RESUMO
INTRODUCTION: In prostate cancer, androgens are key in the growth of both normal prostate and cancer cells. Abiraterone acetate inhibits CYP17, an important target in prostate cancer given its central role in the production of adrenal and tumor-derived androgens. Although abiraterone is generally well tolerated, common adverse effects such as hypertension, hypokalemia, and hepatotoxicity have been reported. CLINICAL CASE: We present the case of an 83-year-old Mexican man with high-volume EC IV prostate cancer resistant to castration, orchiectomy, and bone, liver, and lung metastases. First-line treatment with the CHAARTED scheme was indicated, by patient decision refuse chemotherapy treatment. On the fourth day of starting treatment, he developed pruritic erythematous macular skin lesions and urticaria on the posterior chest that resolved spontaneously. A generalized erythematous and pruritic maculopapular rash appeared 12 days after starting abiraterone, for which she was referred to allergies. MANAGEMENT AND RESULTS: An oral provocation test was performed for two days, presenting localized macular lesions eight hours after the administration of abiraterone. An oral desensitization protocol was carried out for ten days in which no hypersensitivity reactions were observed, thus achieving the successful administration of abiraterone.
Assuntos
Androstenos , Dessensibilização Imunológica , Hipersensibilidade a Drogas , Neoplasias da Próstata , Humanos , Masculino , Idoso de 80 Anos ou mais , Neoplasias da Próstata/tratamento farmacológico , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/etiologia , Androstenos/uso terapêutico , Androstenos/efeitos adversos , Androstenos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
Breast cancer treatment failure is related to low response rates, high costs, and long-term toxicities. Thus, it is necessary to find less toxic, cheaper, and more effective treatments. In situ administration ensures drug delivery to tumor cells and decreases systemic toxic effects. The androstene-3ß, 17α-diol (α-AED) reduces breast tumor cell proliferation and is an ideal candidate to treat mammary tumors. This study aims to identify the in vitro and in vivo effects of α-AED on a triple-negative mammary tumor model. An in vitro biphasic steroid effect was observed in mouse and human mammary tumor cells treated with α-AED. In this sense, cells treated with higher doses (100 and 200 µM) showed an antiproliferative effect. The α-AED administrated intratumorally reduced average tumor weight and increased the percentage of natural killer cells (NK), plasmatic, and plasmablast cells in mice tumors. Of note, VEGF levels in all α-AED-treated tumors was lower than in the control and vehicle groups. The tumor in situ increased response was reflected systemically by higher anti-4T1 IgG concentration in serum from α-AED-treated mice, but no other associated systemic changes were detected. The reduction in tumor size for the local injection of α-AED is associated with the anti-proliferative effect of this steroid, and the lower local levels of VEGF may be related to the imperceptible macroscopic metastasis in α-AED-treated mice. The above suggests that α-AED may be used in clinical studies to prove its efficacy as an alternative breast tumor treatment or in conjunction with already established therapies.
Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Androstenos , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoglobulina G , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Modelos Teóricos , Fator A de Crescimento do Endotélio VascularRESUMO
INTRODUCTION: Several studies in the Caucasian population have shown the benefit of using docetaxel, abiraterone, or enzalutamide for patients with metastatic prostate cancer at the castration-resistant stage (mCRPC). However, there are no strong data for men of African ancestry. The objective of this study was to estimate the overall and progression-free survival of patients according to these treatments at the mCRPC stage. PATIENTS AND METHODS: This was a monocentric retrospective study that consecutively included 211 men with mCRPC between June 1, 2009 and August 31, 2020. The primary end point was overall survival (OS). The secondary end point was progression-free survival. Kaplan-Meier survival and Cox proportional hazard analyses were performed. RESULTS: The present study included 180 patients for analyses. There was no difference in OS (log-rank test = 0.73), with a median follow-up of 20.7 months, regardless of the treatment administered in the first line. Men with mCRPC who received hormonotherapy (abiraterone or enzalutamide) showed better progression-free survival than those who received docetaxel (log-rank test = 0.004), with a particular interest for abiraterone hazard ratio (HR) = 0.51 (95% confidence interval: 0.39-0.67). The patient characteristics were similar, except for bone lesions, irrespective of the treatment administered in the first line. After univariate then multivariate analysis, only World Health Organization status and metastases at diagnosis were significantly associated with progression. CONCLUSION: Our results suggest the use of hormonotherapy (abiraterone or enzalutamide) with a tendency for abiraterone in first line for men with African ancestry at the mCRPC stage.
Assuntos
Androstenos/uso terapêutico , Benzamidas/uso terapêutico , População Negra/estatística & dados numéricos , Docetaxel/uso terapêutico , Metástase Neoplásica , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração , Antineoplásicos/uso terapêutico , Guadalupe/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/terapia , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/etnologia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Niemann-Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master lysosomal function regulator, reduces the accumulation of lysosomal substrates in LSDs where the degradative capacity of the cells is compromised. Genistein can pass the blood-brain barrier and activate TFEB. Hence, we investigated the effect of TFEB activation by genistein toward correcting the NPC phenotype. We show that genistein promotes TFEB translocation to the nucleus in HeLa TFEB-GFP, Huh7, and SHSY-5Y cells treated with U18666A and NPC1 patient fibroblasts. Genistein treatment improved lysosomal protein expression and autophagic flux, decreasing p62 levels and increasing those of the LC3-II in NPC1 patient fibroblasts. Genistein induced an increase in ß-hexosaminidase activity in the culture media of NPC1 patient fibroblasts, suggesting an increase in lysosomal exocytosis, which correlated with a decrease in cholesterol accumulation after filipin staining, including cells treated with U18666A and NPC1 patient fibroblasts. These results support that genistein-mediated TFEB activation corrects pathological phenotypes in NPC models and substantiates the need for further studies on this isoflavonoid as a potential therapeutic agent to treat NPCD and other LSDs with neurological compromise.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Genisteína/uso terapêutico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/metabolismo , Androstenos/uso terapêutico , Animais , Western Blotting , Linhagem Celular Tumoral , Colesterol/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células HeLa , Humanos , Doenças por Armazenamento dos Lisossomos , Lisossomos/metabolismo , Proteína C1 de Niemann-Pick/metabolismoRESUMO
The treatment of advanced prostate cancer has evolved due to recent advances in molecular research and new drug development. Dynamic aberrations in the androgen receptor, DNA repair genes, PTEN-PI3K, and other pathways drive the behavior of advanced prostate cancer allowing a better selection of therapies in each patient. Tumor testing for BRCA1 and BRCA2 is recommended for patients with metastatic prostate cancer, also considering a broad panel to guide decisions and genetic counseling. In symptomatic metastatic patients, castration should be stared to palliate symptoms and prolong survival. In high-risk or high-volume metastatic hormone-naïve patients, castration should be combined with docetaxel, abiraterone, enzalutamide or apalutamide. Radiotherapy to the primary tumor combined with systemic therapy is recommended in low-volume mHNPC patients. In patients with non-metastatic castration-resistant tumors, risk stratification can define the frequency of imaging. Adding enzalutamide, darolutamide or apalutamide to these patients prolongs metastasis-free and overall survival, but potential adverse events need to be taken into consideration. The choice of docetaxel, abiraterone or enzalutamide for treating metastatic castration-resistant patients depends on previous therapies, with cabazitaxel being also recommended after docetaxel. Olaparib is recommended in BRCA1/BRCA2 mutated castration-resistant patients after progression on at least one new hormonal therapy. Aggressive variants of prostate cancer respond to platinum-based chemotherapy. To optimize treatment efficiency, oncologists should incorporate all of these advances into an overall therapeutic strategy.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Próstata/terapia , Androstenos/uso terapêutico , Benzamidas/uso terapêutico , Terapia Combinada/métodos , Docetaxel/uso terapêutico , Genes BRCA1 , Genes BRCA2 , Testes Genéticos/métodos , Humanos , Masculino , Oncologia , Nitrilas/uso terapêutico , Orquiectomia , Feniltioidantoína/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/terapia , Radioterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sociedades Médicas , Espanha , Tioidantoínas/uso terapêuticoRESUMO
Therapeutic drug monitoring (TDM) approaches may benefit patients treated with abiraterone acetate (AA) as drug efficacy is imprecise and important pharmacokinetic variability is known. Current methods based on the analysis of plasma present the disadvantage of the fast degradation of the analytes in the liquid sample. Dried blood spots (DBS) consist of a minimally invasive and unexplored sampling strategy to monitor the levels of abiraterone (ABI) and delta(4)-abiraterone (D4A) in patients. This study presents the development and validation of a precise and accurate method to monitor ABI and D4A in DBS samples by UPLC-MS/MS. Bioanalytical method validation was carried out according to current guidelines, evaluating the impact of DBS-specific parameters such as hematocrit and spot volume on accuracy. Based on the analysis of quality control samples prepared at low, medium and high concentrations, the method was precise with CV ≤ 6.97 % and 10.26 % for ABI and D4A, respectively. The method was also highly accurate, between 93.6-106.8 % for ABI and 96.0-108.5 % for D4A. The DBS method is compatible with the analysis of samples of unknown volume and hematocrit range of the studied population. In addition, ABI and D4A were stable for 7 days in DBS at room temperature, which is feasible for sample transportation in postal service and analysis in the laboratory. Method application to 16 clinical samples revealed good correlation between measured plasma concentrations and estimated plasma concentrations for ABI (r = 0.884, P < 0.05) and D4A (r = 0.920, P < 0.05). Passing-Bablok regression analysis and Bland-Altmann plots indicated correlation between the results obtained from DBS and plasma, with a slight overestimation of the concentrations of ABI in DBS, which could be related to the small study cohort. Therefore, the results of this first work indicate that DBS consist of a promising alternative sampling strategy in TDM studies of AA.
Assuntos
Monitoramento de Medicamentos , Neoplasias da Próstata , Androstenos , Cromatografia Líquida , Teste em Amostras de Sangue Seco , Humanos , Masculino , Reprodutibilidade dos Testes , Espectrometria de Massas em TandemRESUMO
AIM: Combined hormonal contraceptives, despite their high efficacy, are associated with an increased relative risk of cardiovascular events. The contraceptive mechanism of action of combined pills depends fundamentally on their progestin component. METHODS: A narrative review was performed. RESULTS: The drospirenone-only pill, including this synthetic progestogen with antimineralocorticoid and antiandrogenic activity, has high contraceptive efficacy that has been demonstrated with a 24-day schedule of 4-day administration of hormone-free pills. Due to its safety profile, the drospirenone-only pill is suitable even in high-risk populations, such as women with high blood pressure, thromboembolism, smoking or dyslipidemia. CONCLUSION: Considering the increasing prevalence of these comorbidities in Latin America, the 4 mg drospirenone-only pill is suggested as one of the strategies of choice in the region for those women who choose oral contraceptives.
Assuntos
Androstenos , Anticoncepcionais Orais Sintéticos , Antagonistas de Receptores de Mineralocorticoides , Androstenos/uso terapêutico , Anticoncepção , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Sintéticos/uso terapêutico , Estrogênios , Feminino , Humanos , América Latina/epidemiologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêuticoRESUMO
Abiraterone acetate efficacy against prostate cancer is dependent on the circulating levels of abiraterone and its active metabolites, which present significant pharmacokinetic variability among patients. Thus, therapeutic drug monitoring can be performed to improve treatment outcomes. To support such studies, there are only a limited number of bioanalytical methods in current literature. This work presents a fast method to quantify abiraterone and D4A in plasma in 4 min by UPLC-MS/MS. Bioanalytical method validation was performed according to the recommendations of the US Food and Drug Administration. The method was linear within the range of 1-400 ng/ml for abiraterone and 0.2-20 ng/ml for D4A (r2 > 0.99). Based on the analysis of quality control samples at the lower limit of quantification, low, medium and high concentrations, the method was precise (CVabiraterone ≤ 9.72%; CVD4A ≤ 14.64%) and accurate (CVabiraterone 95.51-107.59%; CVD4A 98.04-99.89%). Application of the method to the quantification of abiraterone and D4A in 10 clinical samples revealed important variability in the conversion ratio of abiraterone to D4A (CV 90.85%). Considering the current literature, this is the fastest method to quantify abiraterone and D4A in plasma, allowing for optimization of the analytical routine.