RESUMEN
BACKGROUND: Paclitaxel (Taxol) is a new drug with efficacy against a variety of malignant tumors. The clinical formulation of paclitaxel contains 50% Cremophor EL, a polyethoxylated castor oil vehicle (carrier) that can reverse multidrug resistance (MDR) mediated by P-glycoprotein. Three-hour intravenous infusions of paclitaxel can yield end-of-infusion plasma Cremophor concentrations of 1 microL/mL or more, which are sufficient to reverse MDR in vitro by at least 50%. Despite extensive clinical use, the pharmacokinetics of Cremophor have not been described. PURPOSE: We studied the pharmacokinetics of Cremophor in patients with ovarian cancer who were undergoing treatment with paclitaxel to determine whether plasma Cremophor concentrations achieved during and following 3-, 6-, and 24-hour drug infusions were similar to those shown to modulate MDR in vitro. METHODS: Eleven patients with previously treated (i.e., with platinum-containing chemotherapy regimens) ovarian cancer were randomly assigned to receive one 3-hour, one 6-hour, and one 24-hour infusion of paclitaxel in varied sequences during their first three cycles of treatment with this drug. Blood samples were collected both during and following the three infusion periods, and Cremophor concentrations in these samples were measured by use of a bioassay based on the ability of Cremophor in plasma samples to reverse cellular resistance to daunorubicin in vitro. RESULTS: Ten patients were treated with paclitaxel at a dose level of 175 mg/m2, and one patient was treated at a dose level of 135 mg/m2. At the 175-mg/m2 dose level, peak plasma Cremophor concentrations of 1 microL/mL or more were achieved in eight of 10 patients during both the 3-hour and the 6-hour infusions; with the 24-hour infusion, only one patient achieved a peak plasma Cremophor concentration of 1 microL/mL or more. The eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 3-hour infusion were above this level 30 minutes into the infusion; the total time that the plasma concentration was greater than 1 microL/mL was 8.9 +/- 5.0 hours (mean +/- standard deviation; range, 4.1-15.6 hours). For the eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 6-hour infusion, the total time that the concentration was greater than 1 microL/mL was 10.2 +/- 9.0 hours (range, 0.3-21.9 hours). The patient who received paclitaxel at a dose of 135 mg/m2 achieved a peak plasma Cremophor concentration of 1 microL/mL or more only during the 3-hour infusion. CONCLUSIONS: Paclitaxel infusions of 3 and 6 hours can result in sustained plasma Cremophor concentrations sufficient for substantial reversal of P-glycoprotein-mediated MDR in vitro. These plasma Cremophor concentrations are not achieved during 24-hour infusions of paclitaxel.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Carcinoma/sangre , Neoplasias Ováricas/sangre , Paclitaxel/administración & dosificación , Vehículos Farmacéuticos/farmacocinética , Polietilenglicoles/farmacocinética , Anciano , Carcinoma/tratamiento farmacológico , Carcinoma/fisiopatología , Esquema de Medicación , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Femenino , Humanos , Infusiones Intravenosas , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/fisiopatología , Factores de TiempoRESUMEN
The disposition of the methotrexate analogue trimetrexate (TMTX, NSC 352122; 2,4-diammino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]qui nazoline) was determined in a Phase I study in 16 patients with refractory or relapsing cancer. The drug was administered by continuous 5-day infusion at doses of 5 to 60 mg/m2/120 h (1-12 mg/m2 daily for 5 days). Plasma and urine collections were made during and after infusion and TMTX levels were quantitated by a specific and sensitive high-performance liquid chromatographic assay. Estimates of pharmacokinetic parameters were similar when determined by either compartmental or noncompartmental methods. There were no significant differences in parameters between the first and second courses of treatment to 10 of the patients. Significant linear relations between TMTX dose and the area under curve of plasma TMTX (r2 = 0.858, P = 0.0001) and the steady-state TMTX plasma level (r2 = 0.764, P = 0.0001) were established. Total TMTX clearance was 30.4 +/- 7.6 (SD) ml/min/m2, renal clearance 7.80 +/- 3.9 ml/min/m2, nonrenal clearance 23.2 +/- 7.1 ml/min/m2, volume of distribution 32.8 +/- 16.6 liters/m2, and terminal half-life 13.4 +/- 7.0 h. The percentage of the trimetrexate dose excreted unchanged in urine ranged from 8.4 to 40.7% (mean, 24.9 +/- 9.2%) and was related to creatinine clearance (r2 = 0.312, P = 0.010). Trimetrexate renal clearance was also related to urine flow (r2 = 0.330, P = 0.008). Trimetrexate pharmacokinetics was linear over the dose range 5 to 60 mg/m2 when given by 5-day continuous infusion to patients but there was evidence of urine flow-dependent renal clearance which requires further examination.
Asunto(s)
Antineoplásicos/metabolismo , Quinazolinas/metabolismo , Adulto , Anciano , Niño , Evaluación de Medicamentos , Femenino , Antagonistas del Ácido Fólico/metabolismo , Humanos , Riñón/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Quinazolinas/administración & dosificación , TrimetrexatoRESUMEN
Twenty patients with extravasation of anthracyclines were treated on a single-arm pilot study with topical 99% dimethyl sulfoxide (DMSO) and observed for 3 months with regular examinations and photographs. DMSO was applied to approximately twice the area affected by the extravasation and allowed to air dry. This was repeated every six hours for 14 days. The initial signs of extravasation included swelling in 17 patients, erythema in 15, and pain in 12. The median area of damage was 8.25 cm2 and a median of 25 minutes elapsed between extravasation and application of DMSO with one patient not treated until seven days postextravasation. Sixteen patients were observed for 3 months, two died of disease earlier after receiving 2 weeks of DMSO and three days of DMSO, respectively, and two were lost to follow-up having received one day and five days of DMSO. In no patient did extravasation progress to ulceration or require surgical intervention, suggesting with 95% confidence a true ulceration rate of between 1% and 17%. At 3 months there was no sign of residual damage in six patients, while a pigmented indurated area remained in ten. Two patients had a recall reaction with increased pain at the extravasation site when further intravenous (IV) doxorubicin was administered. The only toxicities of DMSO included a burning feeling on application subsequently associated with itch, erythema, and mild scaling. Blisters occurred in four patients. Six patients reported a characteristic breath odor associated with DMSO. Topical DMSO appears to be a safe and effective treatment for anthracycline extravasation.
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Antibióticos Antineoplásicos , Dimetilsulfóxido/uso terapéutico , Extravasación de Materiales Terapéuticos y Diagnósticos/tratamiento farmacológico , Administración Tópica , Dimetilsulfóxido/administración & dosificación , Humanos , Proyectos Piloto , Estudios ProspectivosRESUMEN
The efficacy and toxicity of carboplatin 100 mg/m2, administered intravenously (IV) daily X 3, and VP-16-213 120 mg/m2, IV daily X 3, administered every 28 days for six courses, was assessed in 94 (36 limited stage, 58 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to all limited-stage patients with a complete (CR) or partial response (PR) after three chemotherapy courses. Cranial irradiation was administered to all patients with CR. Objective responses were seen in 77% (CR 40%, PR 37%) of patients with limited-stage and 58% (CR, 9%; PR, 49%) with extensive-stage disease. Median relapse-free survival for objective responders with limited stage was 14.6 months and 7.9 months for extensive-stage patients. Median relapse-free survival following CR was 15.4 months and 8.5 months for PR. Median survival was 15.3 months for limited-stage and 8.1 months for extensive-stage patients. The combination was well tolerated with mild nausea or less (World Health Organization [WHO] grade 0 or 1) in 62% of patients and minimal mucositis, renal, neurotoxicity, or ototoxicity. Neutropenia less than 1.0 X 10(9)/L (WHO grade 3 or 4) was seen in 63% of patients, with two deaths from infection while neutropenic. The combination of carboplatin and VP-16-213 is a new, active program with low toxicity when applied intensively in previously untreated patients with small-cell lung cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/patología , Evaluación de Medicamentos , Etopósido/administración & dosificación , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos Organoplatinos/administración & dosificaciónRESUMEN
PURPOSE: To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease. RESULTS: The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred. CONCLUSION: The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/administración & dosificación , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Intervalos de Confianza , Supervivencia sin Enfermedad , Hipersensibilidad a las Drogas/etiología , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/inducido químicamente , Paclitaxel/efectos adversos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Lorazepam was compared to placebo to assess its control of nausea and vomiting in patients receiving cytotoxic chemotherapy and prochlorperazine. The study design was a randomized, double-blind crossover in which three consecutive chemotherapy courses were compared so that each patient acted as his or her own control. Of 107 patients entered, 80 were evaluable for analysis. Lorazepam significantly reduced the severity and duration of nausea, the severity of vomiting, and the number of vomiting episodes when compared to placebo. Anxiety was reduced during lorazepam courses but not significantly when compared to placebo. There was significantly more sedation with lorazepam courses. Overall, patients preferred lorazepam courses although this preference was significant only in the patient subset receiving doxorubicin and cyclophosphamide. Lorazepam is a useful adjunct to prochlorperazine in patients receiving cytotoxic chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Lorazepam/administración & dosificación , Náusea/tratamiento farmacológico , Vómitos/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Ensayos Clínicos como Asunto , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/tratamiento farmacológico , Proclorperazina/administración & dosificación , Distribución Aleatoria , Vómitos/inducido químicamenteRESUMEN
PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Taxoides , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Cisplatino/administración & dosificación , Docetaxel , Esquema de Medicación , Femenino , Humanos , Neoplasias Pulmonares/sangre , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/análogos & derivados , Resultado del TratamientoRESUMEN
PURPOSE: To determine the place of single-agent paclitaxel compared with nonanthracycline combination chemotherapy as front-line therapy in metastatic breast cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic breast cancer were randomized to receive either paclitaxel 200 mg/m(2) intravenously (IV) over 3 hours for eight cycles (24 weeks) or standard cyclophosphamide 100 mg/m(2)/d orally on days 1 to 14, methotrexate 40 mg/m(2) IV on days 1 and 8, fluorouracil 600 mg/m(2) IV on days 1 and 8, and prednisone 40 mg/m(2)/d orally on days 1 to 14 (CMFP) for six cycles (24 weeks) with epirubicin recommended as second-line therapy. RESULTS: A total of 209 eligible patients were randomized with a median survival duration of 17.3 months for paclitaxel and 13.9 months for CMFP. Multivariate analysis showed that patients who received paclitaxel survived significantly longer than those who received CMFP (P =.025). Paclitaxel produced significantly less severe leukopenia, thrombocytopenia, mucositis, documented infections (all P <.001), nausea or vomiting (P =.003), and fever without documented infection (P =.007), and less hospitalization for febrile neutropenia than did CMFP (P =.001). Alopecia, peripheral neuropathy, and myalgia or arthralgia were more severe with paclitaxel (all P <.0001). Overall, quality of life was similar for both treatments (P > = .07). CONCLUSION: Initial paclitaxel was associated with significantly less myelosuppression and fewer infections, with longer survival and similar quality of life and control of metastatic breast cancer compared with CMFP.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Paclitaxel/uso terapéutico , Adulto , Anciano , Análisis de Varianza , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/secundario , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Neutropenia/inducido químicamente , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Prednisona/administración & dosificación , Prednisona/efectos adversos , Calidad de VidaRESUMEN
PURPOSE: Granulocyte colony-stimulating factor (G-CSF) administered prophylactically after chemotherapy reduces the duration and severity of neutropenia. This randomized crossover study was designed to assess whether a lower dose of G-CSF is as effective as a standard dose of 5 microg/kg daily. PATIENTS AND METHODS: Patients who received standard-dose chemotherapy regimens expected to cause neutropenia received G-CSF (lenograstim) that started the day after chemotherapy for 14 days or until the absolute neutrophil count (ANC) recovered to greater than 10 x 10(9)/L. The lenograstim dose was randomly allocated to be 2 or 5 microg/kg daily in the first cycle of chemotherapy and crossed over to the alternate dose for the second cycle. The study was designed to accrue 40 assessable patients to provide a power of 80% to detect a difference in duration of neutropenia of 1 day. Fifty-two patients were randomized to treatment and 43 patients completed two cycles of identical chemotherapy. RESULTS: There was little neutropenia irrespective of the dose used. Twenty-three patients (53%) had no grade III or IV neutropenia and 30 patients (70%) had no grade IV neutropenia. Crossover trial methodology was used to assess the difference in outcome caused by the lower dose compared with the standard dose (estimated treatment effect). There was no significant difference in the measures of neutropenia, hospitalization, or other clinical outcomes. The 95% confidence interval (one-sided) for the additional duration of neutropenia caused by the lower dose of lenograstim was 0.43 days or less for grade III or IV neutropenia and 0.34 days or less for grade IV neutropenia. CONCLUSION: Lenograstim 2 microg/kg provides similar protection to 5 microg/kg against neutropenia that complicates standard-dose chemotherapy. The use of a lower dose has important implications for the cost-effectiveness of prophylactic G-CSF therapy.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neutropenia/prevención & control , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios Cruzados , Esquema de Medicación , Femenino , Humanos , Lenograstim , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Estudios Prospectivos , Proteínas Recombinantes/administración & dosificación , Resultado del TratamientoRESUMEN
Patients fail to be cured of acute myeloid leukemia (AML) because they develop absolute or relative resistance to antileukemic drugs such as ara-C (cytarabine) or because they die of complications of bone marrow failure. The Australian Leukemia Study Group (ALSG) has been investigating strategies to improve leukemia control by changing the methods of induction treatment. High-dose ara-C (HIDAC) may overcome ara-C resistance in leukemic blasts, and it has been used as a successful salvage regimen and in postremission therapy. The data from ALSG suggest that a dose-effect relationship exists for ara-C in AML, that the use of HIDAC prolongs remission duration and disease-free survival and that it is tolerable when used as initial induction therapy in patients with de novo AML. A fundamental question still to be answered in ongoing clinical trials is: When should AML treatment be optimally intensified--during the induction phase, immediately after remission, or after 2 to 3 months of preparative regimens, as in some transplantation programs?
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Antineoplásicos/uso terapéutico , Citarabina/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Adulto , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Humanos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Terapia Recuperativa , Factores de TiempoRESUMEN
To determine the incidence and prognostic significance of mutation in the N-ras gene in de novo acute myeloid leukemia (AML) we performed an analysis of bone marrow smears from 219 patients with de novo AML treated between 1984 and 1986 and followed for at least six years. DNA extracted from bone marrow smears taken at diagnosis was screened for the presence of mutations in codons 12 and 13 of exon 1 by using the polymerase chain reaction to insert an Hph1 restriction enzyme site into DNA. Presumptive mutations were confirmed by direct sequencing. Mutations were detected in a total of 26 patients (12%); in nine patients (4%) in codon 12 only, in ten patients (5%) in codon 13 only, and in seven patients (3%) in both codons. Mutations in codon 12 or codon 13 were not associated with any clinical features. Mutations in codon 12 had no prognostic significance but mutations in codon 13 were associated with an increased remission rate, a more durable remission, and a significantly prolonged survival which appeared to be independent of other prognostic factors.
Asunto(s)
Codón/genética , Genes ras/genética , Leucemia Mieloide Aguda/genética , Mutación , Secuencia de Bases , Distribución de Chi-Cuadrado , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Pronóstico , Modelos de Riesgos Proporcionales , Mapeo Restrictivo , Sensibilidad y Especificidad , Tasa de SupervivenciaRESUMEN
Ninety-three stage III and IV patients with non-Hodgkin's lymphoma were randomized to either high dose CVP (cyclophosphamide 1500 mg/m2 i.v. day 1, vincristine 1.4 mg/m2 day 1, and prednisone 40 mg/m2 orally days 1-10) or high dose CAVP (cyclophosphamide 1000 mg/m2 i.v. day 1, doxorubicin 45 mg/m2 i.v. day 1, vincristine and prednisone as above). Overall, the complete response (CR) rates were similar (CVP 51%, CAVP 51%). Patients with the International Working Formulation diffuse large cell lymphoma had significantly higher CR with CAVP. No difference in CR duration was detected between the two regimens. CRs were durable with 68% of diffuse and 86% of diffuse large cell complete responders alive and disease free at 7 years. Survival was similar with both regimens except for patients with diffuse large cell lymphoma who survived longer with CAVP. Both regimens were equitoxic with neutropenia less than 1.0 x 10(9)/liter in 36% of courses, infections in 15% of courses, and fatal infections in three patients. These intermittent high dose cyclophosphamide equitoxic regimens produced durable responses. However, the doxorubicin-containing regimen is superior in diffuse large cell lymphoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Estudios de Seguimiento , Hematopoyesis/efectos de los fármacos , Humanos , Prednisona/administración & dosificación , Prednisona/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
The erythromycin breath test (EBT) is a putative in vivo probe for drug metabolism by cytochrome P450 3A4 (CYP3A4). Because many anticancer drugs are metabolized by this system, we sought to further develop the EBT as a tool for predicting the clearance, in cancer patients, of drugs metabolized by CYP3A4. Sixteen adult patients with incurable cancer were studied. The EBT was performed on day 1 and breath sampled after the i.v. injection of 4 microCi of 14C-erythromycin. The breath 14CO2 flux (CERt) was estimated at 11 time points over 2 h. On day 2, the EBT was repeated midway through a 10-min infusion of 100 mg of erythromycin lactobionate, and the plasma pharmacokinetics of erythromycin were determined. The infusion of 100 mg of erythromycin did not modify the EBT results significantly. The values of the conventional EBT parameter CER20 min obtained on day 1 were comparable for most subjects (0.03-0.06% dose/min), with the exception of an individual receiving the known CYP3A4 inducers dexamethasone and phenytoin who returned a value of 0.14% dose/min. There was no significant correlation between any of the conventional EBT parameters and erythromycin clearance. However, two parameters reflecting early emergence of breath radioactivity (1/TMAX and CER3 min/CERMAX) correlated significantly with erythromycin clearance (P = 0.005 and 0.006, respectively). Novel parameters derived from the EBT are significantly correlated with the clearance of erythromycin even in the presence of confounding factors, such as metastatic liver disease, altered protein binding, and comedication. These parameters may enable dose optimization of cytotoxics metabolized by CYP3A4.
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Sistema Enzimático del Citocromo P-450/metabolismo , Eritromicina/farmacocinética , Oxigenasas de Función Mixta/metabolismo , Neoplasias/metabolismo , Adulto , Anciano , Antineoplásicos/metabolismo , Pruebas Respiratorias/métodos , Radioisótopos de Carbono , Citocromo P-450 CYP3A , Eritromicina/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/enzimología , Unión ProteicaRESUMEN
Cremophor EL (cremophor), a component of the paclitaxel formulation, can potentially reverse P-glycoprotein-associated multidrug resistance. A Phase I trial of cremophor as a 6-h infusion every 3 weeks was performed with bolus doxorubicin (50 mg/m2). The cremophor dose was escalated from 1 to 60 ml/m2. A standard paclitaxel premedication was given before cremophor. Using a bioassay, potentially active cremophor levels (> or = 1 microl/ml) were measured in plasma from patients receiving cremophor doses of 30, 45, and 60 ml/m2. A cross-over design was used to assess the influence of cremophor 30 ml/m2 on the pharmacokinetics of doxorubicin and doxorubicinol. The plasma area under the concentration versus time curve (AUC) of doxorubicin increased from 1448 +/- 350 to 1786 +/- 264 ng/ml x h (P = 0.02) in the presence of cremophor, whereas the AUC of doxorubicinol increased from 252 +/- 104 to 486 +/- 107 ng/ml x h (P = 0.02). This pharmacokinetic interaction was associated with significantly increased neutropenia. With reduction of the doxorubicin dose to 35 mg/m2, the cremophor dose was increased to 60 ml/m2. Dose-limiting toxicities occurred in two of six patients after 45 ml/m2 and two of four patients after 60 ml/m2, which included febrile neutropenia and grade III cremophor-related toxicities of rash, pruritus, headache, and hypotension. All patients who received 45 ml/m2 cremophor reached plasma levels > or = 1.5 microl/ml, but at 60 ml/m2, only two of four reached this level, and the calculated plasma clearance of cremophor was significantly faster at this dose. One patient with hepatoma resistant to epirubicin achieved a near-complete response. Cremophor 45 ml/m2 over 6 h with 35 mg/m2 doxorubicin is recommended for further studies. The pharmacokinetic interaction between cremophor and doxorubicin is quantitatively similar to that described in trials of paclitaxel with doxorubicin and suggests that the cremophor in the paclitaxel formulation is responsible.
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Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Glicerol/análogos & derivados , Neoplasias/tratamiento farmacológico , Vehículos Farmacéuticos/administración & dosificación , Adulto , Anciano , Estudios Cruzados , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Femenino , Glicerol/administración & dosificación , Glicerol/farmacocinética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Using extracts of AtT-20 cell nuclei, protein binding sites on the POMC gene 5'-flanking region were examined with an exonuclease protection approach. One such binding site, located from -119 to -106 bp upstream from the mouse POMC gene transcription initiation site, which exhibited a close homology to the activator protein-2 (AP-2) site [1]. A double-stranded oligonucleotide containing this site was subsequently used in gel shift assays to demonstrate AP-2 consensus sequence binding activity in extracts of AtT-20 cell nuclei. Gel shift competition experiments using both homologous and heterologous competitor DNA sequences revealed that the AP-2 like factor(s) exhibited specific binding to the mouse AP-2 consensus sequence. Furthermore, AP-2 factor binding was also modulated by a CTF/NF1-like factor. Pretreatment of AtT-20 cell nuclear extracts with alkaline phosphatase prior to inclusion in gel shift assays led to a reduction in the intensities of AP-2 factor-specific bands, indicating a potential involvement of protein phosphorylation in AP-2 factor binding in AtT-20 cells.
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Proteínas de Unión al ADN/metabolismo , Genes , Proopiomelanocortina/genética , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Núcleo Celular/metabolismo , Genes Reguladores , Ratones , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , Neoplasias Hipofisarias , Factor de Transcripción AP-2 , Transcripción GenéticaRESUMEN
The endpoints assessed by both patients and nurses were compared in three anti-emetic studies. In a parallel subjects study, there was no significant difference between the patients' and nurses' assessment of the number of vomiting episodes, but the duration of vomiting, the severity and duration of nausea, and the side-effects of the anti-emetic were given higher scores by the nurses. In two cross-over studies, the patients recorded more vomiting episodes than the nurses, while the nurses recorded more anxiety and sedation than the patients. This resulted in the patients detecting a difference between the side-effects of the anti-emetics being compared that was not apparent from the nurses' forms. Many of the differences reflect differences in the timing and frequency of data collection. Nurses collected data regularly during the assessment period whereas patients reported their experiences only at the completion of 24 h. Both assessments provide useful perspectives on the study outcomes.
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Metoclopramida/administración & dosificación , Proclorperazina/administración & dosificación , Vómitos/tratamiento farmacológico , Estudios Cruzados , Método Doble Ciego , Humanos , Lorazepam/administración & dosificación , Metoclopramida/efectos adversos , Enfermeras y Enfermeros , Variaciones Dependientes del Observador , Pacientes , Proclorperazina/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Vómitos/diagnósticoRESUMEN
Patients with locally advanced stage 3 or 4 recurrent squamous cell carcinoma of the head and neck received 5-fluorouracil (5-FU) 200 or 300 mg/m2/day by prolonged ambulatory infusion concomitantly with radiotherapy (60-66 Gy) to the primary site and neck nodes in 30-33 fractions at five fractions per week, boosting to smaller volumes after 60 Gy. Of 39 patients, the complete response rate was 82% (95% CI: 67-93%). The estimated percentage without failure at 2 years was 59% (S.E. 8%) and at 4 years was 50% (S.E. 8%). Estimated head and neck cancer specific survival was 64% (S.E. 8%) at 2 years and 52% (S.E. 8%) at 4 years. Acute toxicities included moist desquamation in 49% and dry desquamation in 28%, confluent mucositis in 56% and patchy mucositis in 44%. Late effects, more than 6 months after completing treatment, assessed in 35 patients, included severe salivary dysfunction in 3 patients and moderate in 21, severe osteonecrosis in 4 patients and moderate toxicity in subcutaneous tissues in 13, skin in 3 and mucosa in 2 patients. It is feasible to give continuous 5-FU concurrently with radiotherapy in locally advanced or recurrent head and neck cancer, albeit with increased toxicity. The response rate and survival obtained in this trial justify further investigation of the combined treatment in a randomised trial.
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Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Fluorouracilo/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Adulto , Anciano , Atención Ambulatoria , Carcinoma de Células Escamosas/patología , Terapia Combinada , Esquema de Medicación , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/patología , Humanos , Bombas de Infusión Implantables , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Radioterapia/efectos adversos , Tasa de SupervivenciaRESUMEN
Patients receiving outpatient chemotherapy, without cisplatin, were randomised to receive four doses of either domperidone 60 mg or prochlorperazine 25 mg suppositories every 4 h, starting 30 min before the chemotherapy. They were crossed over for the next chemotherapy cycle. To enable analysis of 100 patients who had received identical chemotherapy in each course, 136 patients were randomised. Patients experienced a higher grade of nausea on domperidone (P = 0.05). Only 18% of patients vomited on domperidone and 14% on prochlorperazine, but the number of vomits was higher on domperidone (P = 0.003) and the duration was significantly increased (P = 0.02). Patients experienced significantly more diarrhoea on domperidone (P < 0.0001), although it was predominantly mild. Patients were significantly more sedated on prochlorperazine on the second course (P = 0.006), but not on the first course (P = 0.9). More patients preferred their second course (P < 0.0001), and were significantly less anxious (P = 0.0002). Patients reported tolerating their treatment similarly for both antiemetics, but more patients preferred prochlorperazine (P = 0.003), mainly due to reductions in nausea and vomiting and other side-effects, particularly diarrhoea.
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Domperidona/administración & dosificación , Proclorperazina/administración & dosificación , Vómitos/prevención & control , Adulto , Anciano , Antineoplásicos/efectos adversos , Diarrea/inducido químicamente , Domperidona/efectos adversos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proclorperazina/efectos adversos , Estudios Prospectivos , Supositorios , Vómitos/inducido químicamenteRESUMEN
To define further the place of dexamethasone in antiemetic combinations, lorazepam, prochlorperazine and placebo (LP) were compared with lorazepam, prochlorperazine and dexamethasone (DLP) in a randomised, double-blind, crossover study. Both patient and observer assessments were documented in 84 patients receiving both cisplatin and non-cisplatin chemotherapy. The addition of dexamethasone significantly reduced the severity of nausea (P = 0.002) and vomiting (P less than 0.0001), duration of nausea (P = 0.01) and vomiting (P = 0.002) and the number of vomiting episodes (P = 0.003). DLP was the superior regimen in subsets of patients receiving cisplatin and the non-cisplatin chemotherapy. The improvements produced by the dexamethasone regimen were large and of major benefit to our patients. Patients documented significantly improved tolerance to chemotherapy with DLP courses (P = 0.0006). Overall, significantly more patients preferred DLP (P less than 0.0001). Patient assessments produced results similar to observer assessments but gave a broader understanding of their experience. The addition of dexamethasone to prochlorperazine and lorazepam significantly improved our patients' experience while receiving chemotherapy.
Asunto(s)
Antieméticos/uso terapéutico , Dexametasona/uso terapéutico , Lorazepam/uso terapéutico , Neoplasias/tratamiento farmacológico , Proclorperazina/uso terapéutico , Adulto , Anciano , Cisplatino/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Vómitos/inducido químicamenteRESUMEN
High-dose prochlorperazine 0.8 mg/kg administered intravenously 30 min pre and 7 h 30 min post the initial dose of emetogenic chemotherapy was compared to high-dose metoclopramide 2 mg/kg over 20 min every 2 h for five doses starting 30 min prior to chemotherapy in a randomised, double-blind, parallel subjects design study. On the prochlorperazine arm intravenous dextrose placebos every 2 h maintained blinding. Complete suppression of vomiting occurred in 42% on metoclopramide (53% with non-cisplatin regimens) and 36% on prochlorperazine (52% with non-cisplatin-containing regimens) while major responses (2 or less vomits) occurred in 58% on metoclopramide and 54% on prochlorperazine. In patients who vomited after cisplatin, prochlorperazine achieved a significantly shorter duration of vomiting, a median of 5 h compared to 15 h on metoclopramide (P = 0.03). The response rate to prochlorperazine for cisplatin-induced emesis between 12 and 24 h was significantly better than for metoclopramide (prochlorperazine = 0.02). Toxicities were equivalent except for significantly greater sedation and dry mouth on prochlorperazine. Extrapyramidal reactions were recorded equally on both arms but were only severe enough to stop treatment on metoclopramide. The metoclopramide regimen was five times as expensive as prochlorperazine. High-dose prochlorperazine is an active and cost-effective antiemetic.