RESUMO
This phase II trial was conducted to evaluate the percentage of objective responses and the toxicity profile of combination doxorubicin (Adriamycin) and paclitaxel (Taxol) with granulocyte colony-stimulating factor as first-line therapy for patients with metastatic breast cancer (MBC) not previously exposed to anthracycline-containing regimens. Patients with measurable, visceral-dominant MBC and a performance status of 0 to 2 were included in the study. Doxorubicin 60 mg/m2 was administered as a short intravenous infusion, followed by paclitaxel 250 mg/m2 as a 3-hour intravenous infusion on day 1. Granulocyte colony-stimulating factor 5 micrograms/kg/d was given prophylactically as a subcutaneous injection from day 2 until granulocyte recovery to > or = 1,500/mm3. Treatment was repeated every 21 days for a maximum of six courses. Dose reductions (to doxorubicin 50 mg/m2 and paclitaxel 175 mg/m2) and/or treatment delay were applied in case of severe toxicity. All 25 women who entered were evaluable for response and toxicity. The main grade 3/4 toxicities observed were leukopenia, thrombocytopenia, and mucositis. Alopecia occurred in all patients. No clinically relevant cardiovascular toxicity was observed. Severe myelosuppression and/or mucositis necessitated dose reductions at courses 2 or 3 in all but one patient. The complete response rate was 28%, and the partial response rate was 52% for an overall objective response rate of 80%. Median progression-free survival for complete responders was 11 months (range, 3 to 24 months), while the progression-free survival was 7+ months (range 2 to 14+ months) for partial responders and 5 months (range, 3 to 9 months) for nonresponders. This combination produces a high objective response rate in women with MBC, but dose reductions were necessary in almost all cases. Toxicity was manageable after dose reduction, allowing patients to be re-treated for two to six courses without life-threatening toxicity or toxic deaths. Unfortunately, the duration of response was limited even among complete responders. Further trials of this combination in patients with MBC should explore improvements in this study regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Progressão da Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Neutropenia/prevenção & controle , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , SobrevidaRESUMO
AIMS AND BACKGROUND: To evaluate the response rate, toxicity and survival of patients with AIDS-related Kaposi's sarcoma (AIDS-KS) treated in a phase II clinical trial of pentosan polysulpate (PPS), an inhibitor of basic-fibroblast growth factor (b-FGF) which blocks the growth of Kaposi's sarcoma cells both in culture and in animal models. PATIENTS AND METHODS: Between March 1992 and March 1994 16 homosexual males with histopathologically confirmed AIDS-KS were accrued for this phase II clinical trial. PPS was administered at the dose of 25 mg/m2 q6 hrs at day 1, followed by 25 mg/m2 q12 hrs daily by a subcutaneous injection. The number of patients to be included in the trial was calculated according to the two-stage Gehan method. Toxicity was graded according to the NCl Common Toxicity Criteria, while responses were evaluated according to the WHO Criteria adapted for KS lesions. Patients were all homosexual males, median age 35 (27-43) years, performance status (WHO) 1 (0-2), NYU stage II-IV and prior therapy included vincristine and etoposide (3 cases), local irradiation (4 cases) and megestrol acetate (2 cases). Concomitant AZT (zidovudine) was given to 3 patients, while DDI (dideoxyinosine) was administered in one case. RESULTS: A median of 5 (3-11) weeks of therapy was administered to the patients. Pain at the injection site and low grade fever were the only toxicities observed. Drug-related effects on coagulation parameters or thrombocytopenia were not observed in the trial. One objective response (6%) was documented, which lasted for 9 weeks, while stable disease was observed in three patients, lasting for 11, 9 and 5 weeks, respectively. CONCLUSION: This is the first observation of objective antitumor activity with a b-FGF inhibitor in patients with AIDS-KS. Considering it novelty and the lack of significant toxicity, the authors suggest that this experimental approach deserves further evaluation.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Poliéster Sulfúrico de Pentosana/uso terapêutico , Sarcoma de Kaposi/virologia , Síndrome da Imunodeficiência Adquirida/etiologia , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Homossexualidade Masculina , Humanos , Masculino , Poliéster Sulfúrico de Pentosana/administração & dosagem , Poliéster Sulfúrico de Pentosana/efeitos adversos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Rats submitted to one, two, or seven sessions of exploration to a new environment (habituation) or exposed to an inhibitory avoidance training showed different degrees of anxiety, evaluated by the elevated plus-maze test. Also, the brain regional levels of benzodiazepine (BDZ)-like molecules in rats submitted to one, two, or seven sessions of habituation were differentially decreased with respect to nontrained rats. The percentage of time spent in the open arms of the elevated plus-maze for each group correlates with the data of decrease in the BDZ-like immunoreactivity in amygdala (r = 0.77, p < 0.0005), hippocampus (r = 0.68, p < 0.0005), and septum (r = 0.57, p < 0.005). These results suggest that the limbic system responds to anxiogenic experiences by changing the BDZ-like molecule levels in relation to the degree of anxiety and/or stress that accompany these experiences.
Assuntos
Ansiedade/metabolismo , Comportamento Animal/fisiologia , Benzodiazepinas/metabolismo , Química Encefálica/fisiologia , Condicionamento Operante/fisiologia , Animais , Masculino , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologiaAssuntos
Doenças Cardiovasculares/prevenção & controle , Ácidos Graxos/metabolismo , Óleos de Peixe/administração & dosagem , Doenças Cardiovasculares/metabolismo , Gorduras na Dieta/administração & dosagem , Óleos de Peixe/efeitos adversos , Óleos de Peixe/metabolismo , Humanos , Hipertensão/prevenção & controle , Isquemia Miocárdica/prevenção & controle , Doenças Vasculares Periféricas/prevenção & controleRESUMO
Adult rats were submitted to two different behavioral tasks using the same apparantus: the habituation of exploration of the apparatus considered as a novel environment as measured by the decrease in number of reaings and of ambulation between training and testing, and step-down inhibitory avoidance as measured by the increase in the latency to step down from a start platform into an electrified grid between the training and the test session.The training-test interval for both tasks was 20 h.The immediate post-training injection of the benzodiazepine receptor antagonist flumazenil (10 nmol) bilateral into the hippocampus enhanced retention of the two tasks.Application of the same drug, at the same dose to the septum or amygdala had no effect on habituation but enhanced retention of the avoidance task. The data are consistent with previous findings showing that both tasks are accompanied by the release of benzodiazepine like immunoreactivity in the three structures and that this release is greater after the avoidance task. The present findings suggest a differential regional involvement of endogenous benzodiazepine-mediated mechanisms in memory modulation, according to the task undertaken
Assuntos
Ratos , Animais , Masculino , Tonsila do Cerebelo/efeitos dos fármacos , Flumazenil/farmacologia , Habituação Psicofisiológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Retenção Psicológica/efeitos dos fármacos , Septo Pelúcido/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Flumazenil/administração & dosagem , Habituação Psicofisiológica/fisiologia , Hipocampo/fisiologia , Microinjeções , Receptores de GABA/efeitos dos fármacos , Receptores de GABA/fisiologia , Retenção Psicológica/fisiologia , Septo Pelúcido/fisiologiaRESUMO
Adult rats were submitted to two different behavioral tasks using the same apparatus: the habituation of exploration of the apparatus considered as a novel environment as measured by the decrease in number of rearings and of ambulation between training and testing, and step-down inhibitory avoidance as measured by the increase in the latency to step down from a start platform onto an electrified grid between the training and the test session. The training-test interval for both tasks was 20 h. The immediate post-training injection of the benzodiazepine receptor antagonist flumazenil (10 nmol) bilaterally into the hippocampus enhanced retention of the two tasks. Application of the same drug, at the same dose to the septum or amygdala had no effect on habituation but enhanced retention of the avoidance task. The data are consistent with previous findings showing that both tasks are accompanied by the release of benzodiazepine-like immunoreactivity in the three structures and that this release is greater after the avoidance task. The present findings suggest a differential regional involvement of endogenous benzodiazepine-mediated mechanisms in memory modulation, according to the task undertaken.