Descripción de polimorfismos genéticos en CYP3A5 y MDR-1 y su impacto en el rechazo agudo clínico de pacientes trasplantados de hígado del Hospital San Vicente Fundación Rionegro / Description of genetic polymorphisms in CYP3A5 and MDR-1 and their impact on clinical acute rejection in liver transplant patients at Hospital San Vicente Fundación Rionegro

Introducción. El tacrolimus es un medicamento inmunosupresor ampliamente usado en trasplante hepático, que presenta una gran variabilidad interindividual la cual se considera asociada a la frecuencia de polimorfismos de CYP3A5 y MDR-1. El objetivo de este estudio fue evaluar la frecuencia de los polimorfismos rs776746, rs2032582 y rs1045642 y su asociación con rechazo clínico y toxicidad farmacológica. Métodos. Se incluyeron pacientes inmunosuprimidos con tacrolimus a quienes se les realizó trasplante hepático en el Hospital San Vicente Fundación Rionegro entre 2020 y 2022, con supervivencia mayor a un mes. Se evaluaron las variables clínicas, rechazo agudo y toxicidad farmacológica. Se secuenciaron los genes de estudio mediante PCR, comparando la expresión o no en cada uno de los pacientes. Resultados. Se identificaron 17 pacientes. El 43 % de los pacientes se clasificaron como CYP3A5*1/*1 y CYP3A5*1/*3, entre los cuales se encontró asociación con aumento en la tasa de rechazo agudo clínico, al comparar con los pacientes no expresivos (100 % vs. 44 %, p=0,05); no hubo diferencias en cuanto a la toxicidad farmacológica u otros desenlaces. Se encontró el polimorfismo rs2032582 en un 50 % y el rs1045642 en un 23,5 % de los pacientes, sin embargo, no se identificó asociación con rechazo u otros eventos clínicos. Conclusiones. Se encontró una asociación entre el genotipo CYP3A5*1/*1 y CYP3A5*1/*3 y la tasa de rechazo clínico. Sin embargo, se requiere una muestra más amplia para validar estos datos y plantear modelos de medicina personalizada.

Introduction. Tacrolimus is an immunosuppressive drug widely used in liver transplantation, which presents great interindividual variability which is considered associated with the frequency of CYP3A5 and MDR-1 polymorphisms. The objective of this study was to evaluate the frequency of the rs776746, rs2032582 and rs1045642 polymorphisms and their association with clinical rejection and drug toxicity. Methods. Immunosuppressed patients with tacrolimus who underwent a liver transplant at the Hospital San Vicente Fundación Rionegro between 2020 and 2022 were included, with survival of more than one month. Clinical variables, acute rejection and pharmacological toxicity were evaluated. The study genes were sequenced by PCR, comparing their expression or not in each of the patients. Results. Seventeen patients were identified. 43% of the patients were classified as CYP3A5*1/*1 and CYP3A5*1/*3, among which an association was found with increased rates of clinical acute rejection when compared with non-expressive patients (100% vs. 44%, p=0.05). There were no differences in drug toxicity or other outcomes. The rs2032582 polymorphism was found in 50% and rs1045642 in 23.5% of patients; however, no association with rejection or other clinical events was identified. Conclusions. An association was found between the CYP3A5*1/*1 and CYP3A5*1/*3 genotype and the clinical rejection rate. However, a larger sample is required to validate these data and propose models of personalized medicine.

Associação do poliformismo rs2228570 no gene VDR com o desfecho terapêutico em hanseníase / Association of rs2228570 polyformism in the VDR gene with therapeutic outcome in leprosy

A hanseníase é uma doença crônica que afeta principalmente os nervos periféricos e a pele, causada pelo Mycobacterium leprae, um parasita intracelular. O tratamento de primeira escolha na hanseníase é a poliquimioterapia (PQT) composta por rifampicina, dapsona e clofazimina. Estudos têm investigado a influência de fatores genéticos na suscetibilidade à hanseníase per se, porém não há investigações sobre a associação destes fatores com a resposta ao tratamento. Segundo os registros da OMS, o Brasil é o segundo país no mundo em número de casos retratamento da hanseníase. O gene do receptor de vitamina D (VDR) é um dos genes já associado com a doença. Além do papel importante no sistema imunológico, esse fator de transcrição, codificado por este gene, também atua no metabolismo de drogas. Assim, variações genéticas do tipo polimorfismos de nucleotídeo único (SNPs), no gene VDR podem afetar a resposta do organismo à doença e ao tratamento. Este estudo teve como objetivo avaliar a associação do polimorfismo rs2228570 no gene VDR com o desfecho terapêutico em casos de hanseníase multibacilar, através de estudo do tipo caso-controle. Foram analisados 315 prontuários de pacientes do estado de São Paulo, sendo 149 casos com necessidade de retratamento e 166 controles com sucesso terapêutico. A genotipagem do polimorfismo rs2228570 foi realizada por meio da técnica de discriminação alélica. A associação entre os genótipos e o desfecho terapêutico foi analisada por modelo de regressão logística multinomial, com ajuste dos dados pelas covariáveis sexo e etnia. Os resultados mostraram que o genótipo AA da variante rs2228570 no gene VDR está associado com o risco de retratamento na hanseníase multibacilar (Odds Ratio= 2.56; IC95: 1.13-5.82). Esse dado reafirma a importância da farmacogenética na terapêutica da hanseníase para a identificação de pacientes com maior risco de retratamento quando submetidos a poliquimioterapia convencional.

Leprosy is a chronic disease that mainly affects the peripheral nerves and skin, caused by Mycobacterium leprae, an intracellular parasite. The first-line treatment for leprosy is multidrug therapy (MDT) composed of rifampicin, dapsone, and clofazimine. Studies have investigated the influence of genetic factors on susceptibility to leprosy per se, but there have been no investigations into the association of these factors with treatment response. According to WHO records, Brazil is the second country in the world in the number of cases of leprosy retreatment. The vitamin D receptor (VDR) gene is one of the genes already associated with the disease. In addition to its important role in the immune system, this transcription factor, encoded by this gene, also plays a role in drug metabolism. Thus, genetic variations such as single nucleotide polymorphisms (SNPs) in the VDR gene can affect the body's response to the disease and treatment. This study aimed to evaluate the association of the rs2228570 polymorphism in the VDR gene with the therapeutic outcome in cases of multibacillary leprosy, through a case-control study. A total of 315 patient records from the state of São Paulo were analyzed, including 149 cases requiring retreatment and 166 controls with therapeutic success. Genotyping of the rs2228570 polymorphism was performed using the allele discrimination technique. The association between genotypes and therapeutic outcome was analyzed by multinomial logistic regression model, adjusting the data for covariates such as gender and ethnicity. The results showed that the AA genotype of the rs2228570 variant in the VDR gene is associated with the risk of retreatment in multibacillary leprosy (Odds Ratio= 2.56; IC95: 1.13-5.82). This data reaffirms the importance of pharmacogenetics in leprosy therapy for identifying patients at higher risk of retreatment when undergoing conventional multidrug therapy.

Role of the IL8 rs4073 polymorphism in central nervous system toxicity in patients receiving multidrug-resistant tuberculosis treatment / Papel do polimorfismo rs4073 do gene IL8 na toxicidade do sistema nervoso central em pacientes em tratamento para tuberculose multirresistente

ABSTRACT Objective: To determine the role of the IL8 rs4073 polymorphism in predicting the risk of central nervous system (CNS) toxicity in patients receiving standard pharmacological treatment for multidrug-resistant tuberculosis (MDR-TB). Methods: A cohort of 85 consenting MDR-TB patients receiving treatment with second-line antituberculosis drugs had their blood samples amplified for the IL8 (rs4073) gene and genotyped. All patients were clinically screened for evidence of treatment toxicity and categorized accordingly. Crude and adjusted associations were assessed. Results: The chief complaints fell into the following categories: CNS toxicity; gastrointestinal toxicity; skin toxicity; and eye and ear toxicities. Symptoms of gastrointestinal toxicity were reported by 59% of the patients, and symptoms of CNS toxicity were reported by 42.7%. With regard to the genotypes of IL8 (rs4073), the following were identified: AA, in 64 of the study participants; AT, in 7; and TT, in 11. A significant association was found between the dominant model of inheritance and CNS toxicity for the crude model (p = 0.024; OR = 3.57; 95% CI, 1.18-10.76) and the adjusted model (p = 0.031; OR = 3.92; 95% CI, 1.13-13.58). The AT+TT genotype of IL8 (rs4073) showed a 3.92 times increased risk of CNS toxicity when compared with the AA genotype. Conclusions: The AT+TT genotype has a tendency to be associated with an increased risk of adverse clinical features during MDR-TB treatment.

RESUMO Objetivo: Determinar o papel do polimorfismo rs4073 do gene IL8 na previsão do risco de toxicidade do sistema nervoso central (SNC) em pacientes em tratamento farmacológico padrão para tuberculose multirresistente (TBMR). Métodos: Amostras de sangue de uma coorte de 85 pacientes com TBMR que assinaram um termo de consentimento livre e esclarecido e que estavam recebendo tratamento com medicamentos antituberculosos de segunda linha foram amplificadas para o gene IL8 (rs4073) e genotipadas. Todos os pacientes foram avaliados clinicamente quanto a evidências de toxicidade do tratamento e categorizados de acordo com os achados. Foram avaliadas as associações brutas e ajustadas. Resultados: As principais queixas enquadraram-se nas seguintes categorias: toxicidade do SNC; toxicidade gastrointestinal; toxicidade cutânea; e toxicidade ocular e ototoxicidade. Sintomas de toxicidade gastrointestinal foram relatados por 59% dos pacientes, e sintomas de toxicidade do SNC foram relatados por 42,7%. Foram identificados os seguintes genótipos de IL8 (rs4073): AA, em 64 dos participantes; AT, em 7; TT, em 11. Houve associação significativa entre o modelo dominante de herança e toxicidade do SNC no modelo bruto (p = 0,024; OR = 3,57; IC95%: 1,18-10,76) e no ajustado (p = 0,031; OR = 3,92; IC95%: 1,13-13,58). O genótipo AT+TT do gene IL8 (rs4073) apresentou risco 3,92 vezes maior de toxicidade do SNC que o genótipo AA. Conclusões: O genótipo AT+TT tende a se associar a um maior risco de características clínicas adversas durante o tratamento da TBMR.

Reshaping neuroimmunology: diagnosis and treatment in the era of precision medicine / Remodelando a neuroimunologia: diagnóstico e tratamento na era da medicina de precisão

Abstract Precision medicine has revolutionized the field of neuroimmunology, with innovative approaches that characterize diseases based on their biology, deeper understanding of the factors leading to heterogeneity within the same disease, development of targeted therapies, and strategies to tailor therapies to each patient. This review explores the impact of precision medicine on various neuroimmunological conditions, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), optic neuritis, autoimmune encephalitis, and immune-mediated neuropathies. We discuss advances in disease subtyping, recognition of novel entities, promising biomarkers, and the development of more selective monoclonal antibodies and cutting-edge synthetic cell-based immunotherapies in neuroimmunological disorders. In addition, we analyze the challenges related to affordability and equity in the implementation of these emerging technologies, especially in situations with limited resources.

Resumo A medicina de precisão está revolucionando o campo da neuroimunologia, com uma abordagem inovadora caracterizada pela classificação de doenças com base em sua biologia, compreensão mais profunda dos fatores que levam à heterogeneidade dentro da mesma doença, desenvolvimento de terapias com alvos específicos e estratégias para adaptar as terapias a cada paciente. Esta revisão explora o impacto da medicina de precisão em várias condições neuroimunológicas, incluindo esclerose múltipla (EM), distúrbio do espectro da neuromielite óptica (NMOSD), doença associada ao anticorpo anti-glicoproteína da mielina do oligodendrócito (MOGAD), neurites ópticas, encefalites autoimunes e neuropatias imunomediadas. Discutimos avanços na subclassificação de doenças, reconhecimento de novas entidades, biomarcadores promissores e desenvolvimento de anticorpos monoclonais mais seletivos e imunoterapias de ponta baseadas em células sintéticas para as condições acima. Além disso, analisamos os desafios relacionados com acessibilidade e equidade na implementação dessas tecnologias emergentes, especialmente em ambientes com recursos limitados.

Siponimod (BAF312): Características generales e implicancias clínicas de la dosificación farmacogenómica en el tratamiento de la Esclerosis Múltiple secundaria progresiva / Siponimod (BAF312): General Characteristics and Clinical Implications of Pharmacogenomic Dosage in the Treatment of Active Secondary Progressive Multiple Sclerosis

Siponimod es un medicamento inmunosupresor selectivo, desarrollado como la primera terapia oral para la esclerosis múltiple secundaria progresiva activa. Este medicamento actúa modulando el receptor de esfingosina 1 fosfato (S1P), como antagonista de S1P1 y S1P5, evitando así la salida de linfocitos desde los nódulos linfáticos y previniendo procesos inflamatorios en el Sistema Nervioso Central que desencadenan una desmielinización. Existe amplio conocimiento científico respecto a que la administración del medicamento a pacientes va a depender de sus características farmacogenéticas, por lo que la FDA recomienda fuertemente realizar un estudio de genotipificación de la enzima que metaboliza siponimod, CYP2C9, cuyas variantes genéticas *2 y *3 clasifican a pacientes como metabolizadores pobres, extensivos o rápidos. Para pacientes homocigotos de CYP2C9*3 siponimod está totalmente contraindicado. Adicionalmente, antes de su prescripción se debe realizar un electrocardiograma, evaluaciones del estado de anticuerpos, oftálmica, estado de vacunación contra varicela y recuento de linfocitos periféricos, ya que el efecto del medicamento es dependiente de la dosis administrada, por lo que se realiza un proceso de titulación en dosis desde los 0,25mg hasta los 2 mg. El protocolo farmacoterapéutico de siponimod es reflejo fidedigno de la utilidad de la farmacogenética en la medicina personalizada..

Siponimod is a selective immunosuppressive medication, developed as the first oral therapy for active secondary progressive multiple sclerosis. This medication acts by modulating the sphingosine 1 phosphate (S1P) receptor, as an antagonist of S1P1 and S1P5, thus preventing the egress of lymphocytes from lymph nodes and preventing inflammatory processes in the Central Nervous System that trigger demyelination. There is extensive scientific knowledge regarding the administration of the medication to patients, which will depend on their pharmacogenetic characteristics. Therefore, the FDA strongly recommends conducting a genotyping study of the enzyme that metabolizes siponimod, CYP2C9, whose genetic variants *2 and *3 classify patients as poor, extensive, or rapid metabolizers. Siponimod is completely contraindicated for patients who are homozygous for CYP2C9*3. Additionally, before prescribing it, an electrocardiogram, assessments of antibody status, ophthalmic evaluation, varicella vaccination status, and peripheral lymphocyte count should be conducted, as the medication's effect is dose-dependent. Therefore, a titration process is carried out starting from 0.25mg up to 2 mg. The pharmacotherapeutic protocol of siponimod is a reliable reflection of the utility of pharmacogenetics in personalized medicine.

Polimorfismo de proteína 5, 10-metilentetrahidrofolatoreductasa en población venezolana / Polymorphisms proteína 5, 10-metilentetrahidrofolatoreductasa in venezuelan people

El folato es un miembro del grupo de la vitamina B y está relacionado con enfermedades crónicas como anemia megaloblástica, enfermedad cardiovascular, cáncer, disfunción cognitiva y riesgo de defectos del tubo neural. La proteína 5,10-metilentetrahidrofolato reductasa (MTHFR) juega un papel clave en el metabolismo del folato mediante la síntesis de nucleótidos y reacciones de metilación. El gen MTHFR se encuentra en el cromosoma 1 (1p36.3), y se han descrito dos alelos comunes, el alelo C677T (termolábil) y el alelo A1298C.El objetivo de este estudio es evaluar la distribución de los polimorfismos genéticos en MTHFR C677T y A1298C en la población venezolana. METODOS: estudio de tipo transversal, descriptivo, experimental y correlacional Las muestras de sangre se colectaron en 314 donantes no emparentados y sanos de la población. Los polimorfismos de un solo nucleótido(SNP) MTHFR 677C>T y 1298A>C se analizaron mediante polimorfismo de longitud de fragmento de restricción de reacción en cadena de polimerasa (PCR-RFLP). El desequilibrio de ligamiento (LD) entre pares de SNP se calculó mediante la prueba X. usando Prism 5 (GraphPad software, Inc). RESULTADOS: Encontramos mayor frecuencia genotípica de heterocigotos para el polimorfismo MTHFR C677T en la población general venezolana, con excepción del grupo caucásico. El polimorfismo MTHFR A1298C en el 70%de la población de estudio es homocigoto de tipo salvaje, encontrándose una baja frecuencia de homocigoto mutado. CONCLUSIONES: Se encontraron diferencias significativas entre grupos étnicos, destacando la importancia del genotipado racial de estos polimorfismos en la población venezolana(AU)

Folate is a member of the vitamin B and it has also been indicated that may be related to chronic diseases such as megaloblastic anemia, cardiovascular disease, cognitive dysfunction and risk of neural tube. Methylenetetrahydro folatereductase (MTHFR) is a key enzyme of folate pathway by nucleotide synthesis and methylation reactions. Several polymorphisms were reported in MTHFR gene but C677Tand A1298 polymorphism are most studied and these have been reported to be risk factor for several diseases/disorders. The present study was designed to determine the frequency of MTHFR polymorphisms in Venezuelan healthy population. METHODS: The blood samples were collected from 314 unrelated and healthy donors from population. Both the MTHFR 677C>T and 1298A>C single nucleotide polymorphisms (SNPs) were analyzed by Polymerase chainreaction-restriction fragment length polymorphism (PCR-RFLP). Linkage disequilibrium (LD) between pair of SNPs was calculated through the .. test using Prism 5 (GraphPad sftoware, Inc). RESULTS: We find higher genotypic frequency of heterozygotes for the MTHFR C677T polymorphism in the Venezuelan general population, with the exception of the Caucasian group. MTHFR A1298C polymorphism in 70%of the study population is homozygous wild type, finding alow frequency of homozygous mutated. CONCLUSIONS: Significant differences between ethnic groups were found,highlighting the importance of racial genotyping of these polymorphisms in the Venezuelan population(AU)

Impact of pharmacogenetics on aspirin resistance: a systematic review / Impacto da farmacogenética na resistência à aspirina: uma revisão sistemática

Abstract Background Pharmacogenetics promises better control of diseases such as cardiovascular disease (CVD). Acetylsalicylic acid, aspirin, prevents the formation of an activating agent of platelet aggregation and vasoconstriction, and it is used to prevent CVD. Nevertheless, patients may have treatment failure due to genetic variants that modify the metabolism of the drug causing aspirin resistance (AR). Objectives To realize a systematic literature review to determine the impact of genetic variants on AR. Methods Articles published in the MEDLINE/PubMed, Cochrane, Scopus, LILACS, and SCIELO databases were systematically screened. A total of 290 articles were identified and 269 articles were excluded because they did not comply with the previously established inclusion criteria. A total of 20 case-control studies and 1 cohort was included. Results The genetic variants rs1126643 (ITGA2), rs3842787 (PTGS1), rs20417 (PTGS2), and rs5918 (ITGB3) were the most studied. As for relevance, of the 64 genetic variants evaluated by the articles, 14 had statistical significance (p< 0.05; 95% confidence interval [CI]) in at least one article. Among them, the following have had unanimous results: rs1371097 (P2RY1), rs1045642 (MDR1), rs1051931 and rs7756935 (PLA2G7), rs2071746 (HO1), rs1131882 and rs4523 (TBXA2R), rs434473 (ALOX12), rs9315042 (ALOX5AP), and rs662 (PON1), while these differ in real interference in AR: rs5918 (ITGB3), rs2243093 (GP1BA), rs1330344 (PTGS1), and rs20417 (PTGS2). As study limitations, we highlight the nonuniform methodologies of the analyzed articles and population differences. Conclusion It is noteworthy that pharmacogenetics is an expanding area. Therefore, further studies are needed to better understand the association between genetic variants and AR.

Resumo Antecedentes A farmacogenética promete melhorar o controle de doenças como as cardiovasculares. O ácido acetilsalicílico, a aspirina, previne a formação de um agente ativador da agregação plaquetária e vasoconstrição e é usado na prevenção de tais doenças. No entanto, os pacientes podem ter falha no tratamento devido a variantes genéticas que modificam o metabolismo da droga causando resistência à aspirina (RA). Objetivos Realizar uma revisão sistemática da literatura para determinar o impacto das variantes genéticas na resistência à aspirina. Métodos Artigos publicados nos bancos de dados MEDLINE/PubMed, Cochrane, Scopus, LILACS e SCIELO foram sistematicamente selecionados. Foram identificados 290 artigos e, destes, 269 artigos foram excluídos por não atenderem aos critérios de inclusão previamente estabelecidos. Um total de 20 estudos caso-controles e 1 coorte foi incluído. Resultados As variantes genéticas rs1126643 (ITGA2), rs3842787 (PTGS1), rs20417 (PTGS2) e rs5918 (ITGB3) foram as mais estudadas. Quanto à relevância, das 64 variantes genéticas avaliadas pelos artigos, 14 tiveram significância estatística (p< 0,05; intervalo de confiança [IC] de 95%) em pelo menos um artigo. Entre eles, os seguintes tiveram resultados unânimes: rs1371097 (P2RY1), rs1045642 (MDR1), rs1051931 e rs7756935 (PLA2G7), rs2071746 (HO1), rs1131882 e rs4523 (TBXA2R), rs434473 (ALOX12), rs9315042 (ALOX5AP) e rs662 (PON1), enquanto estes diferiram na interferência real na RA: rs5918 (ITGB3), rs2243093 (GP1BA), rs1330344 (PTGS1) e rs20417 (PTGS2). Como limitações do estudo, destacam-se as metodologias não uniformes dos artigos analisados e as diferenças populacionais. Conclusão Vale ressaltar que a farmacogenética é uma área em expansão. Portanto, mais estudos são necessários para entender melhor a associação entre variantes genéticas e RA.

Genetic testing for cannabinoid use / Testes genéticos para uso de canabinoides

ABSTRACT BACKGROUND AND OBJECTIVES: Cannabis is the most popular and consumed illicit drug in the world, it has about 540 bioactive phytocannabinoids, including tetrahydrocarbinol (THC) and cannabidiol (CBD). The therapeutic potential of phytocannabinoids has been the subject of many studies in recent decades for many medical situations, including the management of chronic pain. The advent of pharmacogenetics currently allows the indication of the Cannabis dose to be evaluated individually. The objective of this work was to carry out a survey of the literature on the medicinal use of Cannabis and the application of pharmacogenetics in this therapy. CONTENTS: THC and CBD phytocannabinoids are the most abundant and researched. In the endocannabinoid system there are compounds similar to phytocannabinoids, cell receptors and metabolism enzymes. All these molecules are secreted from genes, which may have individual genetic polymorphisms that determine the modulation of the endocannabinoid system, and consequently impact the patients' therapeutic response. CONCLUSION: The existence of genetic tests for the prior assessment of the patients genetic profile in order to avoid side effects and to have more assertiveness in the indication of the cannabis product is an important tool to increase adherence to cannabis treatment.

RESUMO JUSTIFICATIVA E OBJETIVOS: A cannabis é a droga ilícita mais popular e consumida no mundo, possuindo cerca de 540 fitocanabinoides bioativos, entre eles o tetra-hidrocarbinol (THC) e o canabidiol (CBD). O potencial terapêutico dos fitocanabinoides tem sido alvo de muitos estudos nas últimas décadas para muitas situações médicas, incluindo o manejo da dor crônica. O advento da farmacogenética permite que atualmente a indicação da dose de cannabis seja avaliada individualmente. O objetivo deste estudo foi realizar um levantamento da literatura sobre o uso medicinal da cannabis e a aplicação da farmacogenética nessa terapia. CONTEÚDO: Os fitocanabinoides THC e CBD são os mais abundantes e pesquisados. No sistema endocanabinoide, existem compostos similares aos fitocanabinoides, receptores celulares e enzimas de metabolismo. Todas essas moléculas são secretadas a partir de genes que podem possuir polimorfismos genéticos individuais determinantes para a modulação do sistema endocanabinoide e, consequentemente, impactam a resposta terapêutica do paciente. CONCLUSÃO: A existência de testes genéticos para avaliação prévia do perfil genético do paciente a fim de evitar efeitos colaterais e ter mais assertividade na indicação do produto de cannabis é uma importante ferramenta para aumentar a aderência ao tratamento com cannabis.

Bioética e medicina personalizada no envelhecimento: explorando complexidades / Bioethics and concierge medicine in aging: exploring complexities / Bioética y medicina personalizada en el envejecimiento: explorar las complejidades

Resumo A medicina personalizada surgiu como uma abordagem promissora para fornecer tratamentos exclusivos e personalizados para doenças usando ferramentas genômicas. No campo dos estudos do envelhecimento, a medicina personalizada tem grande potencial para transformar o tratamento e a prevenção de doenças associadas à idade e relacionadas à nutrigenômica e à farmacogenômica. No entanto, o uso de dados genômicos na medicina personalizada levanta preocupações bioéticas significativas, incluindo questões como privacidade, consentimento, equidade e potencial uso indevido de dados genômicos para fins discriminatórios. Portanto, é crucial considerar cuidadosamente os aspectos biomédicos, sociais e éticos da medicina personalizada no contexto de condições relacionadas à idade. Esta revisão tem o objetivo de explorar os principais aspectos da medicina personalizada concernentes a doenças relacionadas à idade nos dados farmacogenômicos e nutrigenômicos, abordando as preocupações bioéticas envolvidas no uso desses dados.

Abstract Concierge medicine emerged as a promising approach to offer exclusive and personalized treatments using genomic tools. In aging studies, concierge medicine has the potential to transform the treatment and prevention of age-associated and related diseases through pharmacogenetics and nutrigenomics; however, its use of genomic data raises important bioethical concerns, including privacy, consent, equity issues and potential misuse of these data for discriminatory purposes. Hence, careful consideration should be given to the biomedical, social, and ethical aspects of concierge medicine in aging contexts. Our review explores the main aspects of age-related pharmacogenetics and nutrigenomics data in concierge medicine, discussing the bioethical concerns involved in its use.

Resumen La medicina personalizada surgió como un enfoque prometedor con el fin de proporcionar tratamientos únicos y personalizados a enfermedades utilizando herramientas genómicas. En los estudios de envejecimiento, la medicina personalizada puede transformar el tratamiento y la prevención de enfermedades asociadas a la edad y relacionadas con la nutrigenómica y la farmacogenómica. Sin embargo, el uso de datos genómicos en medicina personalizada plantea importantes preocupaciones bioéticas, incluidos temas como la privacidad, el consentimiento, la equidad y el posible uso indebido de los datos genómicos con fines discriminatorios. Así, es fundamental ponderar cuidadosamente los aspectos biomédicos, sociales y éticos de la medicina personalizada en el contexto de las afecciones relacionadas con la edad. Esta revisión pretende explorar los principales aspectos de la medicina personalizada sobre las enfermedades relacionadas con la edad en los datos farmacogenómicos y nutrigenómicos al abordar las preocupaciones bioéticas involucradas en el uso de estos datos.

Pharmacogenetic studies in Alzheimer disease.

INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response. DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial. CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.

Metodología de investigación en farmacogenética: estudios de casos y controles / Methodology for research in pharmacogenetics: Case-control studies

RESUMEN La farmacogenética estudia la asociación entre el fenotipo farmacológico de un individuo con su constitución genética, y el diseño de estudios de casos y controles es una metodología de uso frecuente. Este diseño consiste en que se analiza la frecuencia de las variantes genéticas en los casos, es decir, de los pacientes que presentan el fenotipo (desenlaces o resultados) comparado con los controles. Para obtener una calidad metodológica adecuada en este tipo de estudios es importante trabajar con fenotipos precisos, adecuada selección de los casos y controles y tamaño de la muestra; seleccionar una metodología adecuada para la identificación de variantes genéticas; y en el momento del análisis de resultados utilizar el Equilibrio de Hardy-Weinberg (EHW) e interpretar los resultados considerando la posibilidad de un fenómeno de fenoconversión.

ABSTRACT Pharmacogenetics studies the association between the pharmacological phenotype of an individual with his/her genetic constitution. Case-control studies is a commonly used methodology when performing pharmacogenetics research. This design analyses the frequency of genetic variants in cases; that is, of those patients who have a particular phenotype (outcomes or results) compared with controls. For obtaining adequate methodological quality in pharmacogenetic case-control studies, it is important to work with precise phenotypes, have adequate case and control selection and appropriate sample size; select an adequate methodology for the identification of genetic variants, analyze the results using Hardy-Weinberg Equilibrium (HWE); and interpret the results considering the possibility of a phenoconversion phenomenon.

Análisis farmacogenético retrospectivo de una paciente pediátrica en tratamiento anticoagulante: caso clínico / Retrospective pharmacogenetic analysis of a pediatric patient under anticoagulant treatment: Clinical case

Se presenta el caso clínico de una paciente de 10 años diagnosticada con miocardiopatía dilatada, quien registró valores en el índice internacional normalizado (International Normalized Ratio, INR) superiores a 10 con la dosis estándar de acenocumarol, además de otros valores que indicaban el estado incoagulable, lo que obligó a suspender y reiniciar el tratamiento en varias ocasiones. Después de más de 30 días de tratamiento, sorprendentemente se lograron los niveles esperados y estables en el INR con la mitad de la dosis recomendada para una paciente de su edad y peso.Se decidió hacer un análisis farmacogenético retrospectivo del caso mediante RT-PCR con sondas TaqMan™ que incluyó cinco polimorfismos de un solo nucleótido y distinto grado de asociación con la dosis-respuesta a los fármacos antivitamínicos K (AVK): rs2108622 (gen CYP4F2), rs9923231, rs7294 (gen VKORC1), rs1799853 y rs1057910 (gen CYP2C9). La paciente resultó ser homocigota para el rs9923231 (VKORC1) y heterocigota para el rs2108622 (CYP4F2). Se ha evidenciado a nivel nacional e internacional que este perfil genético está fuertemente asociado con una necesidad de dosis menores de antivitamínicos K.En conclusión, el análisis farmacogenético confirmó que la condición genética de la paciente, la cual conlleva una baja expresión de la enzima VKORC1 (blanco terapéutico de los antivitamínicos K), hacía predecible la necesidad de una dosis menor a la establecida según los protocolos clínicos recomendados por la Food and Drug Administration (FDA) y PharmGKB™ para los fármacos cumarínicos. El análisis genotípico previo de la paciente hubiese permitido alcanzar el rango terapéutico más prontamente, evitando potenciales riesgos de hemorragia, lo que demuestra la importancia de los análisis farmacogenéticos en tratamientos de gran variabilidad y estrecho rango terapéutico.

Abstract We present the clinical case of a 10-year-old patient diagnosed with dilated cardiomyopathy who registered INR values above 10 upon receiving standard doses of acenocoumarol, as well as other values reported as uncoagulable, forcing the discontinuation and restart of treatment more than once. Expected and stable INR levels were achieved after more than 30 days of treatment, surprisingly with half the recommended dose for a patient of her age and weight. We decided to conduct a retrospective pharmacogenomic analysis including nucleotide genetic polymorphisms (SNPs) with different degrees of association with the dose/response to antivitamin K (AVK) drugs: rs2108622 (gene CYP4F2), rs9923231, rs7294 (gene VKORC1), rs1799853, and rs1057910 (CYP2C9 gene) using TaqMan® RT-PCR. The patient was homozygous for rs9923231 (VKORC1) and heterozygous for rs2108622 (CYP4F2), a genetic profile strongly associated with a requirement of lower AVK doses as shown by national and international evidence. In conclusion, the pharmacogenetic analysis confirmed that this patient's genetic conditions, involving low expression of the VKA therapeutic target, required a lower dose than that established in clinical protocols as recommended by the Food and Drug Administration (FDA) and the PharmGKB® for coumarin drugs. A previous genotypic analysis of the patient would have allowed reaching the therapeutic range sooner, thus avoiding potential bleeding risks. This shows the importance of pharmacogenetic analyses for highly variable treatments with a narrow therapeutic range.

Susceptibility to thiopurine toxicity by TPMT and NUDT15 variants in Colombian children with acute lymphoblastic leukemia / Asociación de variantes genéticas en TPMT y NUDT15 con los eventos de toxicidad durante la terapia de mantenimiento en niños colombianos con Leucemia Linfoide Aguda

Abstract Objective: This study aimed to correlate the genetic profile of the NUDT15 and TPMT genes with the side effects of the treatment of pediatric patients with acute lymphoid leukemia who were undergoing maintenance therapy at a tertiary care hospital in 2017. Methods: This was an analytical, longitudinal, observational study in which the genotypes of the genes of interest were determined by PCR allelic discrimination with TaqMan® probes in patients receiving chemotherapy during the maintenance phase in the Pediatric Hematology and Oncology Unit in 2017. Sociodemographic and clinical data corresponding to the first six months of their maintenance chemotherapy were collected, and the correlation between the genotypes obtained and the development of side effects during the maintenance phase of chemotherapy in these patients was evaluated. Results: Seventy pediatric patients were included in the study. Genetic analyses were carried out of these for NUDT15 and TPMT (rs1800462 and rs1800460) on 68 patients, while for the rs1142345 polymorphism, typing was achieved in 42 patients. 4/68 patients were heterozygous for NUDT15, and the same number of patients were heterozygous for rs1800462 and rs1142345, while for rs1800460, 6 heterozygous patients were identified. No statistically significant association was identified between the genetic variants and the outcomes of interest. Conclusion: Studies with a larger population size are needed and the evaluation of other genetic variants that may influence the development of side effects during maintenance chemotherapy.

Resumen Objetivo: la finalidad de este estudio fue evaluar las asociaciones entre los perfiles de los genes NUDT15 y TPMT con los efectos adversos del tratamiento de mantenimiento en pacientes pediátricos con Leucemia Linfoblástica Aguda atendidos en un hospital de referencia durante el 2017. Métodos: Este fue un estudio observacional analítico, de corte longitudinal en el que los genotipos de los genes de interés fueron determinados mediante PCR de discriminación alélica con sondas TaqMan® en pacientes que estaban recibiendo quimioterapia de mantenimiento en la Unidad de Oncohematología Pediátrica durante el 2017. Los datos clínicos y sociodemográficos correspondientes a los primeros 6 meses de sus tratamientos de mantenimiento fueron colectados, y se evaluó la correlación entre los genotipos identificados y el desarrollo de efectos secundarios en estos pacientes. Resultados: setenta pacientes fueron incluidos en el estudio, de estos, los análisis genéticos para NUDT15 y TPMT (rs1800462 and rs1800460) fueron realizados en 68 pacientes, en tanto que para el polimorfismo rs1142345 se logró la tipificación en 42 pacientes. 4/68 pacientes fueron heterocigotos para NUDT15 y el mismo número de pacientes fueron heterocigotos para rs1800462 and rs1142345, mientras que para rs1800460, 6 pacientes heterocigotos fueron identificados. No se identificaron asociaciones estadísticamente significantes entre las variants genéticas y los resultados clínicos de interés. Conclusiones: Estos hallazgos resaltan la importancia de realizar estudios de este tipo con un mayor número de sujetos de estudio, así como plantean la necesidad de evaluar otras variantes genéticas que podrían tener algún impacto en el desarrollo de efectos secundarios durante la quimioterapia de mantenimiento.

Levantamento de dados para estudo dos fatores associados à falha terapêutica em hanseníase / Data collection to study the factors associated with failure leprosy therapy

A Hanseníase é uma doença infectocontagiosa de caráter crônico, evolução lenta, causada pelo Mycobacterium leprae (M. leprae). A transmissão ocorre por meio do trato respiratório, e para o desenvolvimento da doença existe a necessidade da susceptibilidade, além do contato íntimo e prolongado. Para fins terapêuticos a Organização Mundial da Saúde (OMS) traz uma classificação mais simples que é baseada no número de lesões cutâneas. Os casos com até cinco lesões são considerados paucibacilares e aqueles com mais de cinco lesões são multibacilares. Apesar da implantação da poliquimioterapia (PQT) pela OMS ter sido um importante avanço técnico na história do controle da doença, em 2019 ainda foram notificados 202.185 novos casos no mundo, sendo o Brasil o segundo em concentração de casos. Um indicador importante para o controle da hanseníase são as taxas de retratamento, definido como nova notificação de hanseníase em paciente que já tenha recebido tratamento anterior, suas causas incluem abandono, insuficiência terapêutica, falência terapêutica, alteração de esquema por erro diagnóstico e recidiva. Embora um grande número de casos de recidivas seja detectado no Brasil, apenas 8,4%, 13,3% e 1,9% dos casos podem ser explicados por mutações que sabidamente conferem resistência bacilar aos medicamentos utilizados na PQT: rifampicina (RFP), dapsona (DDS) e ofloxacina (OFLO), respectivamente. Além dos aspectos relacionados ao patógeno, a contribuição do hospedeiro para esse cenário, apesar de pouco estudada, deve ser de grande importância. No geral a resposta ao medicamento é variável entre indivíduos, ocasionando falta de eficácia farmacológica ou reação adversas, em partes esses eventos podem ser explicados pela farmacogenética. Conhecer fatores genéticos que interferem no metabolismo dos medicamentos pode contribuir para melhores resultados terapêuticos. Dentre os desafios para atingir a eliminação da hanseníase estão a ausência de novas ferramentas de diagnóstico e de entendimento das causas associadas a recidiva e à não adesão a PQT, uma vez que a resistência medicamentosa explica pouco da reativação da doença, deste modo, o presente estudo teve como finalidade constituir banco de dados em hanseníase para estudos de associação do tipo caso-controle sobre os fatores associados com a falha terapêutica da PQT convencional. Dos 240 prontuários avaliados, 119 foram classificados como casos de falência terapêutica ou recidiva e 121 como sucesso terapêutico, aqui denominados como controles, a maioria dos pacientes era do sexo masculino, branco e procedente do estado de São Paulo; Em relação à faixa etária de diagnóstico, 18% foram diagnosticados com idade entre 40 e 49 anos, enquanto nos controles 14% tiveram diagnóstico com idade inferior a 19 anos; quanto à forma clínica da doença, 59% dos casos e 47% dos controles foram classificados como virchoviano. Dentre os casos de falência terapêutica ou recidiva, a resistência molecular explicou apenas 5,8 % dos casos de retratamento. Esse dado reforça a urgência de estudos que esclareçam as causas da falha terapêutica em hanseníase, contribuindo assim para o estabelecimento de medidas que visem o alcance de melhores índices relacionados aos desfechos terapêuticos.(AU)

Leprosy is a chronic infectious disease with insidious evolution, caused by Mycobacterium leprae (M. leprae). Transmission occurs through the respiratory tract, and the onset of the disease depends on susceptibility, in addition to intimate and prolonged contact with untreated patients. For therapeutic purposes, the World Health Organization's (WHO) classification is based on the number of skin lesions. Cases with up to five lesions are considered paucibacillary and those with more than five lesion are multibacillary. Although the implementation of multidrugtherapy (MDT) by WHO was an important technical advance in the history of disease control. In 2019, 202,185 new cases were reported in the world, with Brazil the second in the highest number of cases. An important indicator for the control of leprosy is retreatment rate, defined as a new notification of leprosy in a patient who has already received previous treatment. Its causes include abandonment, therapeutic failure, , alteration of the regimen due to diagnostic error and relapse. Although a large number of cases of relapses are detected in Brazil, only 8.4%, 13.3% and 1.9% of cases can be explained by mutations that are known to confer bacillary resistance to drugs used in the MDT: rifampicin (RFP), dapsone (DDS) and ofloxacin (OFLO), respectively. In addition to aspects related to the pathogen, the host's contribution to this scenario, although little studied, is highly important. In general, the response to the drug treatment is variable between individuals, causing a lack of pharmacological efficacy or adverse reactions. , These events may be explained by pharmacogenetics. Knowing genetic factors that interfere with drug metabolism can contribute to better therapeutic results. Among the challenges to achieve leprosy elimination are the absence of new diagnostic tools and understanding of the causes associated with relapse and non-adherence to MDT, since drug resistance explains little about the reactivation of the disease. Thus, the present study aimed at constituting a leprosy database for case-control association studies on factors associated with conventional MDT therapeutic failure. Of the 240 medical records evaluated, 119 were classified as cases of therapeutic failure or relapse and 121 as therapeutic success, here referred to as controls. The majority of patients were male, white and from the state of São Paulo. Regarding the age of diagnosis, 18% were diagnosed between 40 and 49 years, while in controls, 14% were diagnosed under 19 years; as to the clinical form of the disease, 59% of the cases and 47% of the controls were classified as lepromatous. Among the cases of therapeutic failure or relapse, molecular resistance explained only 5.8% of retreatment cases. This data reinforces the urgency of studies that clarify the causes of therapeutic failure in leprosy, thus contributing to the establishment of measures aimed at achieving better therapeutic outcomes(AU).

Farmacogenómica: principios y aplicaciones en la práctica médica / Pharmacogenomics: principles and application on medical practice

Introducción: La farmacogenómica, como parte de la medicina de precisión, garantiza un tratamiento óptimo de los pacientes basado en su perfil genético. Objetivo: Describir los principales principios en que se sustenta la farmacogenómica y sus aplicaciones a la práctica clínica diaria. Materiales y Métodos: Se realizó una revisión crítica de la farmacogenómica en las bases de datos principales: SciELO, MedLine/PubMed/PMC y Scopus con los descriptores farmacogenómica/pharmacogenomics, farmacogenética/pharmacogenetics, medicina personalizada/personalized medicine y medicina de precisión/precision medicine. También en la biblioteca virtual de salud de Infomed. El periodo de búsqueda y localización de artículos: noviembre 2019-enero 2020. Se seleccionaron artículos publicados entre 2008 y enero de 2020. Resultados: Los principios de la farmacogenómica se basan en el conocimiento del genoma humano que permite determinar el perfil genético de los pacientes y la mejor respuesta al tratamiento medicamentoso con un mínimo de reacciones adversas. Se aplica en diferentes especialidades médicas como oncología, cardiología, medicina interna y endocrinología. Entre los biomarcadores farmacogenéticos estudiados están CACNA1S, RYR1, CYP2D6, SLCO1B1, CYP2C19, F5, CFTR, CYP2C9, CYP4F2, VKORC1, HLA-B, UGT1A1, IFNL3, CYP3A5, TPMT, G6PD, HLA-A, BRCA1, DPYD, RARG, SLC28A3, TPMT y UGT1A6. Conclusiones: Los biomarcadores farmacogenéticos constituyen valiosas herramientas para la identificación de genes implicados en la respuesta medicamentosa, importantes para aplicar una medicina personalizada que mejore la respuesta a los medicamentos y evite o minimice los efectos adversos, aunque quedan desafíos para convertirla en una herramienta de uso frecuente en la práctica médica(AU)

Introduction: Pharmacogenomics, as part of precision medicine, guarantees patients´ optimal treatment based on their genetic profile. Objective: To describe the principles of pharmacogenomics and its application in daily clinical practice. Materials and Methods: A critical review of pharmacogenomics was carried out in SciELO, MedLine/PubMed/PMC, Scopus databases and the Cuban Virtual Health Library using Spanish and English descriptors such as: farmacogenómica/pharmacogenomics, farmacogenética/pharmacogenetics, medicina personalizada/personalized medicine and medicina de precisión/precision medicine. The articles were searched and located during the period between November 2019 and January 2020. The articles published between 2008 and January 2020 were selected. Results: The principles of pharmacogenomics are based on the knowledge of the human genome that allows the determination of the genetic profile of patients and the best response to drug treatment with a minimum of adverse reactions. It is applied in different medical specialties such as Oncology, Cardiology, Internal Medicine and Endocrinology. The most studied pharmacogenetic biomarkers include: CACNA1S, RYR1, CYP2D6, SLCO1B1, CYP2C19, F5, CFTR, CYP2C9, CYP4F2, VKORC1, HLA-B, UGT1A1, IFNL3, CYP3A5, TPMT, G6PD, HLA-A, BRCA1, DPYD, RARG, SLC28A3, TPMT and UGT1A6. Conclusions: Pharmacogenetic biomarkers are valuable tools for the identification of genes involved in the drug response. They are very important in the application of personalized medicine which is intended to improve the response to drugs and avoid or minimize adverse effects. However, substantial challenges remain in respect of making it a frequently used tool in medical practice(AU)

Farmacogenômica e Doença Cardiovascular: Onde Estamos e Para Onde Vamos / Pharmacogenomics and Cardiovascular Disease: Where are We and Where do We go from Here?

Resumo A farmacogenômica (FGx) investiga a interação entre genes e medicamentos. Através da análise de regiões específicas do DNA, informações sobre o perfil de metabolização do paciente para um determinado fármaco podem ser descritas, assim como o perfil esperado de resposta ao tratamento. Objetivamente, esse tipo de teste pode ter impacto no tratamento de pacientes que não estão respondendo adequadamente a um determinado medicamento, seja pela ausência dos efeitos esperados ou em virtude do aparecimento de efeitos adversos. Neste cenário, o objetivo desta revisão é o de informar o cardiologista clínico sobre esta importante área do conhecimento e atualizá-lo sobre o tema, procurando preencher as lacunas no que diz respeito à relação custo-benefício da aplicação da FGx nas doenças cardiovasculares, além de fornecer informações para a implementação da terapia guiada pela FGx na prática clínica.

Immunopharmacology 2020. V International Congress on Immunopharmacology

The Organizing Committee of the V International Congress on Immunopharmacology (Immunopharmacology 2020) organized by the Cuban Society of Pharmacology, BioCubaFarma and the International Union of Basic and Clinical Pharmacology (IUPHAR) would like to invite you to participate in this important event, scheduled for June 9 to 13, 2020 at the Convention Centre of the Melia Marina Varadero Hotel, Varadero Beach, Matanzas, Cuba. The Congress will be formed by different workshops and symposia such as: Fifth workshop on new advances in immunopharmacology Fifth workshop on neuroimmunology, neuroimmunopharmacology and neuroimmunomodulation. Immunopharmacology of brain tumors Symposium on hereditary ataxias Fifth symposium on pharmacology of cytochrome P450 and transporters Fourth symposium on inflammation and pain 2nd symposium on NFkB Synthetic peptides as immunopharmacological tools Novel designs in clinical trials. Biosimilar pharmaceuticals Pharmacogenetics, pharmacogenomics, proteomics and phosphoproteomics Immune response in cancer First symposium on business and international cooperation on biologics Immunopharmacology 2020 is sponsored by: Cuban Society of Pharmacology (SCF) International Union of Basic and Clinical Pharmacology (IUPHAR) Latin-American Association of Pharmacology (ALF) PAHO / WHO BioCubaFarma National research centers: Finlay Vaccine Institute (IFV); Center of Genetic Engineering and Biotechnology (CIGB); Center of Molecular Immunology (CIM); Center for Control of Drugs, Equipment and Medical Devices (CECMED); National Center for Animal and Plant Health (CENSA); Tropical Medicine Institute "Pedro Kourí" (IPK); National Center for Biopreparations (BioCEN); Center for Drug Research and Development (CIDEM); Center for Clinical Trials (CENCEC); among others International Manufacturers and Companies The key objectives of the Congress are: To provide a progressive state-of-the-art report for scientists, manufacturers, governmental authorities and healthcare workers, who need to be updated about the latest scientific developments for human vaccines, including basic science, product development, market introduction, immunization programs and epidemiological surveillance. To promote the scientific collaboration among experts and institutions through the experience exchange, the presentation of results and the discussion on the conference topics. To accelerate progress in the development of vaccines and the acceptance and introduction of new methods and technologies. Opening lectures, oral presentations and posters will provide you the opportunity to be involved in a high quality congress to discuss about the progress in the field of immunology and pharmacology sciences(AU)

Nurse empowerment through Pharmacogenetics / Empoderamento do enfermeiro por meio da Farmacogenética / Empoderamiento del enfermero a través de la farmacogenética

Objective: to verify the existence of elements that justify the use of pharmacogenetics by the Brazilian nurse. Method: this is a quantitative, cross-sectional, observational, descriptive study, whose final sample was 67 individuals. The participants were healthy at the time of the study and reported a history of previous use and the occurrence of adverse effects by drugs commonly used and metabolized by CYP2C9. We collected 4 mL of venous blood for subsequent DNA extraction by salting out method and genotyping of the CYP2C9*2 and CYP2C9*3 polymorphisms, using Polymerase Chain Reaction in real time using Taqman assays. Results: the use of drugs metabolized by CYP2C9 was frequent (more than 75% of the individuals have already used between 2 or 4 of these drugs). Regarding adverse events, there were 19 perceived symptomatic occurrences associated with drugs metabolized by CYP2C9. The allele frequency of the polymorphism * 2 and * 3 in the population studied was 11.1% and 7.5%, respectively, and there was a coincidence between the presence of alleles of low enzyme activity and the occurrence of adverse effects. Conclusion: there are elements that justify the adoption of pharmacogenetics in the nursing care to reduce the occurrence of adverse reactions to drugs metabolized by CYP2C9.

Objetivo: verificar a existência de elementos que justifiquem o uso da farmacogenética pelo enfermeiro brasileiro. Método: trata-se de um estudo quantitativo, do tipo transversal, observacional descritivo, cuja amostra final foi de 67 indivíduos. Os participantes estavam saudáveis no momento do estudo e reportaram histórico de uso prévio e ocorrência de efeitos adversos por fármacos comumente utilizados e metabolizados pela CYP2C9. Coletamos 4 mL de sangue venoso para posterior extração de DNA por método salting out e genotipagem dos polimorfismos CYP2C9*2 e CYP2C9*3 através de Polymerase Chain Reaction em tempo real, utilizando ensaios Taqman. Resultados: o uso de fármacos metabolizados pela CYP2C9 foi frequente (mais de 75% dos sujeitos já utilizaram entre 2 ou 4 desses fármacos). A respeito dos eventos adversos, houve 19 ocorrências sintomáticas percebidas, associadas a fármacos metabolizados pela CYP2C9. A frequência alélica do polimorfismo *2 e *3 na população estudada foi de 11,1% e 7,5%, respectivamente, com coincidência entre a presença dos alelos de baixa atividade enzimática e ocorrência de efeitos adversos. Conclusão: existem elementos que justificam a adoção da farmacogenética no cuidado do enfermeiro com objetivo de redução da ocorrência de reações adversas a fármacos metabolizados pela CYP2C9.

Objetivo: verificar la existencia de elementos que justifiquen el uso de la farmacogenética por parte del enfermero brasileño. Método: se trata de un estudio cuantitativo, transversal, observacional, descriptivo, cuya muestra final fue de 67 individuos. Los participantes estaban sanos en el momento del estudio e informaron un historial de uso previo y la aparición de efectos adversos por fármacos comúnmente utilizados y metabolizados por el CYP2C9. Recolectamos 4 ml de sangre venosa para la posterior extracción de ADN mediante el método de salazón y genotipificación de los polimorfismos CYP2C9 * 2 y CYP2C9 * 3 a través de la reacción en cadena de la polimerasa en tiempo real utilizando ensayos Taqman. Resultados: el uso de drogas metabolizadas por el CYP2C9 fue frecuente (más del 75% de las personas ya han usado entre 2 o 4 de estas drogas). Con respecto a los eventos adversos, hubo 19 casos sintomáticos percibidos asociados con medicamentos metabolizados por el CYP2C9. La frecuencia alélica del polimorfismo * 2 y * 3 en la población estudiada fue de 11.1% y 7.5%, respectivamente, y hubo una coincidencia entre la presencia de alelos de baja actividad enzimática y la aparición de efectos adversos. Conclusión: existen elementos que justifican la adopción de la farmacogenética en el cuidado del enfermero para reducir la aparición de reacciones adversas a los medicamentos metabolizados por el CYP2C9.

Estudio de las variantes alélicas CYP2C9*2 y CYP2C9*3 en muestras de población mestiza peruana / Study of the allelic variants CYP2C9*2 and CYP2C9*3 in samples of the Peruvian mestizo population

Resumen Introducción. El citocromo CYP2C9 metaboliza, aproximadamente, el 15 % de los fármacos prescritos. Su gen presenta alelos cuyas frecuencias difieren entre grupos étnicos y poblaciones. Los alelos CYP2C9*2 y CYP2C9*3 dan cuenta de una enzima con actividad disminuida cuya frecuencia no ha sido determinada en la población mestiza peruana. Objetivo. Caracterizar la frecuencia de las variantes *2 (rs1799853) y *3 (rs1057910) del gen CYP2C9 en muestras de población mestiza peruana provenientes de Lima, Tacna y Junín. Materiales y métodos. Se hizo un estudio descriptivo, observacional y prospectivo, con muestreo no probabilístico, por conveniencia e incidental. Se incluyeron 218 sujetos según los criterios de inclusión y exclusión; todos los participantes otorgaron su consentimiento informado. El ADN genómico se obtuvo mediante hisopado de mucosa oral, y la detección de los genotipos para los alelos CYP2C9*2 y CYP2C9*3 se hizo mediante reacción en cadena de la polimerasa (PCR) en tiempo real, utilizando sondas TaqMan™. Resultados. Las variantes de CYP2C9*2 y CYP2C9*3 están presentes en la población mestiza peruana con frecuencias de 0,046 y 0,062, respectivamente. El análisis de las frecuencias genotípicas observadas permitió predecir que la frecuencia de fenotipos metabolismo intermedio sería del 15,13 % (CYP2C9*1/*2: 5,96 %; CYP2C9*1/*3: 9,17 %), y la de fenotipos de metabolismo lento, del 3,22 % (CYP2C9*2/*2: 1,38 %; CYP2C9*3/*3: 1,38 %; CYP2C9*2/*3: 0,46 %). Conclusiones. Se lograron determinar las frecuencias genotípicas y alélicas para las variantes *2 y *3 del gen CYP2C9 en una muestra no probabilística de población mestiza peruana. Las frecuencias obtenidas (0,046 y 0,062, respectivamente) están entre las esperadas para una población mestiza sudamericana con ascendencia amerindia, europea, africana y asiática.

Abstract Introduction: CYP2C9 metabolizes approximately 15% of the prescribed drugs. Its gene has alleles whose frequencies differ between ethnic groups and populations. The alleles CYP2C9*2 and CYP2C9*3 account for an enzyme with decreased activity and their frequencies have not been determined in the Peruvian mestizo population. Objective: To characterize the frequencies of the allelic variants *2 (rs1799853) and *3 (rs1057910) of CYP2C9 gen in the Peruvian mestizo population from Lima, Tacna y Junín. Materials and methods: We conducted an observational, prospective cross-sectional study with non-probabilistic, by convenience, and incidental sampling. We included 218 subjects according to the inclusion and exclusion criteria, all of whom had signed the informed consent. We obtained the genomic DNA from oral mucosa swab. For the detection of the CYP2C9*2 and CYP2C9*3 genotypes, we used real-time-polymerase chain reaction with TaqMan® probes. Results: The genotyping revealed that CYP2C9*2 and CYP2C9*3 variants have low frequencies (0.046 and 0.062, respectively). The frequency of intermediate metabolizers was 15.13% (CYP2C9*1/*2: 5.96%; CYP2C9*1/*3: 9.17%) and that of slow metabolizers was 3.22% (CYP2C9*2/*2: 1.38%; CYP2C9*3/*3: 1.38%; CYP2C9*2/*3: 0.46%). Conclusions: It was possible to determine the genotypic and allelic frequencies for the variants *2 and *3 of the CYP2C9 gene in a non-probabilistic sample of the Peruvian mestizo population. The frequencies obtained (0.046 and 0.062, respectively) corresponded to those expected for a South American mestizo population with Amerindian, European, African and Asian ancestry.