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Aproximadamente 40% da metabolização de fármacos pelas enzimas P450 é catalisada por enzimas polimórficas que podem conduzir a metabolismo nulo, diminuido (qualitativa ou quantitativamente) ou aumentado. O recente desenvolvimento da tecnologia de matrizes de oligonucleótidos em microchips para detecção dum elevado número de mutações nos genes pode ser útil na selecção e posologia de medicamentos mais adequados ao perfil genético dos doentes. Contudo, antes da aplicação na prática clínica destes progressos é necessário testar a validação dos pressupostos mediante a realização de ensaios clínicos. No âmbito da terapêutica medicamentosa os ensaios clínicos continuam a ser o suporte da medicina baseada na evidência. Por consequência, sempre que justificado, a investigação e desenvolvimento de novos medicamentos deve incluir a informação farmacogenómica obtida dos estudos pré-clínicos (in vitro, in vivo e in silico) de modo a que os ensaios clínicos possam confirmar a relação entre o perfil genético dos doentes e a respectiva resposta terapêutica., Approximately 40% of human P450 dependent drug metabolism is carried out by polymorphic enzymes, which can cause abolished, quantitatively or qualitatatively altered or enhanced drug metabolism. The recent development of high-through methods for mutation detection and oligogonucleotide chips array technology for the detection of a multitude of mutations in the genes may help to prescription of drugs tailored to the genetic profile of the patients. However before applying this new knowledge in the clinical practice there is a need to test the validity of the assumptions through clinical trials. Within the realm of drug therapy clinical trials remain the mainstay for the practice of evidence based medicine. Therefore whenever justified the investigation and development of new drugs shall include the pharmacogenomic information obtained from the pre-clinical investigations (in vitro, in vivo and in silico) so that the clinical trials may validate the relationship between the genetic profile of the patients and their response to them., Revista Lusófona de Ciências e Tecnologias da Saúde

Headaches and migraines are widely prevalent diseases causing relevant disability and worsened quality of life. Several pharmacological options are available for headache therapy, mostly however without firm rationales and all having high rates of non-responders and often serious side effects. Variability of therapeutic effect and adverse events depend at least in part upon genetic variability, but the genetic factors involved are mostly unknown. Pharmacogenetics, i. e., the application of the knowledge of genomic diversity to the analysis of the phenotypic traits involved in therapeutic response and adverse events, is still in its infancy, but represents a promising approach to therapy in migraine. The extant evidence is summarised here, with special attention to pain therapy and the pharmacogenetics of the serotonergic and the dopaminergic systems.

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Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina

Este trabajo parte de la constatación del importante incremento de estudios farmacológicos que lleva asociado un estudio farmacogenético sin que exista un conocimiento muy claro de sus consecuencias. Su primer reto es dilucidar si estos estudios tienen mayores implicaciones que las determinaciones de parámetros de rutina. No se puede obviar que la genética genera cierta preocupación debido, entre otros factores, al lenguaje técnico, la desinformación, las simplificaciones que generan los medios de comunicación, y su complejidad. El segundo objetivo es definir qué figura de propiedad tienen los investigadores o las empresas patrocinantes de las muestras biológicas y los datos genéticos en los estudios de farmacogenética This work starts stating the great increase of pharmacological studies associated with pharmacogenetic studies without clear knowledge of their consequences. The first challenge is to find out whether pharmacogenetic studies have greater implications than the determination of routine parameters. We cannot obviate that genetics engenders special worries due to several factors, such as: technical language, lack of information, media simplifications and complexity. The second goal is to define which property rights researchers or sponsor companies have on biological samples and genetic data in pharmacogenetic studies Este trabalho parte da constatação do importante incremento dos estudos farmacológicos que leva associado um estudo farmacogenético sem que exista um conhecimento muito claro de suas conseqüências. Seu primeiro objetivo é esclarecer se estes estudos tem maiores implicações que as determinações de parâmetros de rotina. Não se pode considerar obvio que a genética gera certa preocupação devido, entre outros fatores, à linguagem técnica, à desinformação, às simplificações geradas pelos meios de comunicação, e sua complexidade. O segundo objetivo é definir que figura de propriedade tem os pesquisadores ou as empresas patrocinadoras das amostras biológicas e os dados genéticos nos estudos de farmacogenética

Characterization of acetylator and oxidative metabolizers phenotypes is of clinical relevance, as it has been shown that the pharmacological response of several therapeutic agents. The studies of phenotypage and genotipage have as purpose to detect and to mensurar polimorfismos in these enzymes. In this study, we assessed in vivo activities of CYP1A2, CYP2A6, Xantine Oxidase (XO) and NAT2 in sample of 82 volunteers (40 men and 42 women) from Ceará – Brazil using caffeine as probe. The volunteers were free from significant cardiac, hepatic, renal, pulmonary, gastrointestinal and hematological disease, as assessed by physical investigation, ECG and hematological and biochemical tests. The study was open, the volunteers were hospitalized, having already had a normal evening meal, and after an overnight fast they received a single 200 mg dose of caffeine tablet. Blood samples were collected in regular interview ( 0; 5min; 15min; 25min; 35min; 45min; 1h; 1,25h; 1,5h; 2h; 4h; 6h; 8h; 12h and 24 hour) after the administration of caffeine. Urine was harvested in its total volume during the 10 hours after the administration of caffeine, the total urinário volume was quantified and an aliquot one was stored for determination of the metabólitos. The caffeine was determined in human plasma and the metabolites were determined in human urinary by HPLC using teobromina as an internal standard. The metabolites assessed were: 1U – 1-methyluric acid; 17U – 1, 7-dimethyluric acid; 1X – 1-methylxantine; 17X – 1, 7-1-dimethylxantine e AFMU – 5-acetylamino-6-formylamino-3methyluracil. The following molar ratios were calculated as an index for CYP1A2 activity [(AFMU + 1X + 1U)/ 17U]; CYP2A6 activity [17U / (AFMU + 1X + 1U + 17X + 17U)]; NAT2 activity [AFMU/ (AFMU + 1X + 1U)] and Xanthine Oxidase activity [1U/ (1X + 1U)]. The enzymatic activities were plotted in histogram. The frequency distributions of the CYP1A2, CYP2A6, XO and NAT2 were not normally distributed, showing three phenotypes. Afterwards the volunteers were classified by enzymatic activities in ten groups, and the lowest and highest metabolizers groups were chosen to determine the following pharmacokinetic parameters: AUC0-24, t1/2, ke, CL and Vd/Kg. The comparison of these parameters (test “t” de Student) between these two groups it showed significant differences (p

Este trabajo parte de la constatación del importante incremento de estudios farmacológicos que lleva asociado un estudio farmacogenético sin que exista un conocimiento muy claro de sus consecuencias. Su primer reto es dilucidar si estos estudios tienen mayores implicaciones que las determinaciones de parámetros de rutina. No se puede obviar que la genética genera cierta preocupación debido, entre otros factores, al lenguaje técnico, la desinformación, las simplificaciones que generan los medios de comunicación, y su complejidad. El segundo objetivo es definir qué figura de propiedad tienen los investigadores o las empresas patrocinantes de las muestras biológicas y los datos genéticos en los estudios de farmacogenética

Las diferencias alélicas en los genes del Citocromo P450 2D6 (GSTM1), de la N-aceliltransferasa (NAT2) y del Glutatión transferasa m1 (GSTM1) han mostrado estar asociadas con el riesgo genético de desarrollar enfermedades ambientales y ocupacionales. Estas enzimas exhiben variabilidad en la actividad metabólica, ocasionada por variantes alelicas producidas por mutaciones. Este es un estudio preliminar de las frecuencias alélicas de los genes CYP2D6, NAT2 y GSTM1 en Nativos Americanos. Se han analizado 128 cromosomas pertenecientes a 6 poblaciones diferentes: 4 de Argentina (Wichi, Tehuelche, Mapuche y Jujuy) y 2 de Paraguay (Lengua, Ayoreo). Se analizaron 9 mutaciones diagnósticas del gen CYP2D6: C188T, G212A, Ins T226, Del T1795, G1846T/A, G1934A, C2938T, DelA2637 y G1749C; 3 mutaciones de gen NAT2: 481T, 590A y 857C; y la pérdida del gen GSTM1. Se encontró un aumento significativo (P, Asociación de Antropología Biológica de la República Argentina

Luis Alberto Magna Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: A fenitoína e a carbamazepina são fármacos anticonvulsivantes de faixa terapêutica estreita, sendo indicada sua monitorização terapêutica. Neste trabalho descrevemos uma técnica de cromatografia líquida de alta resolução para medir os níveis plasmáticos dos anticonvulsivantes fenitoína, carbamazepina e fenobarbital nos pacientes do Ambulatório de Epilepsia do HC da UNICAMP, supervisionado pela Disciplina de Neurologia da FCM. Dosamos 925 amostras, com as quais obtivemos uma visão geral dos níveis plasmáticos de cada anticonvulsivante e detivemo-nos, com mais profundidade, na análise da distribuição dos pacientes segundo os níveis da fenitoína e da carbamazepina. As amostras dos usuários de fenitoína totalizaram 216 e apresentaram um alto percentual de níveis plasmáticos deslocados da faixa terapêutica (44,48% abaixo e 27,12% acima da FI) , indicando maior dificuldade de ajuste de doses. Além disso, 7 pacientes sob monoterapia apresentaram níveis plasmáticos muito acima da faixa terapêutica, sugerindo uma distribuição bimodal cuja explicação pode estar numa menor atividade enzimática devida à herança genética. Esses pacientes merecem uma investigação mais aprofundada. As amostras de carbamazepina totalizaram 421 e comparativamente à fenitoína, apresentaram um percentual menor de níveis plasmáticos deslocados da faixa terapêutica (9,74% abaixo e 22,09% acima da FI) . Mesmo no caso da carbamazepina, cujo percentual de amostras com nível dentro da faixa terapêutica é maior, o trabalho tomou clara a importância de um controle sistemático dos níveis plasmáticos para detecção da aderência ao tratamento e das variações metabólicas em nossa população, dentre cujas causas as diferenças genéticas- foram objeto especial de nossa atenção. Além das amostras de fenitoína e carbamazepina, foram dosadas ainda 96 de pacientes usuários de fenobarbital e 192 de pacientes sob regime de politerapia, cujos resultados foram descritos no capítulo 6 (apêndice). O método cromatográfico utilizado para as dosagens viabilizou a implantação de um serviço de rotina de controle dos níveis plasmáticos de anticonvulsivantes para o Departamento de Neurologia. Assim, cumprimos os objetivos propostos, e fornecemos subsídios para outros trabalhos que venham a ser desenvolvidos Abstract: This thesis describes the use of a high perfonnance liquid chromatography (HPLC) procedure to measure the plasma levels of the anticonvulsivants phenytoin, carbamazepine and phenobarbital in patients attended at the Epilepsy Ambulatory ofthe Department ofNeurology at the university hospital ofthe State University of Campinas (UNICAMP). A total of 925 plasma samples were assayed for their anticonvulsivant levels with particular attention being paid to the concentrations of phenytoin and carbamazepine. Ofthe 216 samples in wich phenytoin was detected, the plasma levels were below and above the therapeutic range in 44.5 and 27.1 %, respectively. This wide distribution outside of the recommended limits suggests a difficu1ty in regulating the circulating levels ofthis drug. In seven patients ofthe latter group, the concentrations were marlced1y greater than the acceptable upper limito Such variation is suggestive of a bimodal distribution and may reflect a genetica1ly-detennined lower activity ofthe enzyme (s) involved in the metabolism of phenytoin, although the precise cause (s) of the high concentrations in these patients would merit further detailed investigation. Carbamazepine was detected in 421 plasma samples, a lower percentage of wich feU outside the recommended therapeutic range (9.7% below and 22.1% above) compared to phenytoin. Although the proportion of individuais with carbamazepine concentrations within the therapeutic range was greater than for phenytoin, rigorous monitoring of the plasma levels was still necessary in order to ascertain the levels of patient compliance and genetic variation in this drug's metabolism within the population. In addition to the above drugs, the levels ofthe phenobarbital were also determined in 96 patients usin this anticonvulsivant and in 192 individuais undergoing multi-drug therapy. The results for these two groups are provided in chapter 6 (Appendix). The chromatographic method employed in this study proved to be useful for the routine monitoring of plasma anticonvulsivant levels in patients attended by the Departrnent ofNeurology. This procedure and the findings of this study should provide a starting point for further investigations into anticonvulsivant therapy Doutorado Genética e Biologia Molecular Doutor em Genética Animal e Evolução

RESUMEN: El campo de la investigación relacionado con las respuestas de base hereditaria a las drogas se ha denominado farmacogenética. Se han descrito al menos 60 polimorfismos farmacogenéticos en la medicina clínica; muchos de ellos son responsables de las marcadas diferencias en la predisposición genética para desarrollar toxicidad por drogas o cáncer. En este momento los polimorfismos de mayor atención son los de la debrisoquina-esparteína y de la N-acetilación por el gran número de fármacos de prescripción común y de aminas carcinogénicas que utilizan estas enzimas para su inactivación. ABSTRACT: Research concerning hereditary basis of response to drugs is known as pharmacogenetics; at least 60 pharmacogenetic polymorphisms have been described in clinical medicine; many of them are responsible for marked differences in predisposition towards drug toxicity or cancer. The debrisoquine-esparteine and the N-acetylation polymorphisms are presently the most important, since they involve both many frequently prescribed drugs, and carcinogenic amines that use this enzyme for inactivation.

La farmacogenética es la ciencia que permite identificar las bases genéticas de las diferencias interindividuales en la respuesta a drogas. Este artículo de revisión utiliza un número de ejemplos publicados de diferencias heredadas en enzimas metabolizadoras de drogas, para ilustrar la importancia de la herencia en la determinación de la eficacia y la toxicidad de medicamentos en humanos. Aunque tienen un desarrollo incipiente, ya existen pruebas para el diagnóstico molecular mediante las cuales médicos y farmacéuticos pueden seleccionar los fármacos y las dosis para cada paciente de forma individual. El desarrollo de la farmacogenética, provee de, al menos, una vía para hacer prescripciones médicas sin el empirismo corriente e ir hacia una terapia más personalizada.Pharmacogenetics is a science that allows to identify the genetic bases of the interindividual differences in the response to drugs. This review article uses a number of published examples of differences inherited in drug-metabolizing enzimes to illustrate the importance of inheritance in the determination of the efficiency and toxicity of drugs in human beings. Although their development is incipient, there are already tests for the mollecular diagnosis by which the physicians and pharmacists may select the drugs and the dosing for each patient in an individual way. The development of pharmacogenetics provides at least one way to prescribe medicines without the usual empirism and to advance towards a more personalized therapy.

Introducción: imatinib es un inhibidor de la tirosina-kinasa BCR-ABL que revolucionó el tratamiento de pacientes con leucemia mieloide crónica (LMC) positivos para cromosoma Philadelphia (Ph+). Este medicamento se metaboliza principalmente por la enzima CYP3A4, cuyo gen presenta variaciones interindividuales tipo SNPs que pueden interferir con la efectividad del tratamiento, como son los polimorfismos CYP3A4*1B y CYP3A4*2 que han mostrado influencia significativa en la actividad metabólica de esta importante enzima farmacológica. Objetivos: Evaluar la frecuencia de polimorfismos de importancia farmacogenética en el gen CYP3A4 en una población de pacientes con LMC tratados con imatinib y en una población control de 164 personas. Correlacionar el genotipo con la evolución de la expansión clonal Ph(+) y la duración del tratamiento. Metodología: Genotipificación PCR-RFLP para los SNPs CYP3A4*1B y CYP3A4*2. Bandeo replicativo tipo RBHG para la evaluación citogenética de blastos espontáneos con o sin presencia del marcador Ph(+). Resultados: Los análisis citogenéticos revelaron una correlación directa entre el tiempo de tratamiento con imatinib y el porcentaje de reducción de blastos Philadelphia (+). Las genotipificaciones evidenciaron que la presencia del polimorfismo CYP3A4*1B no influye en la respuesta citogenética de los pacientes Ph+ tratados con imatinib, y que el polimorfismo fármaco relevante CYP3A4*2 está ausente en esta población colombiana de controles y pacientes. Conclusiones: El farmacogenotipo CYP3A4*2 (exón 7) no afecta la respuesta citogenética positiva inducida por el imatinib en pacientes con LMC, en quienes la frecuencia de células Ph(+) por lo general se reduce en relación directa con la duración del tratamiento. Introduction: Imatinib is an inhibitor of the BCR-ABL tyrosine-kinase that has dramatically changed the treatment of patient with Chronic myeloid leukemia (CML) positive for the Philadelphia chromosome (Ph+). This compound is mainly metabolized by the cytochrome CYP3A4 enzyme, coded by a gene with individual variations that could interfere with the effectiveness of the treatment, due to the fact that particular single nucleotide polymorphisms (SNPs), i.e., CYP3A4*1B y CYP3A4*2, have shown to exert a significant influence on the metabolic activity of this pharmacologically important enzyme. Objective: Evaluate the frequency of pharmacogenetically important polymorphisms in the CYP3A4 gen in a Colombian population of patients with CML being treated with this novel drug (Imatinib), in parallel with a control population of 164 healthy individuals. Correlate the evolution of the clonal expansion Ph(+) with the presence of these SNPs and the length of treatment. Methodology: PCR-RFLP genotyping for the CYP3A4* 1B y CYP3A4*2 SNPs. RBHG replication banding for the evaluation of the presence of the Ph(+) markers in spontaneous mitotic blasts. Results: A positive cytogenetic response and/or correlation was detected between the length of the imatinib treatment and a reduction in the percentage of Ph(+) blasts. Genotyping indicate that CYP3A4*1B polymorphism does no affect the cytogenetic response in imatinib treated Ph(+) patients, and that the pharmacorelevant CYP3A4*2 SNP is not present in this population of patients and controls (N=194). Conclusions: The pharmacogenotype CYP3A4*2 (exon 7) does not affect the induced positive cytogenetic response triggered by the imatinib treatment, that generally induces a reduction in Ph(+) blasts en relation with the duration of the treatment.

El objetivo del estudio fue determinar la frecuencia de las variantes del gen CYP2D6: *4, *6 y *10 y predecir el fenotipo metabolizador en una muestra de 145 individuos no consanguíneos, aparentemente sanos, residentes del estado Aragua, Venezuela. Los genotipos fueron determinados mediante ensayos de reacción en cadena de la polimerasa seguidos de digestión con endonucleasas de restricción. La predicción del fenotipo metabolizador se realizó con base al sistema Activity score. Las frecuencias de CYP2D6 *4, *6 y *10 fueron de 14,5%, 0,3% y 1%, respectivamente; un porcentaje significativo de individuos fueron categorizados como metabolizador rápido heterocigoto/metabolizador intermedio (23,5%) y metabolizador lento (4,1%). Esta información tiene impacto clínico potencial, porque CYP2D6 interviene en el metabolismo de fármacos de prescripción frecuente como: carvedilol, captopril, cloroquina, codeína, fluoxetina, fluvastatina, haloperidol, idarrubicina, indinavir, imatinib, loperamida, nifedipina, ondansetrón y tamoxifeno The aim of this study was to determine the CYP2D6: * 4, * 6 and * 10 gene variants frequency and to predict the metabolizer phenotype in a sample of 145 unrelated apparently healthy individuals residing in the state of Aragua, Venezuela. Genotypes were determined by Polymerase chain reaction assays followed by restriction endonucleases digestion. The metabolizer phenotype prediction was made based on the activity score system. The frequencies of CYP2D6 * 4, * 6 and * 10 allelic variants were 14.5%, 0.3% and 1%. A significant percentage of individuals were categorized as heterozygote-extensive/intermediate (23.5%) and poor metabolizers (4.1%), this information has potential clinical impact, because the CYP2D6 protein is involved in the metabolism of drugs frequently prescribed as: carvedilol, captopril, chloroquine, codeine, fluoxetine, fluvastatin, haloperidol, idarubicin, indinavir, imatinib, loperamide, nifedipine, ondansetron and tamoxifen

ResumenEn el campo de la dermatología en los últimos años se han producido grandes avances en el diagnóstico y tratamiento de las enfermedades cutáneas.La extensión del tegumento, su gran diversidad celular y su fácil accesibilidad han estimulado la realización de múltiples estudios e investigación. De gran relevancia han sido los que han utilizado células madre mesenquimáticas de la piel, ya que tendrán un gran impacto en la medicina de este siglo en relación al aporte terapéutico que esto implica.La farmacogenética, que es el estudio del efecto de la variabilidad genética en un individuo para aumentar las posibilidades de una respuesta terapéutica y disminuir las chances de una reacción adversa a drogas, se acerca al ideal de una medicina personalizada y se ha constituido en una realidad en algunas enfermedades de la piel. Finalmente la fotonanodermatología (interface entre fotobiología, dermatología y nanotecnología), es una tecnología que ha crecido rápidamente en el campo de la medicina y especialmente la dermatología, donde tiene aplicaciones múltiples tanto en productos para la protección de la piel, como en el diagnóstico y tratamiento de enfermedades cutáneas.SummaryIn the dermatology field in the last years, there have been great advances in the diagnosis and treatment of cutaneous diseases. The skin with their large surface and easy accesibility has stimulated the realization of multiplestudies and research.The skin mesenchymal stems cells research is expected to have a great impact on the medicine of the 21st century, specially related with their therapeutic implications.Pharmacogenetics refers to the study of the genetic variability between patients that is been used to optimizate drug efficacy, minimizing toxicity is near the ideal of a personalized medicine and it is being used in some skin diseases. Finally photonanodermatology (interface of photobiology, dermatology and nanotechnology) is a technology that has grown quickly in medicine and specially dermatology, where it has multiple uses in skin protection products and in diagnosis and treatment of skin diseases.

Personalized medicine is the use of biomarkers, most of them molecular markers, for detection of specific genetic traits to guide various approaches for preventing and treating different conditions. The identification of several genes related to heredity, oncology and infectious diseases lead to the detection of genetic polymorphisms that are involved not only in different clinical progression of these diseases but also in variations in treatment response. Currently, it is possible to detect these polymorphisms using several methodologies: detection of single nucleotide polymorphisms using polymerase chain reaction methods; nucleic acid microarray detection; and nucleic acid sequencing with automatized DNA sequencers using Sanger-derived methods and new generation sequencing. Personalized medicine assays are directed towards detecting genetic variations that alter interactions of drugs with targets or the metabolic pathways of drugs (upstream and downstream) and can be utilized for the selection of drug formulations and detect different immunogenicities of the drug. Personalized medicine applications have already been described in different areas of Medicine and allow specific treatment approaches to be applied to each patient and pathology according to the results of these assays. The application of such a protocol demands an increasing interaction between the clinical laboratory and the clinical staff. For its implementation, a coordinated team composed of basic researchers and physicians highly specialized in their areas supported by a highly specialized team of clinical analysts particularly trained in molecular biology assays is necessary. Medicina personalizada é o uso de biomarcadores, em sua maioria marcadores moleculares, para a detecção de traços genéticos específicos, a fim de orientar diversas abordagens para a prevenção e o tratamento de diferentes doenças. A identificação de vários genes relacionados a doenças hereditárias, oncológicas e infecciosas permite a detecção de polimorfismos genéticos que estão envolvidos em diferentes evoluções clínicas dessas doenças, bem como com variações na resposta ao tratamento. Atualmente, já é possível detectar esses polimorfismos utilizando diversas metodologias: a detecção de polimorfismos de nucleotídeo único pela reação de polimerização em cadeia; a detecção de microarranjos de ácidos nucleicos; e o sequenciamento de ácidos nucleicos com sequenciadores de DNA automatizados usando métodos derivados de sequenciamento Sanger ou de nova geração. Os ensaios de medicina personalizada são dirigidos para detectar variações genéticas que alteram interações de fármacos com alvos ou vias metabólicas de fármacos (anabólicas e catabólicas), podendo ser utilizados para a seleção de formulações farmacêuticas e para detectar diferentes imunogenicidades da droga. As aplicações de medicina personalizada já foram descritas em várias áreas da Medicina e permitem que abordagens de tratamento específicas sejam aplicadas para cada paciente e para cada doença, de acordo com os resultados dos ensaios utilizados. A aplicação de um protocolo desse tipo exige uma relação intensa entre o laboratório e o corpo clínico. Para sua execução, é necessária uma equipe coordenada, composta por investigadores de pesquisa básica e médicos altamente especializados em suas áreas, apoiada por um time bastante especializado de analistas clínicos treinados em testes de biologia molecular.

The inconclusive and non-replicated results of pharmacogenetic studies of antidepressant response could be related to the lack of acknowledgement of its mechanism of action. In this scenario, gene expression studies provide and interesting framework to reveal new candidate genes for pharmacogenetic studies or peripheral biomarkers of fluoxetine response. We propose a system biology approach to analyse changes in gene expression induced by eight weeks of treatment with fluoxetine in peripheral blood. 21 naïve child and adolescents participated in the present study. Our analysis include the identification of gene co-expression modules, using Weighted Gene Co-expression Network Analysis (WGCNA), followed by protein-protein interaction (PPi) network construction coupled with functional annotation. Our results revealed two modules of co-expression genes related to fluoxetine treatment. The constructed networks from these modules were enriched for biological processes related to cellular and metabolic processes, cell communication, immune system processes, cell death, response to stimulus and neurogenesis. Some of these processes, such as immune system, replicated previous findings in the literature, whereas, neurogenesis, a mechanism proposed to be involved in fluoxetine response, had been identified for first time using peripheral tissues. In conclusion, our study identifies several biological processes in relation to fluoxetine treatment in peripheral blood, offer new candidate genes for pharmacogenetic studies and valuable markers for peripheral moderator biomarkers discovery.

La warfarina, el anticoagulante oral de mayor prescripción en el mundo, es un fármaco difícil de manejar por su estrecho margen terapéutico, amplia gama de interacciones y gran variabilidad inter-individual en la respuesta. De una cohorte de 145 pacientes en anticoagulación crónica con warfarina reportamos una serie de casos de sensibilidad (dosis ≤ 15 mg/semana) y de resistencia (dosis ≥ 70 mg/ semana) al fármaco y, tras una breve revisión de sus aspectos farmacológicos relevantes, discutimos los posibles factores causantes de estas respuestas exageradas al medicamento.

Typical antipsychotics have a high affinity for dopamine receptors. It is therefore of interest to investigate such loci in pharmacogenetic studies on psychosis. We investigated the hypothesis that Ser9Gly polymorphism of the DRD3 gene may play a role in the differences in individual response to typical antipsychotics between schizophrenic patients. The sample was composed of 53 good responders and 59 poor ones. No significant differences between the good and poor responders were found in the allelic distribution (good responders: Ser9 61.32%, Gly9 38.67%; poor responders: Ser9 64.40%, Gly9 35.59%; odds ratio, OR = 0.88, 0.49 < OR < 1.56; chi2 = 0.23, 1 degree of freedom, df, p = 0.63) and genotype distribution (good responders: Ser9/Ser9 37.73%, Ser9/Gly9 47.16%, Gly9/Gly9 15.09%; poor responders: Ser9/Ser9 42.37%, Ser9/Gly9 44.06%, Gly9/Gly9 13.55%; chi2 = 0.25, 2 df, p = 0.88). Nor was there any association with homozygosity (good responders: homozygous: 52.82%, heterozygous: 47.16%; poor responders: homozygous: 55.92%, heterozygous: 44.06%; odds ratio, OR = 0.88, 0.39 < OR < 1.99; chi2 = 0.11, 1 df, p = 0.74). The results did not support the hypothesis that Ser9Gly polymorphism of the DRD3 gene influences the response to typical antipsychotics in our sample of schizophrenics. Antipsicóticos típicos apresentam alta afinidade pelos receptores dopaminérgicos, que são, portanto, regiões de interesse para os estudos de farmacogenética das psicoses. No presente estudo, investigamos a hipótese de que o polimorfismo Ser9Gly do gene do DRD3 possa exercer um papel na diferença de resposta inter-individual ao uso de antipsicóticos típicos em pacientes com esquizofrenia. Nossa amostra foi composta por 53 pacientes bons respondedores e 59 maus respondedores. Não houve diferenças nas distribuições alélicas (bons respondedores: Ser9 61,32%, Gly9 38,67%; maus respondedores: Ser9 64,40%, Gly9 35,59%; odds ratio, OR = 0,88, 0,49 < OR < 1,56; chi2 = 0,23, 1 degree of freedom, d.f., p = 0,63) e genotípica (bons respondedores: Ser9/Ser9 37,73%, Ser9/Gly9 47,16%, Gly9/Gly9 15,09%; maus repondedores: Ser9/Ser9 42,37%, Ser9/Gly9 44,06%, Gly9/Gly9 13,55%; chi2 = 0,25, 2 d.f., p = 0,88) entre os grupos. Não houve também associação com homozigosidade (bons respondedores: homozigotos: 52,82%, heterozigotos: 47,16%; maus repondedores: homozigotos: 55,92%, heterozigotos: 44,06%; odds ratio, OR = 0,88, 0,39 < OR < 1,99); chi2 = 0,11, 1 d.f., p = 0,74). Os resultados não dão suporte à hipótese de que o polimorfismo Ser9Gly do gene do DRD3 possa influenciar a resposta terapêutica aos antipsicóticos típicos na nossa amostra de pacientes com esquizofrenia.

La ‘era posgenómica’ ha impactado las ciencias biológicas y biomédicas desde la identificación de un significativo componente de variabilidad genética interindividual. La Farmacología no escapa a esta realidad, y esta ciencia, en conjunto con la Toxicología, ya desde hace varios años ve desarrollados campos como la Farmacogenética y la Farmacogenómica. Dichas disciplinas estudian la influencia de la variabilidad genética de la población respecto a la respuesta que se tiene ante el contacto con los fármacos y las sustancias tóxicas. Las variantes genéticas, reflejadas en el polimorfismo de los genes, tienen implicaciones en el manejo de xenobióticos en el organismo y además determinan las respuestas aumentadas, normales o disminuidas durante la administración de algunos fármacos. Muchos genes se relacionan con reacciones adversas y fallas terapéuticas de fármacos administrados a dosis predeterminadas y siguiendo protocolos establecidos. Es por esto que las herramientas de caracterización genética molecular se aplican en muchos países con el fin de adaptar estos protocolos a cada individuo, es decir, personalizar la terapia farmacológica, donde las dosificaciones son evaluadas de acuerdo con las características genéticas de la persona, para evitar o prevenir reacciones adversas en individuos predispuestos. Costa Rica es un país que hace grandes esfuerzos para brindar una atención médica de primer mundo a sus habitantes, sin embargo, el campo de la Farmacogenética aún no se ha desarrollado en nuestro medio. No obstante, el Centro Nacional Innovaciones Biotecnológicas financia un proyecto pionero junto con la Universidad de Costa Rica, para desarrollar la aplicación de esta disciplina en el país. El presente artículo presenta las bases biológicas y la utilidad clínica de la Farmacogenética, así como detalles de las iniciativas para el desarrollo de esta disciplina en Costa Rica. The ‘post-genomic era’ has had an impact on biological and biomedical sciences since the recognition of a significant interindividual genetic variation. Pharmacology has not escaped this influence. This discipline, together with toxicology, has seen the development of areas such as pharmacogenetics and pharmacogenomics for several years now. These disciplines study the influence of the population’s genetic variability on the response people have to drugs and toxic substances. Different polymorphisms (genetic variants) in genes involved in the handling of xenobiotics in the body are able to determine an exaggerated, normal or reduced response to a certain dose of any drug. Many genes have been associated with poor response to pre-determined dosing protocols or with hypersensitivity reactions. Because of this, molecular genetics characterization tools are applied in many countries to adapt this protocol individually, i.e. a personalized pharmacology, where dosages are evaluated according to the genetic determinants a person carries in order to avoid or prevent adverse reactions in predisposed individuals. Costa Rica is a country that makes great efforts 208 Acta méd. costarric Vol 54 (4), octubre-diciembre 2012 to give first-world medical care to its residents, but the field of pharmacogenetics has not been developed in our medium yet. Notwithstanding, the National Center for Biotechnology Innovations is currently funding a pioneering joint project with the University of Costa Rica in order to develop the application of this discipline in the country. This article presents the biological basis and clinical utility of pharmacogenetics, as well as the details regarding the efforts that are being made to develop this discipline in Costa Rica. UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones Farmacéuticas (INIFAR)

Introducción: La farmacogenética tiene utilidad clínica para evaluar los efectos de los fármacos según perfil genético y aporta a la medicina poblacional y personalizada. La diabetes mellitus tipo 2 (DMT2) es una enfermedad prevalente en el Perú y el mundo. Para su tratamiento existen varios fármacos, entre ellos la metformina. La respuesta individual puede estar influenciada por el polimorfismo Val/Met en el gen octT1 y las frecuencias varían según grupo étnico. Se ha relacionado al alelo Met con una menor respuesta a la metformina. Objetivo: Evaluar la distribución del polimorfismo Val/Met en el gen OCT1 en muestras de sangre de sujetos de Lima y Puno, e inferir su impacto en la farmacogenética de la DMT2. Diseño: Estudio descriptivo, transversal. Lugar: Facultades de Farmacia y Bioquímica, Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú; Centro de Genética y Biología Molecular, Facultad de Medicina, Universidad de San Martín de Porres, Lima, Perú. Participantes: 56 individuos de Puno y 57 de Lima-ciudad. Intervenciones: Análisis del polimorfismo Val/Met en el gen OCT1 con la técnica PCR-RFLP. Principales medidas de resultados: Frecuencias genotípicas y alélicas. Resultados: Las frecuencias de los genotipos, en general, fueron: Val/Val=85,0% y Val/Met=15,0%. La frecuencia del alelo Val, en general, fue mayor al 93%; el alelo Met, asociado con una menor respuesta a metformina, se encontró presente en Amantaní (8,3%) y Lima (9,6%), y ausente en Taquile. Conclusiones: Para el alelo Val del gen OCT1, se ha encontrado la más alta frecuencia registrada en el mundo. Respecto al alelo Met, aunque es menos frecuente, existen diferencias entre las subpoblaciones peruanas evaluadas, y ese conocimiento puede ayudar en la farmacogenética y la toma de decisiones en el tratamiento con los antidiabéticos orales como la metformina., Introduction: Pharmacogenetics can be used in clinical analysis to assess the efficiency of drugs according to the patient’s genetic profile, and it is becoming important for population genetics and precision medicine. The type 2 diabetes mellitus (T2DM) is highly prevalent all over the world, including Peru. Among the different drugs for T2DM, metformin is used the most and patient’s response to it can be influenced by the Val/Met polymorphism of the OCT1 (SLC22) gene, where Met is associated with a lower response. The frequencies of these polymorphisms vary according to ethnic origin. Objective: To evaluate the distribution of the Val/Met polymorphism in the OCT1 gene in samples of Lima and Puno, and to assess their impact on pharmacogenetics of T2DM. Design: Descriptive, cross-sectional study. Settings: Faculties of Pharmacy and Biochemistry, and Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru; Centro de Genética y Biología Molecular, Facultad de Medicina, Universidad de San Martín de Porres, Lima, Peru. Participants: DNA samples of 56 non-selected subjects from Puno and 57 from Lima regions. Interventions: Analysis of the Val/Met polymorphism in OCT1 gene using the PCR-RFLP technique. Main outcome measures: Phenotypic and allelic frequencies. Results: Genotype frequencies were Val/Val=85,0% and Val/Met=15,0%. The Val allele frequency was higher than 93%, the Met allele was associated with a lower response to metformin and was present in Amantaní (8.3%) and in Lima (9.6%), and absent in Taquile. Conclusions: We found the highest Val allele frequency in the world. Regarding the Met allele, less frequent, we found differences among the Peruvian subpopulations tested, and this knowledge can help in the pharmacogenetics and decision making about oral treatment of metformin against diabetes.

Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU and Yoruba people of Ibadan, Nigeria (YRI) HapMap lymphoblastoid cell lines in 23 resequenced genes. Among 356 cis-eQTLs, 155 and 174 were unique to CEU and YRI, respectively, and 27 were shared between CEU and YRI. Two cis-eQTLs provided mechanistic evidence for two genome-wide association study findings. Five eQTLs were tested for function in luciferase assays and the effect of two KRAS variants was concordant with the eQTL effect. Two eQTLs found in each of PRKCE, PIK3C2A, and MAP2K6 could predict 44%, 37%, and 45% of the variance in gene expression, respectively. This is the first analysis focusing on the pattern of functional genetic variation of the VEGF pathway genes in CEU and YRI populations and providing mechanistic evidence for genetic association studies of diseases for which angiogenesis plays a pathophysiologic role. (C) 2013 Wiley Periodicals, Inc.

In previous work we developed a pharmacogenetic predictor of antipsychotic (AP) induced extrapyramidal symptoms (EPS) based on four genes involved in mTOR regulation. The main objective is to improve this predictor by increasing its biological plausibility and replication. We re-sequence the four genes using next-generation sequencing. We predict functionality “in silico” of all identified SNPs and test it using gene reporter assays. Using functional SNPs, we develop a new predictor utilizing machine learning algorithms (Discovery Cohort, N = 131) and replicate it in two independent cohorts (Replication Cohort 1, N = 113; Replication Cohort 2, N = 113). After prioritization, four SNPs were used to develop the pharmacogenetic predictor of AP-induced EPS. The model constructed using the Naive Bayes algorithm achieved a 66% of accuracy in the Discovery Cohort, and similar performances in the replication cohorts. The result is an improved pharmacogenetic predictor of AP-induced EPS, which is more robust and generalizable than the original.

Podeu consultar el llibre complet a: http://www.trnres.com/ebookcontents.php?id=149, The aim of this work was to design a novel strategy to detect new targets for anticancer treatments. The rationale was to build Biological Association Networks from differentially expressed genes in drug-resistant cells to identify important nodes within the Networks. These nodes may represent putative targets to attack in cancer therapy, as a way to destabilize the gene network developed by the resistant cells to escape from the drug pressure. As a model we used cells resistant to methotrexate (MTX), an inhibitor of DHFR. Selected node-genes were analyzed at the transcriptional level and from a genotypic point of view. In colon cancer cells, DHFR, the AKR1 family, PKC¿, S100A4, DKK1, and CAV1 were overexpressed while E-cadherin was lost. In breast cancer cells, the UGT1A family was overexpressed, whereas EEF1A1 was overexpressed in pancreatic cells. Interference RNAs directed against these targets sensitized cells towards MTX.

Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.

Dissertação de mestrado em Tecnologias do Medicamento na especialidade de Farmacologia, apresentada à Faculdade de Farmácia da Universidade de Coimbra A saúde pública abrange várias preocupações actuais, entre elas, o uso racional do medicamento com a consequente optimização das terapêuticas. Esta optimização assenta em dois grandes focos: a segurança e a efectividade, sendo intervenções prioritárias a anulação de problemas relacionados com a segurança (reacções adversas) e a maximização de questões relacionadas com a efectividade. Neste contexto, a Farmacogenómica é hoje uma área em expansão e poderá deter as ferramentas necessárias que possibilitam a construção de respostas terapêuticas dirigidas ao perfil genético dos indivíduos, permitindo respeitar a variabilidade intra e inter-individual. Este trabalho tem como objectivos: avaliar a utilização da Farmacogenómica na prática clínica hospitalar em Portugal Continental; identificar as competências necessárias a desenvolver para aplicação de técnicas de Farmacogenómica - Médico/Farmacêutico; analisar quais as futuras áreas potenciais de aplicação da Farmacogenómica na prática clínica. Para dar resposta aos objectivos definidos foram realizados dois sub-estudos distintos. O sub-estudo 1, um estudo transversal descritivo, cuja informação foi recolhida junto de serviços hospitalares previamente definidos; e o sub-estudo 2, que se baseou numa técnica de consenso – Painel Delphi. No sub-estudo 1 obteve-se informação de 4 serviços do IPO de Lisboa, 1 serviço do IPO do Coimbra e 4 serviços do IPO do Porto, e nestes serviços maioritariamente a utilização da genética nas decisões terapêuticas, quando se verifica, não é numa perspectiva farmacogenómica, mas sim numa perspectiva de caracterização da doença ou do seu estadio. No sub-estudo 2, das instituições identificadas para a indicação dos peritos, as poucas respostas recepcionadas foram maioritariamente via telefone, (uma vez que foi feito um reforço telefónico para maior brevidade na resposta), foram todas negativas, argumentando que não havia peritos na área de estudo identificada. Da pesquisa e das informações recolhidas a farmacogenómica/farmacogenética parece ser um campo de investigação que apresenta ainda algumas fragilidades. Podem ser identificados nichos de potencial interesse na utilização da Farmacogenómica, nomeadamente nas áreas da genética, oncologia e doenças infecciosas, em que os fármacos manuseados são aqueles que se encaixam exactamente na utilidade da farmacogenómica/farmacogenética: fármacos com margem terapêutica estreita. Na perspectiva de concretizar o estado da arte da utilização da farmacogenómica/farmacogenética numa área clínica em particular optou-se por realizar uma revisão bibliográfica sobre esta matéria em doentes que fazem terapêutica com varfarina.

Cell 166(3), 740-754 (2016). doi:10.1016/j.cell.2016.06.017, Published by Elsevier, New York, NY

A falência terapêutica aos antimaláricos constituí um problema relevante para os pacientes, um obstáculo e desafio para os programas de controlo da malária. Com base nos estudos de eficácia terapêutica e de acordo com as recomendações da OMS, em 2006, Angola substituiu a cloroquina pela combinação Artemeter + Lumefantrina (AL) como fármaco de 1ª linha, no tratamento de malária não complicada. Sendo a falência terapêutica uma ocorrência multifatorial, realizamos um estudo integrado, que incluiu fatores inerentes ao parasita e, os associados à metabolização de fármacos no hospedeiro humano. Foram incluídos 103 pacientes com malária não complicada, selecionados entre 2011 e 2013, tratados com AL, seguidos durante 28 dias, de acordo com o protocolo da OMS para o estudo de eficácia terapêutica e colhidas amostras de sague para exames moleculares e HPLC. A extração de DNA das amostras sanguíneas em papel de filtro foi realizada com Fenol-Clorofórmio. A identificação de espécies de Plasmodium e a genotipagem do pfmsp2 foram efetuadas por Nested-PCR; os polimorfismos nos genes pfmdr1 e pfatp6 de P. falciparum e os SNPs em genes das famílias MDR1 e CYP450 no hospedeiro humano foram analisados por PCR-RFLP e RT-PCR, tendo os SNP’s do pfK13 sido processados por sequenciação. A taxa de cura foi de 91,3%; 12,6% (n = 13) dos 103 pacientes apresentavam parasitémia no D3; 73,4% das amostras eram portadoras do alelo selvagem pfmdr1 86N, tendo o alelo mutante pfmdr1-1246Y sido identificado em apenas uma amostra; 11% das amostras apresentaram aumento do número de cópias do pfmdr1; não foram identificadas amostras portadoras de mutação no SNP 769 do gene pfatp6, nem de mutações nos codões estudados do gene pfK13. Relativamente aos polimorfismos nos genes do hospedeiro humano, as variantes que codificam para proteínas de atividade alterada apresentaram as seguintes frequências: MDR1 3435TT (6,9%), MDR1 129CC (1%); CYP1A1 * 2B (0%); CYP2C8 * 2 (4%), CYP2C8 * 3 (0%); CYP3A4 * 1B (54,5%) e CYP3A5 * 3 (4,85%). Os resultados deste estudo sugerem uma alteração do perfil do P. falciparum no que concerne a genética e à suscetibilidade à Artemeter + Lumefantrina em comparação com os dados de 2004; a resposta clínica após tratamento com AL não foi associado com os SNPs analisados no parasita; a taxa de falência encontrada (8.7%) não justificam uma mudança de política terapêutica do país, de acordo com as diretrizes da OMS, mas reforçam a necessidade de uma monitorização regular do fármaco. Em relação aos polimorfismos em genes humanos, os SNP’s analisados apresentaram frequências alélicas semelhantes às reportadas noutros estudos em populações africanas. Não foram observadas associações significativas entre os SNP’s analisados nos genes CYP3A4/5 e a resposta terapêutica à AL; no entanto, foi observada uma associação significativa entre a variante mutante ABC1 3435TT e pacientes com parasitémia recrudescente no período de tratamento, o que sugere um envolvimento deste transportador na resposta ao tratamento com Artemeter + Lumefantrina. Foram constatadas frequências relevantes das variantes alélicas dos genes CYP1B1 e CYP2C8, com atividade enzimática associada à lenta metabolização da amodiaquina, o que sugere a existência na população analisada, de risco de efeitos adversos ao tratamento contendo amodiaquina. Antimalarials therapeutic failure is a relevant problem for patients, an obstacle and challenge to the malaria control programs. Based on therapeutic efficacy studies and in accordance with WHO recommendations, in 2006, Angola replaced chloroquine by Artemether + Lumefantrine (AL) combination as first line drug for the malaria uncomplicated treatment. Considering the therapeutic failure as a multifactorial event, we developed an integrated study, which includes factors inherent to the parasite susceptibility as well as those associated with the metabolism of drugs in the human host. 103 patients with uncomplicated malaria were include between 2011 and 2013, treated with Artemether + Lumefantrine, followed for 28 days, according to the WHO Protocol for the therapeutic efficacy study and blood samples were collected for molecular analyses and HPLC. DNA extraction from blood samples on filter paper was processed by Phenol-Chloroform method. Plasmodium species identification and pfmsp2 genotyping were performed by Nested-PCR; polymorphisms in the pfmdr1 and pfatp6 of malaria P. falciparum genes and those in CYP450 and MDR1 families genes of the human host was analyzed by RFLP-PCR and RT-PCR and the pfK13 SNP's were performed by sequencing. The cure rate was 91.3%; 12.6% (n = 13) of 103 patients had parasitémia in the D3. The wild type pfmdr1 86N allele was found in 73.4% of the samples; mutant pfmdr1-1246Y was identified in only one sample; 11% of samples showed an increase in the pfmdr1 number of copies. No samples had mutation in the 769 SNP of the pfatp6 gene, as well as in the studied codons of the pfK13 gene. Regarding to the human host genetic polymorphisms, the allelic variants encoding for proteins with altered activity showed the following frequencies: MDR1 3435TT (6,9%), MDR1 129CC (1%); CYP1A1 * 2B (0%); CYP2C8 * 2 (4%), CYP2C8 * 3 (0%); CYP3A4 * 1B (54,5%) e CYP3A5 * 3 (4,85%). The results of this study suggest some change of the P. falciparum regarding the susceptibility to AL combination and to the genetics profile in comparison with 2004 data. The clinical outcome after AL treatment was not associated with any allelic status of the analyzed SNPs of the parasite; the failure rate found (8.7%) do not justify a therapeutic policy change according to WHO guidelines, but reinforce the need for regular drug monitoring. In relation to the human host genetics, the analyzed SNP's displayed allele frequencies similar to those usually reported in other studies in African populations. No significant associations were detected between the analyzed SNP's of CYP3A4/5 genes and AL treatment outcomes; however, it was observed a significant association between carriers of the ABC1 3435TT mutant variant and malaria recrudescence, which suggests some involvement of this allele in the AL treatment response. There were observed relevant frequencies of mutant variants of CYP1B1 and CYP2C8 genes encoding to enzymes associated with low metabolizing activity for amodiaquine, that suggests the existence in the studied population a potential risk of adverse effects to treatment containing amodiaquine.