RESUMO
PURPOSE: To develop and validate a population pharmacokinetic model of Methotrexate (MTX) in Mexican children with acute lymphoblastic leukemia (ALL) for the design of personalized dosage regimens based on the anthropometric and physiological characteristics of each patient. METHODS: A prospective study was developed in 50 children (1-15 years old) with ALL diagnosis attended at Pediatric Hemato-Oncology Service from Hospital Central "Dr. Ignacio Morones Prieto" and under treatment with high doses of MTX administered in 24-h continuous intravenous infusion. Plasma concentrations of MTX were determined in blood samples collected at 24, 36, 42 or 48 h post-infusion, by means of the CMIA immunoassay. The development of the population pharmacokinetic model was performed using the NONMEM® software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volume of distribution of MTX. RESULTS: A two-compartment open model was selected to describe concentration-time data and body surface area (BSA) was the covariate that influences on MTX total CL. The population pharmacokinetic model obtained was: CL (L/h) = 6.5 × BSA0.62, Vc (L) = 0.36 × Weight, Q (L/h) = 0.41 and Vp (L) = 3.2. Internal validation was performed by bootstrap and visual predictive check. Predictive performance of final model was evaluated by external validation in a different group of patients. Initial MTX dosing regimens were established by stochastic simulation with final population pharmacokinetic model. CONCLUSIONS: The establishment of MTX dosing criteria in children with ALL should be adjusted based on the BSA of each patient to optimize oncological therapy and reduce the development of adverse effects. Therapeutic drug monitoring is an essential tool to individualize MTX doses to reduce toxicity and improve patients' outcomes.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Superfície Corporal , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Seguimentos , Humanos , Lactente , Masculino , México/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Prospectivos , Distribuição TecidualRESUMO
PURPOSE: The presence of deleterious variants of dihydropyrimidine-dehydrogenase gene (DPYD) is associated with 5-Fluorouracil toxicity. Most of the data are based on findings in Caucasian populations. The variant Y186C (rs115232898) is found almost exclusively in African populations and is related to low DPD function. Its prevalence may vary among African subpopulations and in African Americans. There is no information in other populations. Brazil has the biggest African population outside Africa. We studied for the first time the frequency of this mutation in African Brazilians. METHODS: We amplified exon 6 of DPYD extracted from genomic DNA of 79 healthy volunteers of genetically defined African ancestry from Southeast Brazil and 36 self-reported African descendants from Northeast Brazil in order to determine the prevalence of the variant Y186C in Brazilians of African ancestry. RESULTS: The variant Y186C was found in heterozygosity in two samples from Southeast (2.53%) and one from Northeast (2.77%) Brazil. Overall, the prevalence of this mutation in the 115 African Brazilians was 2.6%. CONCLUSIONS: The variant Y186C is prevalent among Brazilians of African ancestry and should be taken in account in targeted genotyping for fluoropyrimidine risk variants.
Assuntos
População Negra/genética , Deficiência da Di-Hidropirimidina Desidrogenase/etnologia , Di-Hidrouracila Desidrogenase (NADP)/genética , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Brasil/epidemiologia , Capecitabina/farmacocinética , Capecitabina/uso terapêutico , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Feminino , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Voluntários Saudáveis , Humanos , Masculino , Mutação , Neoplasias/tratamento farmacológico , PrevalênciaRESUMO
Methotrexate (MTX), a structural analog of folic acid, is widely employed in the treatment of different cancers and autoimmune diseases. Despite the successful results observed, the main disadvantage lies in interpatient variability in the pharmacokinetic and pharmacodynamic parameters. In particular, adverse events and toxicities induced by MTX are a matter of concern and can be the cause of dose reduction or treatment discontinuation. Among the different approaches to reduce MTX therapeutic limitations, pharmacogenomics contributes by considering the effect of inherited genetic differences on those parameters. This review provides an update on MTX pharmacogenomics. It reports the contribution of main gene polymorphisms involved in the influx, efflux, cellular effect, and elimination on MTX toxicity and efficacy, on all the diseases treated with this drug. From the analysis of the data presented in this review, we concluded that only gene polymorphisms MTHFR rs1801133, SLC19A1 rs1051266, and TYMS rs34743033 could influence clinical decision-making.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Imunossupressores/efeitos adversos , Metotrexato/efeitos adversos , Farmacogenética/métodos , Variantes Farmacogenômicos , Polimorfismo Genético , Medicina de Precisão/métodos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Tomada de Decisão Clínica , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Seleção de Pacientes , Testes Farmacogenômicos , Valor Preditivo dos Testes , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Medição de Risco , Timidilato Sintase/genética , Timidilato Sintase/metabolismoRESUMO
OBJECTIVE: to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment. METHODS: Pre-chemotherapy plasma, fresh saliva and DSS samples were obtained from gastrointestinal patients (Nâ¯=â¯40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for 5FU area under the curve (AUC) determination by HPLC-DAD. Data on toxicity was reported according to CTCAE. RESULTS: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% of the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rsâ¯=â¯0.960; rsâ¯=â¯0.828; rsâ¯=â¯0.910, respectively). 5FU AUC ranged from 11.3 to 37.31â¯mgâ¯hâ¯L-1, with 46.2% of under-dosed and 10.3% over-dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (râ¯=â¯-0.412, rsâ¯=â¯-0.373, rsâ¯=â¯0.377) and toxicity (râ¯=â¯-0.363, rsâ¯=â¯-0.523, rsâ¯=â¯0.542). Metabolic ratios were lower in patients with severe toxicity (Pâ¯<â¯.01 salivary ratios, and Pâ¯<â¯.5 plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable. CONCLUSIONS: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Deficiência da Di-Hidropirimidina Desidrogenase/diagnóstico , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Fluoruracila/efeitos adversos , Neutropenia/induzido quimicamente , Saliva/metabolismo , Uracila/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Biomarcadores/sangue , Biomarcadores/metabolismo , Biotransformação , Deficiência da Di-Hidropirimidina Desidrogenase/sangue , Deficiência da Di-Hidropirimidina Desidrogenase/complicações , Deficiência da Di-Hidropirimidina Desidrogenase/metabolismo , Di-Hidrouracila Desidrogenase (NADP)/sangue , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Leucopenia/sangue , Leucopenia/induzido quimicamente , Leucopenia/metabolismo , Leucopenia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/metabolismo , Neutropenia/fisiopatologia , Índice de Gravidade de Doença , Caracteres Sexuais , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Trombocitopenia/fisiopatologia , Uracila/análogos & derivados , Uracila/sangueRESUMO
Poly(lactic acid) (PLA) or poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) blend nanoparticles were developed loading 5-fluorouracil (5-FU), an antitumor agent broadly used in therapy. A 2(3) factorial experimental design was conducted to indicate an optimal formulation and demonstrate the influence of the interactions of components on the mean particle size and drug encapsulation efficiency. Optimized PLA nanoparticles presented 294nm and 51% of 5-FU encapsulation efficiency and PLA-PEG blend nanoparticles presented 283nm and 55% of 5-FU encapsulation efficiency. In vitro release assay demonstrated after 320h about 50% of 5-FU was released from PLA and PLA-PEG blend nanoparticles. Release kinetics of 5-FU from nanoparticles followed second order and the release mechanism calculated by Korsmeyer-Peppas model was diffusion and erosion. In the assessment of cytotoxicity over Hep-2 tumor cells, PLA or PLA-PEG blend nanoparticles presented similar IC50 value than free 5-FU. Pharmacokinetic parameters after oral administration of 5-FU were improved by nanoencapsulation. Bioavailability, Cmax, Tmax, t1/2 and distribution volume were significantly improved, while clearance were decreased. PEG presence in nanoparticles didn't influence physicochemical and biological parameters evaluated. PLA and PLA-PEG nanoparticles can be potential carriers for oral delivery of 5-FU.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Fluoruracila/administração & dosagem , Nanopartículas/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Portadores de Fármacos/farmacocinética , Fluoruracila/sangue , Fluoruracila/farmacocinética , Humanos , Masculino , Poliésteres/farmacocinética , Polietilenoglicóis/farmacocinética , Ratos WistarRESUMO
Cancer is characterized by the uncontrolled growth of cells with the ability of invading local organs and/or tissues and of spreading to other sites. Several kinds of mathematical models have been proposed in the literature, involving different levels of refinement, for the evolution of tumors and their interactions with chemotherapy drugs. In this article, we present the solution of a state estimation problem for tumor size evolution. A system of nonlinear ordinary differential equations is used as the state evolution model, which involves as state variables the numbers of tumor, normal and angiogenic cells, as well as the masses of the chemotherapy and anti-angiogenic drugs in the body. Measurements of the numbers of tumor and normal cells are considered available for the inverse analysis. Parameters appearing in the formulation of the state evolution model are treated as Gaussian random variables and their uncertainties are taken into account in the estimation of the state variables, by using an algorithm based on the auxiliary sampling importance resampling particle filter. Test cases are examined in the article dealing with a chemotherapy protocol for pancreatic cancer.
Assuntos
Neoplasias/patologia , Algoritmos , Antimetabólitos Antineoplásicos/farmacocinética , Simulação por Computador , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Diagnóstico por Computador , Meia-Vida , Humanos , Modelos Biológicos , Método de Monte Carlo , Neoplasias/tratamento farmacológico , Carga Tumoral , GencitabinaRESUMO
Para fundamentar as ações de cuidado integralizado em saúde da mulher é necessário compreender de que modo o apoio social pode contribuir para minimizar as repercussões do diagnóstico e do tratamento da neoplasia mamária. O objetivo deste estudo é analisar a contribuição da produção científica nacional e internacional acerca do apoio social percebido por mulheres diagnosticadas com câncer de mama. A amostra foi constituída de 12 publicações, obtidas a partir de critérios de inclusão preestabelecidos, nas bases de dados MedLine, Lilacs e PsycINFO, na última década (2000-2010). Os resultados foram sistematizados em categorias temáticas: percepção do apoio familiar, apoio social percebido, percepção do apoio educacional, necessidade de aprimoramento da pesquisa e assistência às mastectomizadas e suas famílias. Os estudos dedicados à dimensão subjetiva do apoio social ainda são incipientes. As evidências disponíveis sugerem que a literatura é circunscrita a temas de interesse das profissões tradicionais da área da saúde, como Enfermagem e Medicina, privilegiando construtos que podem ser diretamente quantificados. A preocupação com o apoio social deve estar presente desde a fase de diagnóstico até a reabilitação psicossocial, como parte do processo de enfrentamento.
It is necessary to understand how social support can contribute to minimize the impact of the diagnosis and treatment of mammary tumors in order to underpin the actions of comprehensive women's health care. This study seeks to analyze the contribution of the national and international literature regarding the perceived social support by women diagnosed with breast cancer. Twelve studies were selected from the MedLine, Lilacs and PsycINFO databases over a 10-year period (2000-2010) with pre-defined criteria for inclusion. The results were organized into thematic categories: the perception of family support; perceived social support; the perception of educational support; the need to improve the research and the assistance given to women after mastectomy and their families. The studies dedicated to the subjective dimension of social support are still incipient. The available evidence suggests that the literature is limited to topics of interest to the traditional health professions, such as Nursing and Medicine, focusing on constructs that can be directly quantified. The concern with social support must be present from the time of diagnosis to psychosocial rehabilitation, as part of the process of tackling the situation.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fatores Etários , Antimetabólitos Antineoplásicos/uso terapêutico , Área Sob a Curva , Capecitabina , Neoplasias Colorretais/metabolismo , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Floxuridina/sangue , Fluoruracila/sangue , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Taxa de Filtração Glomerular , Taxa de Depuração Metabólica , Fatores SexuaisRESUMO
This study aimed to evaluate in the Brazilian population, the genotypes and population frequencies of pharmacogenetic polymorphisms involved in the response to drugs used in treatment of acute lymphoblastic leukemia (ALL), and to compare the data with data from the HapMap populations. There was significant differentiation between most population pairs, but few associations between genetic ancestry and SNPs in the Brazilian population were observed. AMOVA analysis comparing the Brazilian population to all other populations retrieved from HapMap pointed to a genetic proximity with the European population. These associations point to preclusion of the use of genetic ancestry as a proxy for predicting drug response. In this way, any study aiming to correlate genotype with drug response in the Brazilian population should be based on pharmacogenetic SNP genotypes.
Assuntos
Antineoplásicos/farmacocinética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Grupos Raciais/genética , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Biotransformação/genética , Brasil , Frequência do Gene , Loci Gênicos , Marcadores Genéticos , Genótipo , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapêutico , Projeto HapMap , Humanos , Mercaptopurina/farmacocinética , Mercaptopurina/uso terapêutico , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Análise de RegressãoRESUMO
BACKGROUND: Lipid nanoemulsions that bind to low-density lipoprotein receptors can concentrate chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression and decrease the toxicity of the treatment. The aim of this study was to develop a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE). METHODS: ddMTX was synthesized by an esterification reaction between methotrexate and dodecyl bromide. The lipid nanoemulsion was prepared by four hours of ultrasonication of a mixture of phosphatidylcholine, triolein, and cholesteryloleate. Association of ddMTX with the lipid nanoemulsion was performed by additional cosonication of ddMTX with the previously prepared lipid nanoemulsion. Formulation stability was evaluated, and cell uptake, cytotoxicity, and acute animal toxicity studies were performed. RESULTS: The yield of ddMTX incorporation was 98% and the particle size of LDE-ddMTX was 60 nm. After 48 hours of incubation with plasma, approximately 28% ddMTX was released from the lipid nanoemulsion. The formulation remained stable for at least 45 days at 4°C. Cytotoxicity of LDE-ddMTX against K562 and HL60 neoplastic cells was higher than for methotrexate (50% inhibitory concentration [IC(50)] 1.6 versus 18.2 mM and 0.2 versus 26 mM, respectively), and cellular uptake of LDE-ddMTX was 90-fold higher than that of methotrexate in K562 cells and 75-fold in HL60 cells. Toxicity of LDE-ddMTX, administered at escalating doses, was higher than for methotrexate (LD(50) 115 mg/kg versus 470 mg/kg; maximum tolerated dose 47 mg/kg versus 94 mg/kg) in mice. However, the hematological toxicity of LDE-ddMTX was lower than for methotrexate. CONCLUSION: LDE-ddMTX was stable, and uptake of the formulation by neoplastic cells was remarkably greater than of methotrexate, which resulted in markedly greater cytotoxicity. LDE-ddMTX is thus a promising formulation to be tested in future animal models of cancer or rheumatic disease, wherein methotrexate is widely used.
Assuntos
Lipídeos/administração & dosagem , Lipídeos/química , Metotrexato/administração & dosagem , Metotrexato/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Contagem de Células Sanguíneas , Sistemas de Liberação de Medicamentos , Emulsões/administração & dosagem , Emulsões/química , Feminino , Células HL-60 , Humanos , Células K562 , Estimativa de Kaplan-Meier , Dose Máxima Tolerável , Metotrexato/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Testes de ToxicidadeRESUMO
5-Fluorouracil (5-FU) is an antineoplasic drug widely used to treat cancer. Its cytotoxic effect has been principally ascribed to the misincorporation of fluoronucleotides into DNA and RNA during their synthesis, and the inhibition of thymidylate synthase (TS) by FdUMP (one of the 5-FU active metabolites), which leads to nucleotide pool imbalance. In the present study, we compared the ability of 5-FU and FdUMP to induce apoptosis and to influence the cell cycle progression in human colon SW620 adenocarcinoma cells in regards to their genotoxic and clastogenic activities. Our study demonstrates that 5-FU induces SSB, DSB and apoptosis earlier than FdUMP. Interestingly, while both drugs are able to induce apoptosis, their effect on the cell cycle progression differed. Indeed, 5-FU induces an arrest in G1/S while FdUMP causes an arrest in G2/M. Independently of the temporal difference in strand breaks and apoptosis induction, as well as the differential cell cycle modulation, both drugs presented similar clastogenic effects. The different pattern of cell cycle arrest suggests that the two drugs induce different types of primary DNA lesions that could lead to the activation of different checkpoints and recruit different DNA repair pathways.