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1.
Front Pharmacol ; 12: 749786, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34776967

RESUMO

Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model's ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients (n = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, p = 1.43 × 10-15). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone (n = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.

2.
J Vasc Bras ; 20: e20200214, 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34104133

RESUMO

Background: Genetic factors can be responsible for part of the populational and interindividual differences observed in warfarin users. Objectives: To identify occurrence of polymorphisms of the CYP2C9 and VKORC1 genes in patients taking warfarin and relate these profiles to their medication dosages and the Time in Therapeutic Range (TTR). Methods: Monthly interviews were conducted for data collection. Data were collected on demographic characteristics and medications in use, especially warfarin, including reason for prescription and weekly dose. TTR was calculated as the percentage of days with international normalized ratio (INR) between 2 and 3. The CYP2C9 and VKORC1 genes were analyzed at a Human Genetics Laboratory. Results: 49 patients (74.2%) had polymorphisms of the CYP2C9 and/or VKORC1 genes; the remaining 17 (25.8%) did not have these polymorphisms. The average weekly dose of warfarin was lower among those who had a polymorphism for any of the genes compared to those who did not, with a significant difference (p = 0.035). The mean TTR was also lower among patients with polymorphism. However, the difference between the two groups was not significant for this variable (p = 0.438). Conclusions: An association was observed between the polymorphisms and the warfarin doses taken by the patients. However, there was no association with adverse events or the time spent within the therapeutic range in this sample.

3.
Oral Dis ; 2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33774891

RESUMO

OBJECTIVES: Oral mucositis (OM) is an acute toxicity related to cancer treatment. This systematic review aimed to identify potential risk factors associated with the development of OM in pediatric cancer patients. METHODS: A search was performed in four electronic databases to identify studies that analyzed risk factors for OM in pediatric cancer patients. RESULTS: Nineteen articles were included. The incidence of OM ranged from 20% to 80.4%. Chemotherapeutic agents were potential risk factors for OM in eight (42%) studies. Hematological, hepatic, and renal parameters were also considered in eight (42%) studies, while specific individual factors were reported in five (26.3%) studies. Baseline disease, oral microbiota, genetic profile, and biomarkers were reported in four (21.5%) studies each. Meta-analysis showed that groups submitted to high-risk chemotherapy for OM had a 2.79-fold increased risk of OM. CONCLUSIONS: Identifying risk factors for OM is essential in order to allow individualized and early prevention treatment.

4.
Haemophilia ; 27(2): e204-e213, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33550700

RESUMO

INTRODUCTION: von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays an important role in haemostasis. von Willebrand disease (VWD) is an inherited heterogeneous bleeding disorder caused by either a quantitative or qualitative defect of VWF. Type 3 VWD, the most severe form of the disease, leads to complete quantitative VWF deficiency. AIM: The present study aims to investigate the molecular pathogenesis of type 3 VWD patients from Southern Brazil. METHODS: The VWF gene was sequenced in 26 cases clinically diagnosed with type 3 VWD by next-generation sequencing using Ion Torrent PGM. RESULTS: In 25 patients, we were able to identify both disease-causing variants. We identified 72 different variants: 31 intronic and 41 exonic. Five novel variants were found: c.6976+5G>T; c.6885_6886insC; c.3378C>T (p.Cys1126); c.3346_3347insCCA; and c.2503G>T (p.Glu835*). Variants p.Pro2063Ser and p.Arg324* co-segregated in 17 patients, 15 of them in homozygosity. CONCLUSION: Our results may contribute to the discussion on whether the variant p.Pro2063Ser is pathogenic or not. Finally, the presence of a common haplotype in patients bearing these two variants suggests a founder effect for this variant in our region.


Assuntos
Doença de von Willebrand Tipo 3 , Fator de von Willebrand , Substituição de Aminoácidos , Brasil , Hemostasia , Humanos , Doença de von Willebrand Tipo 3/genética , Doenças de von Willebrand/genética , Fator de von Willebrand/genética
5.
J. vasc. bras ; 20: e20200214, 2021. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1250238

RESUMO

Abstract Background Genetic factors can be responsible for part of the populational and interindividual differences observed in warfarin users. Objectives To identify occurrence of polymorphisms of the CYP2C9 and VKORC1 genes in patients taking warfarin and relate these profiles to their medication dosages and the Time in Therapeutic Range (TTR). Methods Monthly interviews were conducted for data collection. Data were collected on demographic characteristics and medications in use, especially warfarin, including reason for prescription and weekly dose. TTR was calculated as the percentage of days with international normalized ratio (INR) between 2 and 3. The CYP2C9 and VKORC1 genes were analyzed at a Human Genetics Laboratory. Results 49 patients (74.2%) had polymorphisms of the CYP2C9 and/or VKORC1 genes; the remaining 17 (25.8%) did not have these polymorphisms. The average weekly dose of warfarin was lower among those who had a polymorphism for any of the genes compared to those who did not, with a significant difference (p = 0.035). The mean TTR was also lower among patients with polymorphism. However, the difference between the two groups was not significant for this variable (p = 0.438). Conclusions An association was observed between the polymorphisms and the warfarin doses taken by the patients. However, there was no association with adverse events or the time spent within the therapeutic range in this sample.


Resumo Contexto Fatores genéticos podem ser responsáveis por parte das diferenças populacionais e interindividuais observadas em usuários de varfarina. Objetivos Identificar a ocorrência de polimorfismo dos genes CYP2C9 e VKORC1 em pacientes em uso de varfarina e relacionar esses perfis com a dose do medicamento e o tempo no intervalo terapêutico. Métodos Foram realizadas entrevistas mensais para a coleta de dados. Foram reunidos dados sobre características demográficas e medicamentos em uso, principalmente sobre varfarina, como motivo da prescrição e dose semanal. O tempo no intervalo terapêutico foi calculado como a porcentagem de dias com razão normalizada internacional entre os valores 2 e 3. Os genes CYP2C9 e VKORC1 foram analisados em laboratório de Genética Humana. Resultados Entre os participantes, 49 pacientes (74,2%) apresentaram polimorfismo dos genes CYP2C9 e/ou VKORC1; os 17 restantes (25,8%) não apresentaram esses polimorfismos. A dose média semanal de varfarina foi menor entre os que apresentaram polimorfismo para algum dos genes em comparação aos que não apresentaram, com diferença significativa (p = 0,035). O tempo no intervalo terapêutico médio também foi menor entre os pacientes com polimorfismo. Porém, não houve diferença significativa entre os dois grupos para essa variável (p = 0,438). Conclusões Foi observada associação entre os polimorfismos e a dose de varfarina utilizada pelos pacientes; no entanto, não houve associação com eventos adversos e o tempo de permanência na faixa terapêutica nessa amostra.

6.
J. vasc. bras ; 20: e20200214, 2021. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1287079

RESUMO

Abstract Background Genetic factors can be responsible for part of the populational and interindividual differences observed in warfarin users. Objectives To identify occurrence of polymorphisms of the CYP2C9 and VKORC1 genes in patients taking warfarin and relate these profiles to their medication dosages and the Time in Therapeutic Range (TTR). Methods Monthly interviews were conducted for data collection. Data were collected on demographic characteristics and medications in use, especially warfarin, including reason for prescription and weekly dose. TTR was calculated as the percentage of days with international normalized ratio (INR) between 2 and 3. The CYP2C9 and VKORC1 genes were analyzed at a Human Genetics Laboratory. Results 49 patients (74.2%) had polymorphisms of the CYP2C9 and/or VKORC1 genes; the remaining 17 (25.8%) did not have these polymorphisms. The average weekly dose of warfarin was lower among those who had a polymorphism for any of the genes compared to those who did not, with a significant difference (p = 0.035). The mean TTR was also lower among patients with polymorphism. However, the difference between the two groups was not significant for this variable (p = 0.438). Conclusions An association was observed between the polymorphisms and the warfarin doses taken by the patients. However, there was no association with adverse events or the time spent within the therapeutic range in this sample.


Resumo Contexto Fatores genéticos podem ser responsáveis por parte das diferenças populacionais e interindividuais observadas em usuários de varfarina. Objetivos Identificar a ocorrência de polimorfismo dos genes CYP2C9 e VKORC1 em pacientes em uso de varfarina e relacionar esses perfis com a dose do medicamento e o tempo no intervalo terapêutico. Métodos Foram realizadas entrevistas mensais para a coleta de dados. Foram reunidos dados sobre características demográficas e medicamentos em uso, principalmente sobre varfarina, como motivo da prescrição e dose semanal. O tempo no intervalo terapêutico foi calculado como a porcentagem de dias com razão normalizada internacional entre os valores 2 e 3. Os genes CYP2C9 e VKORC1 foram analisados em laboratório de Genética Humana. Resultados Entre os participantes, 49 pacientes (74,2%) apresentaram polimorfismo dos genes CYP2C9 e/ou VKORC1; os 17 restantes (25,8%) não apresentaram esses polimorfismos. A dose média semanal de varfarina foi menor entre os que apresentaram polimorfismo para algum dos genes em comparação aos que não apresentaram, com diferença significativa (p = 0,035). O tempo no intervalo terapêutico médio também foi menor entre os pacientes com polimorfismo. Porém, não houve diferença significativa entre os dois grupos para essa variável (p = 0,438). Conclusões Foi observada associação entre os polimorfismos e a dose de varfarina utilizada pelos pacientes; no entanto, não houve associação com eventos adversos e o tempo de permanência na faixa terapêutica nessa amostra.

7.
Br J Clin Pharmacol ; 84(5): 987-996, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29352482

RESUMO

AIMS: To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort. METHODS: The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry. Two-step (univariate followed by multivariate) regression modelling was developed to identify covariates associated with systemic exposure to metformin, accessed by the area under the plasma concentration-time curve, between 0 and 48 h (AUC0-48h ), after single oral doses of metformin (500 or 1000 mg). RESULTS: The individual proportions of African, Amerindian and European ancestry varied widely, as anticipated from the structure of the Brazilian population The dose-adjusted, log-transformed AUC0-48h 's (ng h ml-1  mg-1 ) differed largely in the two groups at the opposite ends of the distribution histogram, namely 0.82, 0.79-0.85 and 1.08, 1.06-1.11 (mean, 95% confidence interval; P = 6.10-26 , t test). Multivariate modelling revealed that metformin AUC0-48h increased with age, food and carriage of rs12208357 in SLC22A1 but was inversely associated with body surface area and individual proportions of African ancestry. CONCLUSIONS: A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age, body surface area and individual proportion of African ancestry) and a food effect explained 29.7% of the variability in metformin AUC0-48h .


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Índios Sul-Americanos/genética , Metformina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/genética , Adulto , Brasil , Demografia , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Metformina/sangue , Fenótipo , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como Assunto , Fator de Transcrição Sp1/genética
8.
Pharmacogenomics ; 13(14): 1557-9; author reply 1561-2, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23148630

RESUMO

A letter in response to: Andersson ML, Eliasson E, Lindh JD. A clinically significant interaction between warfarin and simvastatin is unique to carriers of the CYP2C9*3 allele. Pharmacogenomics 13(7), 757-762 (2012).


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Relação Dose-Resposta a Droga , Interações Medicamentosas/genética , Sinvastatina/uso terapêutico , Varfarina/uso terapêutico , Feminino , Humanos , Masculino
9.
Rev. Assoc. Med. Bras. (1992) ; 57(6): 692-696, nov.-dez. 2011. tab
Artigo em Inglês | LILACS | ID: lil-611231

RESUMO

OBJECTIVE:The aim of the study was to identify the frequency of risk factors for hypertensive disorders in pregnancy in Southern Brazil. METHODS: The study included 161 patients with hypertensive disorders and 169 control subjects matched by age and ethnicity. The frequency of the risk factors was compared by Fisher's exact test, chi-square and Student's t test. A multivariate logistic regression analysis assessed the independent role of clinical, social and demographic factors which were associated with occurrence of the hypertensive disease in pregnancy in the univariate analysis. RESULTS: Patients enrolled in the study were predominantly Caucasian (73 percent) and the mean age was 29. In the multivariate analysis, the variables associated were: family history of preeclampsia (p = 0.001; OR = 3.88; 95 percent CI = 1.77-8.46), diabetes (p = 0.021; OR = 3.87; 95 percent CI = 1.22-12.27) and chronic hypertension (p = 0.002; OR = 7.05; 95 percent CI = 1.99-24.93). CONCLUSION: The risk factors associated with hypertensive disorders in pregnancy appear to be similar to those reported in other countries. The knowledge of the risk factors could be helpful in a prenatal care.


OBJETIVO: Identificar a frequência dos fatores de risco para distúrbios hipertensivos durante a gravidez na região Sul do Brasil. MÉTODOS: O estudo incluiu 161 pacientes com distúrbios hipertensivos e 169 controles, compatíveis em idade e etnia. A frequência dos fatores de risco foi comparada a partir do teste exato de Fisher, teste qui-quadrado e teste t de Student. Uma análise logística multivariacional de regressão avaliou a influência de fatores clínicos, sociais e demográficos, associados com a ocorrência de doenças hipertensivas durante a gravidez na análise univariada. RESULTADOS: Os pacientes envolvidos no estudo eram predominantemente caucasianos (73 por cento) e a idade média foi 29 anos. Na análise multivariada as variáveis associadas foram: histórico de pré-eclâmpsia na família (p = 0,001; OR = 3,88; 95 por cento IC = 1,77-8,46), diabetes (p = 0,021; OR = 3,87; 95 por cento IC = 1,22-12,27) e hipertensão crônica (p = 0,002; OR = 7,05; 95 por cento IC = 1,99-24,93). CONCLUSÃO: Os fatores de risco associados a distúrbios hipertensivos durante a gravidez parecem ser similares àqueles relatados em outros países. O conhecimento sobre os fatores de risco pode ser útil durante o acompanhamento pré-natal.


Assuntos
Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Adulto Jovem , Hipertensão Induzida pela Gravidez/epidemiologia , Brasil/epidemiologia , Estudos de Casos e Controles , Hipertensão Induzida pela Gravidez/etiologia , Estudos Prospectivos , Análise de Regressão , Fatores de Risco
10.
Br J Clin Pharmacol ; 72(3): 442-50, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21320153

RESUMO

AIMS: To investigate the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes on warfarin dose-response and develop a model including genetic and non-genetic factors for warfarin dose prediction needed for each patient. METHODS: A total of 279 patients of European ancestry on warfarin medication were investigated. Genotypes for -1639G>A, 1173C>T, and 3730G>A SNPs in the VKORC1 gene, CYP2C9*2 and CYP2C9*3, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene were determined by allelic discrimination with Taqman 5'-nuclease assays. RESULTS: The CYP2C9*2 and CYP2C9*3 polymorphisms in the CYP2C9 gene, -1639G>A and 1173C>T in the VKORC1 gene and 494C>T in the F2 gene are responsible for lower anticoagulant doses. In contrast, 1347C>T in the CYP4F2 gene and 3730G>A in the VKORC1 gene are responsible for higher doses of warfarin. An algorithm including genetic, biological and pharmacological factors that explains 63.3% of warfarin dose variation was developed. CONCLUSION: The model suggested has one of the highest coefficients of determination among those described in the literature.


Assuntos
Anticoagulantes/administração & dosagem , Hidrocarboneto de Aril Hidroxilases/genética , Sistema Enzimático do Citocromo P-450/genética , Grupo com Ancestrais do Continente Europeu/genética , Oxigenases de Função Mista/genética , Polimorfismo de Nucleotídeo Único , Varfarina/administração & dosagem , Idoso , Algoritmos , Brasil/epidemiologia , Citocromo P-450 CYP2C9 , Família 4 do Citocromo P450 , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Estatística como Assunto , Vitamina K Epóxido Redutases
11.
Rev Assoc Med Bras (1992) ; 57(6): 692-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22249551

RESUMO

OBJECTIVE: The aim of the study was to identify the frequency of risk factors for hypertensive disorders in pregnancy in Southern Brazil. METHODS: The study included 161 patients with hypertensive disorders and 169 control subjects matched by age and ethnicity. The frequency of the risk factors was compared by Fisher's exact test, chi-square and Student's t test. A multivariate logistic regression analysis assessed the independent role of clinical, social and demographic factors which were associated with occurrence of the hypertensive disease in pregnancy in the univariate analysis. RESULTS: Patients enrolled in the study were predominantly Caucasian (73%) and the mean age was 29. In the multivariate analysis, the variables associated were: family history of preeclampsia (p = 0.001; OR = 3.88; 95% CI = 1.77-8.46), diabetes (p = 0.021; OR = 3.87; 95% CI = 1.22-12.27) and chronic hypertension (p = 0.002; OR = 7.05; 95% CI = 1.99-24.93). CONCLUSION: The risk factors associated with hypertensive disorders in pregnancy appear to be similar to those reported in other countries. The knowledge of the risk factors could be helpful in a prenatal care.


Assuntos
Hipertensão Induzida pela Gravidez/epidemiologia , Adolescente , Adulto , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Hipertensão Induzida pela Gravidez/etiologia , Pessoa de Meia-Idade , Gravidez , Estudos Prospectivos , Análise de Regressão , Fatores de Risco , Adulto Jovem
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