RESUMEN
The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB(12)) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Eligible patients had incurable solid tumours by standard treatments, a performance status 0-2, and adequate organ function. Pemetrexed from 300 to 1,200 mg m(-2) was administered as a 10-min infusion on day 1 of a 21-day cycle with FA/VB(12). Totally, 31 patients were treated. Dose-limiting toxicities were alanine aminotransferase (ALT) elevation at 700 mg m(-2), and infection and skin rash at 1,200 mg m(-2). The MTD/RD were determined to be 1,200/1,000 mg m(-2), respectively. The most common grade 3/4 toxicities were neutropenia (grade (G) 3:29, G4:3%), leucopenia (G3:13, G4:3%), lympopenia (G3:13%) and ALT elevation (G3:13%). Pemetrexed pharmacokinetics in Japanese were not overtly different from those in western patients. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1,200/1,000 mg m(-2), respectively, that is, a higher RD than without FA/VB(12) (500 mg m(-2)). Pemetrexed with FA/VB(12) showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study.
Asunto(s)
Antineoplásicos/administración & dosificación , Ácido Fólico/administración & dosificación , Glutamatos/administración & dosificación , Guanina/análogos & derivados , Neoplasias/tratamiento farmacológico , Vitamina B 12/administración & dosificación , Adulto , Anciano , Alanina Transaminasa/sangre , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Glutamatos/efectos adversos , Glutamatos/farmacocinética , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/farmacocinética , Humanos , Infusiones Intravenosas , Japón , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia/inducido químicamente , Pemetrexed , Seguridad , Resultado del TratamientoRESUMEN
In recent years, bronchial asthma has come to be regarded pathologically as a chronic inflammatory disease of the respiratory tract. Inhalational steroids and antiinflammatory drugs are recognized as being effective against bronchial asthma. In this study, the effects of Saiboku-to, a Chinese herbal (Kampo) formulation, were investigated on asthmatic guinea pigs sensitized to ovalbumin (OA). Following 7-day administration of Saiboku-to (500 micrograms/kg), the late asthmatic response (LAR) to an antigen challenge was found to be inhibited. The number of eosinophils in fluid obtained by bronchoalveolar lavage (BAL) 4 h after antigen challenge was decreased while the infiltration of eosinophils and T-lymphocytes into the lung parenchyma was inhibited. These findings suggest that Saiboku-to has the potential to become a useful drug in the treatment of bronchial asthma.
Asunto(s)
Asma/fisiopatología , Broncoconstricción/efectos de los fármacos , Broncodilatadores/farmacología , Medicamentos Herbarios Chinos/farmacología , Animales , Antígenos/administración & dosificación , Asma/tratamiento farmacológico , Asma/inmunología , Asma/patología , Broncoconstricción/inmunología , Modelos Animales de Enfermedad , Cobayas , Masculino , Medicina Tradicional China , Ovalbúmina/administración & dosificaciónRESUMEN
In recent years, bronchial asthma has come to be regarded as a chronic inflammatory disease of the respiratory tract, with mast cells, lymphocytes and eosinophils playing important roles in its pathogenesis. Proteins contained in eosinophil granules, especially major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO), can cause tissue injury. When stimulated, eosinophils release mediators such as leukotriene C4 (LTC4) and platelet activating factors (PAF). Thus, they are recognized as effector cells that are actively involved in the development of allergic inflammation. In this study, eosinophils from healthy volunteers were used to investigate the effects of Saiboku-to on eosinophils whose survival had been prolonged through stimulation with eosinophil-activating cytokines such as interleukin (IL)-3, IL-5 and granulocyte macrophage colony stimulating factors (GM-CSF). As a result, the cytokine-enhanced survival of eosinophils was significantly shortened by the addition of Saiboku-to. These findings suggest that Saiboku-to has the potential to inhibit allergic responses by directly affecting eosinophils which are related to allergic inflammation.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Eosinófilos/efectos de los fármacos , Inmunosupresores/farmacología , Medicina Kampo , Supervivencia Celular/efectos de los fármacos , Citocinas/biosíntesis , Citocinas/farmacología , Factor Estimulante de Colonias de Granulocitos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Técnicas In Vitro , Interleucina-3/antagonistas & inhibidores , Interleucina-3/farmacología , Interleucina-5/antagonistas & inhibidores , Interleucina-5/farmacología , Factores de TiempoRESUMEN
The aim of this study was to examine the suppressive effect of simvastatin on intramural coronary arterial lesions in cholesterol-fed rabbits. In one experiment, six groups of rabbits were fed laboratory chow alone or with added 0.1%, 0.2%, 0.3%, 0.5% or 1.0% cholesterol for 16 weeks. In another experiment, four groups of rabbits were fed a 0.5% cholesterol diet and treated with simvastatin at 1, 3, or 5 mg/kg/day or placebo. In each rabbit, the levels of serum total cholesterol (TC) were determined at 1-week intervals to calculate the integrated values. The lesion induction ratio was defined as the ratio of intramural coronary arteries 50-150 microm in diameter with arterial lipoidosis to the total number of arteries of the same diameter. In the two experiments, there were positive correlations between the lesion induction ratio and integrated TC (r=0.785, P<0.0001 and r=0.763, P<0.0001, respectively). The slopes of the regression lines for integrated TC obtained in the two experiments were similar, but the lesion induction ratio in the simvastatin-treated group was always lower, by about 14%, in comparison with that in the non-simvastatin-treated group. These findings suggest that simvastatin induces lesion reduction not only by reducing the levels of circulating cholesterol but also by directly suppressing the development of lipoidosis.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Colesterol en la Dieta/administración & dosificación , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Vasos Coronarios/efectos de los fármacos , Simvastatina/uso terapéutico , Animales , Anticolesterolemiantes/farmacología , Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/patología , Depresión Química , Dieta Aterogénica , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Modelos Lineales , Masculino , Conejos , Distribución Aleatoria , Simvastatina/farmacologíaRESUMEN
We studied tumor samples from 39 patients, who entered our study from January 1989 to May 1990, to assess whether the ability to establish a continually growing tumor cell line from fresh tumor specimens can be associated with decreased survival times in patients with small-cell lung cancer. The tumor samples were used to establish cell lines in culture using a serum-free medium supplemented with hydrocortisone, insulin, transferrin, estrogen, and selenium (HITES). Thirty-three of these specimens were obtained by fiberoptic bronchoscopy from primary sites during routine diagnostic procedures. A total of 11 (28%) cell lines were established: seven (21%) from 33 primary tumors and four (80%) from five peripheral lymph nodes. Survival times of the 11 patients whose tumor cell specimens continually grew in culture at any time during their clinical course were significantly shorter than those of the 28 patients whose tumor cell specimens did not grow in vitro (median survival time of 26 weeks versus 73 weeks; P = .0068). Cox's proportional hazards model, including sex, age, Eastern Cooperative Oncology Group performance status, stage, source of specimen, treatment, and in vitro tumor cell growth in the overall patient group, showed that cell line establishment (P = .0017) and no therapy (P = .0015) were the most important factors indicating poor survival time. For the subgroup of 23 primary tumor patients, the important factors (in decreasing order) that indicated decreased survival times were the establishment of a cell line (P = .0112) and with cyclophosphamide-doxorubicin-vincristine alternating with cisplatin-etoposide, versus cisplatin-vincristine-doxorubicin-etoposide therapy (P = .0463). Our study demonstrates that in vitro tumor cell growth is an adverse predominant prognostic factor in patients with small-cell lung cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/patología , Neoplasias Pulmonares/patología , Anciano , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/radioterapia , División Celular , Cisplatino/administración & dosificación , Terapia Combinada , Técnicas de Cultivo/métodos , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Células Tumorales Cultivadas , Vincristina/administración & dosificaciónRESUMEN
A phase I clinical study of intravenous Tegafur was conducted in nineteen previously treated patients with primary lung cancer. The dose of Tegafur was elevated from 1.0 to 3.0 g/m2/day for five consecutive days to determine the maximum tolerated dose. The dose-limiting factors were gastrointestinal and neurological toxicity and fatigability observed with the dose level of 2.5 g/m2/day for 5 days. Hematologic, hepatic and renal toxicities were not observed. Gastrointestinal toxicity including nausea, vomiting, anorexia and diarrhea of over grade 2 were seen to result from the dose of 2.5 g/m2/day. Neurological toxicity consisted of headache, dizziness, anxiety and depression. At the dose level of 2.0 g/m2/day, one patient, who had epileptic seizures in the past, experienced a psychomotor seizure. Depression (Grade 2 CNS toxicity) was observed at the dose level of 3.0 g/m2/day. Dose limiting factors were neurological toxicities. The pharmacokinetics of tegafur and 5-FU (the active form of Tegafur) has been studied in all patients. Serum level of tegafur was measured by HPLC method, and serum level of 5-FU was analyzed by GC-MS method. At the dose level greater than 2.0 g/m2/day for 5 days, the mean serum 5-FU values appear over the therapeutic range (0.1 micrograms/ml). In conclusion, 2.5 g/m2/day for 5 days was considered to be MTD, and 2.0 g/m2/day for 5 days intravenous administration was recommended for the phase II trial of single agent chemotherapy.
Asunto(s)
Neoplasias Pulmonares/tratamiento farmacológico , Tegafur/administración & dosificación , Esquema de Medicación , Evaluación de Medicamentos , Fluorouracilo/sangre , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/metabolismo , Persona de Mediana Edad , Tegafur/efectos adversos , Tegafur/farmacocinéticaRESUMEN
Cytochrome a1c1 (nitrite-cytochrome c oxidoreductase) purified from Nitrobacter winogradskyi (formerly N. agilis) contained molybdenum, non-heme iron, and acid-labile sulfur in addition to hemes a and c; it contained 1 mol of heme a, 4-5 g atoms of non-heme iron, 2-5 g atoms of acid-labile sulfur, and 1-2 g atoms of molybdenum per mol of heme c, but did not contain copper. The fluorescence spectra of the molybdenum cofactor derivative prepared from cytochrome a1c1 were very similar to those of the cofactor derivative from xanthine oxidase, and the aponitrate reductase of nit-1 mutant of Neurospora crassa was complemented by addition of the molybdenum cofactor derived from the cytochrome. Further, the ESR spectrum of cytochrome a1c1 was similar to that of liver sulfite oxidase. The content of cytochrome a1 in the cells cultivated with the medium in which tungsten was substituted for molybdenum markedly decreased as compared with that in the cells cultivated in the molybdenum-supplemented medium. These results indicate that cytochrome a1c1 is an iron-sulfur molybdoenzyme which contains hemes a and c.
Asunto(s)
Citocromos a1 , Citocromos c1 , Hemo/análogos & derivados , Nitrato Reductasas/análisis , Nitrobacter/enzimología , Oxidorreductasas/aislamiento & purificación , Espectroscopía de Resonancia por Spin del Electrón , Hemo/análisis , Molibdeno/análisis , Azufre/análisis , Tungsteno/metabolismoRESUMEN
Methanol extracts of bracken frond and rhizomes prepared using a metallic extraction vessel, were proved incapable of producing bracken poisoning in calves. Nevertheless, they contained appreciable quantities of pterosins and pterosides. Thus the poisonous principle(s) in bracken responsible for the toxicological effects are not associated with these major sesquiterpenoids of the plant.