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Caracterização dos polimorfismos CYP2C19 mais relevantes para a variabilidade interindividual na resposta à terapêutica com inibidores da bomba de protões : aplicação da farmacogenética na farmácia comunitária portuguesa
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Advisor(s)
Abstract(s)
Introdução: A variabilidade interindividual na resposta à terapêutica com Inibidores da
Bomba de Protões (IBP), resulta da variabilidade genotípica e fenotípica associada ao
gene do citocromo P450 2C19 (CYP2C19).
Objetivos: i) caracterizar o genótipo e fenótipo dos doentes a realizar terapêutica com
IBP, variantes CYP2C19*1, *2, *3 e *17; ii) avaliar se a terapêutica selecionada e a dose
instituída são concordantes com o fenótipo do doente; iii) avaliar a implementação do
serviço de Farmacogenética na farmácia comunitária portuguesa;
Materiais e métodos: No presente estudo transversal piloto, aplicou-se um questionário
de avaliação acerca da terapêutica com IBP e recolheu-se a amostra proveniente das
células da mucosa oral de 33 doentes, seguindo-se a extração de ácido
desoxirribonucleico (ADN), a reação em cadeia da polimerase ou Polymerase Chain
Reaction (PCR), a análise dos fragmentos de restrição dos polimorfismos ou Restriction
Fragment Length Polymorphism (RFLP) e a técnica de sequenciação. Análise estatística
através do software Estatístico R, baseado no teste do qui-quadrado (χ2) e com um
intervalo de confiança (IC) a 95% (*p<0,05). Os resultados obtidos foram ainda
comparados com uma população em equilíbrio Hardy-Weinberg (H-W) (p>0,05).
Resultados: As frequências alélicas do CYP2C19*1 (-806C, rs12248560) e
CYP2C19*17 (-806T) foram 71,21% e 28,79%, respetivamente. As frequências
genotípicas do CYP2C19*1/*1 (-806C/C) e CYP2C19*1/*17 (-806C/T) foram 42,42% e
57,58%, respetivamente, e 19 doentes foram referenciados por carta de opinião
farmacêutica. Na distribuição genotípica do CYP2C19*3 (c.636G>A, rs4986893) foi
apenas encontrado o genótipo wild type CYP2C19*1/*1 (636G/G) e está em equilíbrio
H-W (p>0,05), na distribuição alélica registam-se alterações significativas entre o sexo
(*p<0,05). Na prescrição de IBP, o omeprazol representa 39,4%, a renovação da
terapêutica 72,7% e a Doença de Refluxo Gastro Esofágico (DRGE) 66,7%.
Conclusão: A implementação da Farmacogenética na prática clínica é uma necessidade
imperiosa para o sucesso da terapêutica com IBP, ao considerar a variabilidade do
CYP2C19, na amostra em estudo e o uso crescente, nos últimos anos, de IBP em Portugal.
Introduction: The interindividual variability in response to therapy with Proton Pump Inhibitors (PPIs), results from the genotypic and phenotypic variability associated with the cytochrome P450 2C19 gene (CYP2C19). Objectives: i) characterize the genotype and phenotype of patients that realize therapy with PPIs, CYP2C19*1, *2, *3 and *17 variants; ii) assess whether the selected therapy and the dose instituted are in agreement with the patient's phenotype; iii) evaluate the implementation of a Pharmacogenetics (PGx) service in Portuguese community pharmacy; Materials and methods: In the present pilot cross-sectional study, a questionnaire for the assessment of PPIs therapy was applied and the sample from the oral mucosa cells of 33 patients was collected, followed by the extraction of deoxyribonucleic acid (DNA), polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and sequencing. Statistical analysis with the R Project, based on the chi-square test (χ2), with a 95% confidence interval (CI) (*p-value<0.05). The results obtained were also compared with a population in Hardy-Weinberg Equilibrium (HWE) (p-value>0.05). Results: The allele frequencies of CYP2C19*1 (-806C, rs12248560) and CYP2C19*17 (-806T) were 71.21% and 28.79%, respectively. The genotypic frequencies for CYP2C19*1/*1 (-806C/C) and CYP2C19*1/*17 (-806C/T) were 42.42% and 57.58%, respectively and 19 patients were referred by a pharmaceutical opinion letter. In the genotypic distribution of CYP2C19*3 (c.636G>A, rs4986893), only the wild type genotype CYP2C19*1/*1 (636G/G) was found and is in HWE (p-value>0.05), the allelic distribution had significant changes between sex (*p-value<0.05). In the prescription of PPIs omeprazole represents 39.4%, renewal of therapy 72.7% and Gastro Esophageal Reflux Disease (GERD) 66.7%. Conclusion: The implementation of PGx, in clinical practice is an imperative need for success of PPIs therapy, considering the variability of CYP2C19, in the study sample and the increasing use, in recent years, of PPIs in Portugal.
Introduction: The interindividual variability in response to therapy with Proton Pump Inhibitors (PPIs), results from the genotypic and phenotypic variability associated with the cytochrome P450 2C19 gene (CYP2C19). Objectives: i) characterize the genotype and phenotype of patients that realize therapy with PPIs, CYP2C19*1, *2, *3 and *17 variants; ii) assess whether the selected therapy and the dose instituted are in agreement with the patient's phenotype; iii) evaluate the implementation of a Pharmacogenetics (PGx) service in Portuguese community pharmacy; Materials and methods: In the present pilot cross-sectional study, a questionnaire for the assessment of PPIs therapy was applied and the sample from the oral mucosa cells of 33 patients was collected, followed by the extraction of deoxyribonucleic acid (DNA), polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and sequencing. Statistical analysis with the R Project, based on the chi-square test (χ2), with a 95% confidence interval (CI) (*p-value<0.05). The results obtained were also compared with a population in Hardy-Weinberg Equilibrium (HWE) (p-value>0.05). Results: The allele frequencies of CYP2C19*1 (-806C, rs12248560) and CYP2C19*17 (-806T) were 71.21% and 28.79%, respectively. The genotypic frequencies for CYP2C19*1/*1 (-806C/C) and CYP2C19*1/*17 (-806C/T) were 42.42% and 57.58%, respectively and 19 patients were referred by a pharmaceutical opinion letter. In the genotypic distribution of CYP2C19*3 (c.636G>A, rs4986893), only the wild type genotype CYP2C19*1/*1 (636G/G) was found and is in HWE (p-value>0.05), the allelic distribution had significant changes between sex (*p-value<0.05). In the prescription of PPIs omeprazole represents 39.4%, renewal of therapy 72.7% and Gastro Esophageal Reflux Disease (GERD) 66.7%. Conclusion: The implementation of PGx, in clinical practice is an imperative need for success of PPIs therapy, considering the variability of CYP2C19, in the study sample and the increasing use, in recent years, of PPIs in Portugal.
Description
Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz
Keywords
Citocromo P450 2C19 Variabilidade genotípica Farmacogenética Inibidores da bomba de protões