstata/fisiopatologia , Neoplasias da Próstata/cirurgiaRESUMO
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.
Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Pessoa de Meia-Idade , Nefrectomia , UltrassonografiaRESUMO
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.
Assuntos
Próstata/patologia , Hiperplasia Prostática/sangue , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisões , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Hiperplasia Prostática/terapiaRESUMO
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.
Assuntos
Parede Celular/efeitos dos fármacos , Celulase/genética , Cotilédone/efeitos dos fármacos , Hordeum/efeitos dos fármacos , Ácidos Indolacéticos/farmacologia , beta-Glucosidase/genética , Northern Blotting , Parede Celular/enzimologia , Cotilédone/enzimologia , Cotilédone/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Glucana 1,3-beta-Glucosidase , Glucose/metabolismo , Glicosídeos/farmacologia , Hordeum/enzimologia , Hordeum/crescimento & desenvolvimento , Peso Molecular , Reguladores de Crescimento de Plantas/farmacologia , Polissacarídeos/química , Polissacarídeos/metabolismo , RNA de Plantas/efeitos dos fármacos , RNA de Plantas/genética , RNA de Plantas/metabolismo , Fatores de TempoAssuntos
Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/efeitos dos fármacos , Humanos , Masculino , Nitrilas , Compostos de TosilRESUMO
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.
Assuntos
Interleucina-10/efeitos adversos , Interleucina-10/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Interferon gama/sangue , Interleucina-10/administração & dosagem , Interleucina-10/sangue , Interleucina-6/sangue , Japão , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/imunologia , Neopterina/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Fator de Necrose Tumoral alfa/análiseRESUMO
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.
Assuntos
Reação de Fase Aguda/prevenção & controle , Adenocarcinoma/tratamento farmacológico , Antineoplásicos Hormonais/efeitos adversos , Acetato de Clormadinona/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Pamoato de Triptorrelina/efeitos adversos , Reação de Fase Aguda/etiologia , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/sangue , Quimioterapia Combinada , Humanos , Hormônio Luteinizante/sangue , Masculino , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Testosterona/sangue , Pamoato de Triptorrelina/uso terapêuticoRESUMO
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 =90 mm who were examined between November 1991 and May 1997 were analyzed prospectively. The authors determined whether these specimens obtained by radical nephrectomy had satellite tumors, and whether the satellite tumors were reactive with a monoclonal antibody (MoAb), MIB-1, to assess their proliferative potential. RESULTS: Satellite renal cell carcinomas were detected in 8 of the 124 patients (6.5%). None of the pathologic variables examined (tumor grade, tumor stage, main tumor size, cell pattern, and vascular invasion) were found to be predictive of the presence of satellite tumors. Of these eight tumors, two main tumor specimens and three satellite tumor specimens reacted with the MIB-1 MoAb. The reactivity of MIB-1 correlated with the tumor grade. The satellite tumors were observed to have a proliferative potential compared with the main tumors. Among 86 kidney specimens from patients with urothelial tumors after total nephroureterectomy, 2 (2.3%) contained small renal cell carcinoma but did not show positive staining with the MoAb MIB-1. CONCLUSIONS: The incidence rate of satellite tumors among 124 renal cell carcinoma patients was 6.5% and the presence of satellite tumors was not predictable. Some of these satellite tumors showed positive staining with the MIB-1 MoAb, but small renal tumors detected in kidney specimens with urothelial tumors did not.
Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Segunda Neoplasia Primária/patologia , Adulto , Idoso , Anticorpos Monoclonais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/imunologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/imunologia , Segunda Neoplasia Primária/cirurgia , Nefrectomia , Prognóstico , Estudos ProspectivosRESUMO
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.