RESUMO
BACKGROUND: Neoplastic diseases are often associated with low plasma low-density lipoprotein (LDL) cholesterol and diminished LDL clearance due to upregulation in cancer cells of the receptors that internalize the lipoprotein. Thus, it is possible to use LDL or cholesterol-rich microemulsions (LDE) that bind to LDL receptors as carriers of antineoplastic agents to concentrate those drugs into cancer tissues. Our aim was to determine whether LDL cholesterol concentration plus LDE increased clearance occur in lymphomas. PATIENTS AND METHODS: The LDE labeled with [(3) H]-cholesteryl oleate was injected into four Hodgkin's and 12 non-Hodgkin's lymphoma patients and into 16 healthy control subjects and the LDE plasma residence time (RT) was determined from sequential plasma samples. Two volunteers with relapsed/refractory lymphoma were treated with 300 mg/m(2) body surface etoposide associated with LDE in six cycles at 3-week intervals. RESULTS: The LDL cholesterol was lower in lymphoma patients than in controls (94+/-52 and 115+/-16 mg/dL, p=0.0362, respectively). The LDE RT was 49% smaller in lymphoma patients than in controls (RT=21.9 and 45.7 h; p=0.0134), with positive correlation between RT and LDL cholesterol. LDE-etoposide showed no considerable toxicity in all cycles in the two treated patients and the disease remained stable during the treatment. CONCLUSIONS: Our results suggest that lymphomas overexpress LDL receptors that make room for using LDE as drug-targeting vehicle and that the LDE-etoposide preparation is suitable for patient use.
Assuntos
Antineoplásicos Fitogênicos/toxicidade , Ésteres do Colesterol/farmacocinética , Etoposídeo/toxicidade , Doença de Hodgkin/metabolismo , Linfoma não Hodgkin/metabolismo , Adolescente , Adulto , Idoso , Ésteres do Colesterol/administração & dosagem , Ésteres do Colesterol/efeitos adversos , LDL-Colesterol/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacocinética , Emulsões , Feminino , Doença de Hodgkin/tratamento farmacológico , Humanos , Cinética , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Projetos Piloto , Receptores de LDL/metabolismoRESUMO
We have treated 10 patients suffering from kala-azar in Brazil with Amphocil (amphotericin B cholesterol dispersion) at a dose of 2 mg/kg/d for 5 d, following an earlier study in which this dosage for 7 d was found to cure all of 9 patients, with no relapse during 12 months. In the present study, all patients demonstrated initial resolution of disease. Parasites were absent upon bone marrow re-aspiration 2 weeks after therapy; no spleen extended beyond the costal margin 2 months after therapy; white blood cell counts, platelet counts, and serum levels of albumin rapidly returned to normal. Although one patient relapsed at 5 months, 8 of the other 9 patients had spleens of normal size (undetectable on deep palpation) at 12 months after therapy. Fever, sometimes accompanied by increased respiratory rate, occurred on the first day of drug infusion in 8 of 10 patients and was more severe in patients < 6 years old. Pre-medication with a non-steroidal anti-inflammatory agent (diclofenac potassium) before the next 4 infusions protected against this side effect in 5 of 6 patients. The results of this and our previous study suggest that the most appropriate regimen of Amphocil for kala-azar is 2 mg/kg/d for 7 d, with pre-medication each day, in patients aged > 5 years.
Assuntos
Anfotericina B/análogos & derivados , Antiprotozoários/uso terapêutico , Ésteres do Colesterol/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Adulto , Anfotericina B/efeitos adversos , Anfotericina B/uso terapêutico , Antiprotozoários/efeitos adversos , Brasil , Criança , Pré-Escolar , Ésteres do Colesterol/efeitos adversos , Diclofenaco/uso terapêutico , Feminino , Febre/prevenção & controle , Humanos , Lactente , MasculinoRESUMO
Amphotericin B is an effective but toxic antileishmanial agent. Lipid-encapsulated amphotericin B should have a high therapeutic index for visceral leishmaniasis because reticuloendothelial cells, the sole site in which Leishmania is found, will phagocytize and concentrate the complex. Amphotericin B cholesterol dispersion (Amphocil; 2 mg/[kg.d] intravenously) was administered to 10 Brazilians with kala-azar for 10 days (cohort 1) and to 10 Brazilians with kala-azar for 7 days (cohort 2). All patients were successfully treated: 19 of the 20 patients were without visible parasites in the bone marrow; the mean time to afebrility was 4.2 days; spleen size regressed by a mean of 79% 2 months after therapy; and no patient had clinical or laboratory abnormalities by the end of 6-12 months of follow-up. Side effects were fever and chills accompanied by respiratory distress, but not nephrotoxicity, in children < 3 years of age.