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1.
Biomédica (Bogotá) ; 41(3): 403-408, jul.-set. 2021. tab, graf
Article in Spanish | LILACS | ID: biblio-1345391

ABSTRACT

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.


Subject(s)
Pharmacogenetics , Acenocoumarol , Vitamin K , Anticoagulants
2.
Braz. dent. j ; 32(1): 3-8, Jan.-Feb. 2021. tab, graf
Article in English | LILACS, BBO | ID: biblio-1180729

ABSTRACT

Abstract Saliva is widely used for clinical and laboratory analysis. This study proposed to use DNA extracted from saliva for genotyping and pharmacokinetics of piroxicam. A fast and efficient genotyping method was used to determine relevant allelic variants of CYP2C9 (*2 and *3), since genetic factors can influence in non-steroidal anti-inflammatory drugs (NSAIDs) metabolization. DNA Extract All Reagents Kit® was used for DNA extraction and genotyping was performed using TaqMan® GTXpress™ Master Mix, SNP genotyping assays and a Viia7 Real-Time PCR system. Volunteers performed sequential collections of saliva samples before and after taking a single dose of piroxicam (0.25 to 72 h) which were used for pharmacokinetics assays. Piroxicam concentrations were analyzed using LC-MS/MS. Sixty-six percent of volunteers were ancestral homozygous (CYP2C9*1/*1), and 34% showed one or both polymorphisms. Of these 34%, 22 individuals showed CYP2C9*2 polymorphism, 8 CYP2C9*3, and 4 CYP2C9*2/*3. Piroxicam pharmacokinetics were performed in 5 subjects. Areas under the curve (AUC0-t(h*ng/mL)) for CYP2C9*1/*1, *1/*2 and *1/*3 were, respectively, 194.33±70.93, 166 and 303. Maximum concentrations (Cmax(ng/mL)) for these genotypes were respectively 6.46±2.56, 4.3 and 10.2. Saliva sampling was a very effective matrix for both pharmacogenetic and pharmacokinetic tests, ensuring the speed of the procedure and the well-being and agreement of the participants. Once having the knowledge about the slow and fast metabolizers, it is possible to make an adequate prescription in order to avoid the adverse effects of the medication and to guarantee greater analgesic comfort to the patients respectively.


Resumo Saliva é amplamente utilizada para análises clínicas e laboratoriais. Este estudo propôs o uso de DNA extraído da saliva para genotipagem e farmacocinética do piroxicam. Um método de genotipagem rápido e eficiente foi usado para determinar as variantes alélicas clinicamente relevantes de CYP2C9 (* 2 e * 3), uma vez que fatores genéticos podem influenciar nas respostas metabólicas individuais a medicamentos como anti-inflamatórios não esteroides (AINEs). DNA Extract All Reagents Kit® foi usado para extração de DNA e a genotipagem foi realizada usando TaqMan® GTXpress ™ Master Mix, ensaios de genotipagem SNP e um sistema Viia7 Real-Time PCR. Os voluntários realizaram coletas sequenciais de amostras de saliva antes e após a ingestão de uma única dose de piroxicam (0,25 a 72 h) que foram utilizadas para ensaios farmacocinéticos. As concentrações de piroxicam foram analisadas usando LC - MS / MS. Sessenta e seis por cento dos voluntários eram homozigotos ancestrais (CYP2C9 * 1 / * 1) e 34% apresentaram um ou ambos os polimorfismos. Destes 34%, 22 indivíduos apresentaram polimorfismo CYP2C9 * 2, 8 CYP2C9 * 3 e 4 CYP2C9 * 2 / * 3. A farmacocinética do piroxicam foi realizada em 5 indivíduos. As áreas sob a curva (AUC0-t (h * ng / mL)) para CYP2C9 * 1 / * 1, * 1 / * 2 e * 1 / * 3 foram, respectivamente, 194,33±70,93, 166 e 303. Concentrações máximas (Cmax (ng / mL)) para esses genótipos foram, respectivamente, 6,46±2,56, 4,3 e 10,2. A amostra de saliva foi uma matriz muito eficaz tanto para os testes farmacogenéticos quanto para os farmacocinéticos, garantindo a agilidade do procedimento e o bem-estar e concordância dos participantes. Com o conhecimento dos metabolizadores lentos e rápidos, é possível fazer uma prescrição adequada para evitar os efeitos adversos da medicação e garantir maior conforto analgésico aos pacientes respectivamente.


Subject(s)
Humans , Pharmacogenetics , Saliva , Drug Prescriptions , Chromatography, Liquid , Tandem Mass Spectrometry , Cytochrome P-450 CYP2C9/genetics
3.
Ciencia Tecnología y Salud ; 8(2): 211-219, 2021. il 27 c
Article in Spanish | LILACS-Express | LILACS, LIGCSA, DIGIUSAC | ID: biblio-1353114

ABSTRACT

El proyecto HapMap ha generado información y preguntas sobre la diversidad genética en las distintas poblaciones del mundo. En las últimas décadas, proyectos como la elucidación del genoma del mestizo mexicano han revelado las distancias genéticas entre mestizos y amerindios en México. Cerca de 20 genes son actualmente estudiados en paneles comerciales asociados al metabolismo de fármacos, uno de ellos el gen que expresa la enzima CY P2C19, la cual metaboliza cerca de 26 fármacos de importancia clínica. El objetivo fue revisar la literatura científica en Google Scholar, PubMed y ScienceDirect que reporta resultados sobre estudios farmacogenéticos en Guatemala, otros que presentan hallazgos sobre distancias genéticas en el guatemalteco y se compara con lo que se conoce de otras poblaciones del continente y el mundo, haciendo énfasis en CY P2C19. El mestizaje en Guatemala fue único, por ello es importante investigar sus variantes alélicas asociadas al metabolismo de fármacos, para permitir una terapéutica más efectiva y segura que mejore la calidad de vida del guatemalteco.


The HapMap project has generated information and queries about genetic diversity in the different populations around the world. In recent decades, research projects such as the elucidation of the genome of the Mexican Mestizo, have exposed the genetic distances between mestizos and Amerindians in Mexico. About 20 genes are currently studied in commercial panels associated with drug metabolism. One of them CY P2C19, that expresses the CY P2C19 enzyme, that metabolizes about 26 drugs of clinical importance. The objective was to review the scientific literature in Google Scholar, PubMed and ScienceDirect that reports results on pharmacogenetic studies in Guatemala, others that presented findings over genetic distances in Guatemala, as well as a comparison with the knowledge about other populations of the continent and world, with emphasis in CY P2C19 gen. Miscegenation in Guatemala was unique and is important to investigate the Guatemalan allelic variants associated with drug metabolism to allow a more effective and safe therapeutic and improve their quality of life.


Subject(s)
Humans , Pharmacogenetics , Cytochrome P450 Family 19 , American Native Continental Ancestry Group/genetics , Pharmacogenomic Testing , Guatemala , Metabolism/drug effects
4.
Ciencia Tecnología y Salud ; 8(2): 220-231, 2021. il 27 c
Article in Spanish | LILACS-Express | LILACS, LIGCSA, DIGIUSAC | ID: biblio-1353228

ABSTRACT

El uso de inhibidores de calcineurina, en particular de tacrolimus como terapia inmunosupresora se ha generalizado a nivel mundial, permitiendo mejorar la tasa de sobrevida del injerto y la calidad de vida del paciente trasplantado. Con el acceso a los estudios de farmacogenética, los grupos de trasplante a nivel mundial se han visto motivados a realizar estudios genéticos que permitan interpretar la influencia de polimorfismos de genes como mTOR, PPP3CA, FK BP1A, FKBP2, y FOXP3, sin embargo, los más estudiados en la población trasplantada para optimizar la dosis de tacrolimus y ciclosporina son los polimorfismos del citocromo p450, CYP3A4 y CYP3A5.El objetivo de la presente revisión narrativa es examinar publicaciones recientes que estudien la relación entre el polimorfismo de CYP3A4/5 y el metabolismo de tacrolimus en pacientes trasplantados renales.Se revisó literatura reciente extraída de los sitios NCBI PubMed y PharmGKB.org en la que se hubiera investigado la influencia de los polimorfismos de CYP3A4/5 en el metabolismo de tacrolimus en trasplantados renales. Se identificó variaciones genéticas de CYP3A4/5 en pacientes trasplantados tratados con tacrolimus que permitirán a los médicos trasplantólogos dosificar de manera precisa el inmunosupresor. El uso de análisis farmacogenéticos permite determinar las variables genéticas del CYP3A4/5, y por lo tanto la toma de decisiones personalizadas en la dosis de inicio y de mantenimiento del inmunosupresor tacrolimus para alcanzar los niveles óptimos y con ello disminuir el riesgo de rechazo, de infecciones asociadas a inmunosupresión, y de toxicidad por el medicamento.


The use of the calcineurin inhibitor tacrolimus as immunosuppressive therapy, has become widespread world-wide, improving the graft's survival rate and the quality of life of the transplanted patient. With access to pharmacogenetic studies, transplant groups worldwide have been motivated to conduct genetic studies to inter-pret the influence of polymorphisms of genes such asmTOR, PPP3CA, FK BP1A, FKBP2, and FOXP3, however the most studied in the transplanted population to optimize the dose of tacrolimus and cyclosporine are those of cytochrome p450,CYP3A4 and CYP3A5. The objective of this narrative review is to examine recent publications studying the relationship betweenCYP3A4/5polymorphism, and tacrolimus metabolism in renal transplant patients. Literature extracted from the NCBI PubMed site and PharmGKB.org, from the past five years, which investigated the influence ofCYP3A4/5polymorphism on tacrolimus metabolism in renal transplants had been reviewed. Genetic variations ofCYP3A4/5 were identified in transplant patients treated with tacrolimus that will allow transplant physicians to dose the immunosuppressant accurately. The use of pharmacogenetic analyses makes it possible to determine the genetic polymorphisms ofCYP3A4/5, and therefore the decision-making cus-tomized at the starting and maintenance dose of the tacrolimus immunosuppressant to achieve optimal levels and thereby reduce the risk of rejection, immunosuppression-associated infections, and drug toxicity.


Subject(s)
Humans , Pharmacogenetics , Polymorphism, Genetic/genetics , Kidney Transplantation , Tacrolimus , Cytochrome P-450 CYP3A/drug effects , Immunosuppression/adverse effects , Cytochrome P-450 Enzyme System/genetics , Drug-Related Side Effects and Adverse Reactions , Prescription Drugs/toxicity , Calcineurin Inhibitors
5.
Arq. bras. cardiol ; 115(4): 690-700, out. 2020. tab, graf
Article in Portuguese | SES-SP, LILACS, SES-SP | ID: biblio-1131334

ABSTRACT

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.


Subject(s)
Humans , Pharmacogenetics , Cardiovascular Diseases/genetics
6.
Rev. argent. coloproctología ; 31(2): 51-53, jun. 2020.
Article in English, Spanish | LILACS | ID: biblio-1117007

ABSTRACT

Los contenidos de este capítulo se basan en la 3a edición de las Clínicas Quirúrgicas de Cáncer Colorrectal. C. Vaccaro y N. Peralta. del hospital ediciones 2020 (en prensa)


Subject(s)
Colorectal Neoplasms/genetics , Biomarkers, Tumor/genetics , Precision Medicine/trends , Pharmacogenetics/trends , Colorectal Neoplasms/etiology , Colorectal Neoplasms/therapy , Molecular Epidemiology/trends , Mutation , Neoplasm Metastasis/genetics , Neoplasm Metastasis/therapy
8.
Article in Chinese | WPRIM | ID: wpr-879766

ABSTRACT

Pharmacogenomics is an emerging tool to improve the efficacy and safety of drug treatment through the DNA analysis in the genes related to drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics). Clinicians need to integrate the genomic data in their benefit-risk assessment and then provide the right drug to the right patient at the right time. This tool can help to prevent an ineffective treatment, select right dose and reduce adverse drug reactions that are common in the current practice under the trial-observation-adjustment model. Pharmacogenomics may have extensive impacts on unique paediatric patients to enhance a better relationship between medical professionals and affected children or their guardians and to improve the drug compliance. Clinicians should embrace the advancements in pharmacogenomics and actively participate in clinical research to identify the ancestor-related alleles and develop the population-specific gene panel. It will allow patients to enjoy more achievements in pharmacogenomics by implementing it in first line clinical practice.


Subject(s)
Alleles , Drug-Related Side Effects and Adverse Reactions , Humans , Pharmacogenetics , Precision Medicine , Prescriptions
9.
Article in Chinese | WPRIM | ID: wpr-826324

ABSTRACT

Oral anticoagulants play an important role in the prevention and treatment of thromboembolic diseases.Warfarin,a traditional oral anticoagulant,is limited in clinical use due to its limitations such as narrow therapeutic window and requirements on frequent monitoring and dose adjustment.Direct oral anticoagulants(DOACs)such as dabigatran,rivaroxaban,apixaban,and edoxaban are increasingly used to prevent and treat venous thrombosis or thrombus formation.However,recent studies have documented inter-individual variability in plasma drug levels of DOACs.This article summarizes the recent advances in the pharmacogenomics of DOACs.


Subject(s)
Administration, Oral , Anticoagulants , Therapeutic Uses , Atrial Fibrillation , Drug Therapy , Dabigatran , Pharmacogenetics , Rivaroxaban
10.
Rev. latinoam. enferm. (Online) ; 28: e3265, 2020. tab
Article in English | LILACS, BDENF | ID: biblio-1126975

ABSTRACT

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.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Pharmacogenetics , Polymerase Chain Reaction , Nursing , Drug-Related Side Effects and Adverse Reactions , Drug Utilization , Cytochrome P-450 CYP2C9 , Nursing Care , Nursing Process
12.
Educ. med. super ; 33(2): e1569, abr.-jun. 2019. tab
Article in Spanish | LILACS, CUMED | ID: biblio-1089903

ABSTRACT

Introducción: La introducción de las tecnologías ómicas en la práctica clínica requiere que los profesionales de la salud incorporen conocimientos al respecto. Objetivo: Evaluar los conocimientos sobre tecnologías ómicas de los médicos que inician los estudios de especialidad en el nivel secundario de atención médica. Métodos: Se aplicó un cuestionario a 53 profesionales de la salud, quienes comenzaron sus residencias médicas, tanto clínicas como quirúrgicas, en el Hospital General Docente "Dr. Ernesto Guevara de la Serna" de Las Tunas, Cuba. Se indagó por cuestionario y de forma anónima acerca del conocimiento sobre las pruebas de biología molecular, genéticas y farmacogenéticas, la secuenciación del genoma y las bases de datos de información biológica disponibles en internet. Resultados: El 37,7 por ciento de los participantes no conocía acerca de las pruebas de biología molecular y solo el 3,8 por ciento refirió saber sobre la secuenciación de nueva generación. Aunque el 90,6 por ciento de los interrogados estaban al tanto de alguna prueba genética, ninguno pudo mencionar una correctamente. Solo el 20,8 por ciento declaró su conocimiento de algún gen de susceptibilidad a enfermedades. La posibilidad de secuenciar el genoma completo fue reconocida por el 49,1 por ciento de la muestra. El 90,6 por ciento de los encuestados manifestó interés en recibir información al respecto. Conclusiones: Existe un insuficiente conocimiento sobre las tecnologías ómicas en los participantes en la investigación. Se requiere capacitar a los profesionales de la salud para enfrentar la introducción de la medicina genómica en la práctica clínica, lo que puede y debe hacerse desde la formación médica inicial(AU)


Introduction: The introduction of omic technologies into the clinical practice requires that health professionals incorporate knowledge in this field. Objective: To assess the knowledge about omic technologies of the physicians who are starting their specialty studies in the secondary level of healthcare. Methods: A questionnaire was conducted on 53 health professionals who started their medical residences, both clinical and surgical, at Dr. Ernesto Guevara de la Serna General Teaching Hospital in Las Tunas, Cuba. Both anonymously and by means of the questionnaire, inquiries were made regarding the knowledge about tests in the fields of molecular biology, genetics and pharmacogenetics, about genome sequencing, and about the biological information databases available on the internet. Results: 37.7 percent of the participants did not know about molecular biology tests and only 3.8 percent reported to have some knowledge about next generation sequencing. Although 90.6 percent of the respondents were aware of some genetic test, none could mention one correctly. Only 20.8 percent declared their knowledge about some disease-susceptibility genes. The possibility of sequencing the entire genome was recognized by 49.1 percent of the sample; 90.6 percent of respondents expressed some interest in receiving information about it. Conclusions: There is insufficient knowledge about omic technologies in the research participants. It is required to train health professionals to face the introduction of genomic medicine into the clinical practice, which can and should be done from the beginning ofthe medical training(AU)


Subject(s)
Humans , Pharmacogenetics , Physicians , Technology , Secondary Care , Genes , Molecular Biology
13.
Article in Korean | WPRIM | ID: wpr-766616

ABSTRACT

There are no drugs without the risk of potential adverse reactions. All pharmacologically active substances can cause adverse drug reactions (ADRs). This paper aims at introducing recent trends in pharmacosurveillance systems for ADRs, which can be broadly classified into type A and B reactions. Since type A reactions are associated with drug pharmacology, they are usually dose-dependent and predictable. Whereas, type B reactions occur in some susceptible individuals, regardless of the pharmacological action of drug. Drug hypersensitivity reactions are typical examples of type B reactions and are subclassified according to the underlying pathomechanism. Recent advancements in pharmacogenomics have enlightened the understanding of individual differences in drug efficacy and susceptibility to ADRs. Therefore, expectations for safe personalized medicines are higher than ever before. However, premarketing clinical trials are too small and too short to uncover rare but serious ADRs and detect long-standing ADRs. In the past, post-marketing surveillance systems mainly focused on passive ADR monitoring systems, based on spontaneous reports. Recently, the importance of active pharmacovigilance systems, which use big data, is growing with recent advancements in medical informatics. Thus, regarding ADRs, suspecting and detecting the causative drug using causality assessment based on data science may contribute to decrease suffering induced by ADRs.


Subject(s)
Adverse Drug Reaction Reporting Systems , Drug Hypersensitivity , Drug-Related Side Effects and Adverse Reactions , Humans , Individuality , Medical Informatics , Pharmacogenetics , Pharmacology , Pharmacovigilance
14.
Article in English | WPRIM | ID: wpr-763043

ABSTRACT

Human cytochrome P450 2C9 is a highly polymorphic enzyme that is required for drug and xenobiotic metabolism. Here, we studied eleven P450 2C9 genetic variants—including three novel variants F69S, L310V, and Q324X—that were clinically identified in Korean patients. P450 2C9 variant enzymes were expressed in Escherichia coli and their bicistronic membrane fractions were prepared The CO-binding spectra were obtained for nine enzyme variants, indicating P450 holoenzymes, but not for the M02 (L90P) variant. The M11 (Q324X) variant could not be expressed due to an early nonsense mutation. LC-MS/MS analysis was performed to measure the catalytic activities of the P450 2C9 variants, using diclofenac as a substrate. Steady-state kinetic analysis revealed that the catalytic efficiency of all nine P450 2C9 variants was lower than that of the wild type P450 2C9 enzyme. The M05 (R150L) and M06 (P279T) variants showed high k(cat) values; however, their K(m) values were also high. As the M01 (F69S), M03 (R124Q), M04 (R125H), M08 (I359L), M09 (I359T), and M10 (A477T) variants exhibited higher K(m) and lower k(cat) values than that of the wild type enzyme, their catalytic efficiency decreased by approximately 50-fold compared to the wild type enzyme. Furthermore, the novel variant M07 (L310V) showed lower k(cat) and K(m) values than the wild type enzyme, which resulted in its decreased (80%) catalytic efficiency. The X-ray crystal structure of P450 2C9 revealed the presence of mutations in the residues surrounding the substrate-binding cavity. Functional characterization of these genetic variants can help understand the pharmacogenetic outcomes.


Subject(s)
Codon, Nonsense , Cytochrome P-450 Enzyme System , Cytochromes , Diclofenac , Escherichia coli , Holoenzymes , Humans , Membranes , Metabolism , Pharmacogenetics
15.
Intestinal Research ; : 285-310, 2019.
Article in English | WPRIM | ID: wpr-764161

ABSTRACT

The Asia-Pacific Working Group on inflammatory bowel disease (IBD) was established in Cebu, Philippines, under the auspices of the Asian Pacific Association of Gastroenterology with the goal of improving IBD care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in the conjunction with conventional treatments for ulcerative colitis (UC) and Crohn's disease (CD) in Asia. These statements also address how pharmacogenetics influence the treatments of UC and CD and provide guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of IBD workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing and future revisions are likely as new data continue to emerge.


Subject(s)
Adalimumab , Asia , Asian Continental Ancestry Group , Biological Factors , Biosimilar Pharmaceuticals , Colitis , Colitis, Ulcerative , Consensus , Cooperative Behavior , Crohn Disease , Gastroenterology , Hepatitis B , Humans , Immunologic Factors , Inflammatory Bowel Diseases , Infliximab , Pharmacogenetics , Philippines , Practice Guidelines as Topic , Tuberculosis , Ulcer
16.
Article in Chinese | WPRIM | ID: wpr-774158

ABSTRACT

Based on the pharmacogenomics theory, this study developed a software system for interpretation of drug gene loci and guidance on clinical safe medication with the purpose of providing clinical guidance on the safety and effectiveness of drug use through accurate and efficient detection and interpretation of drug gene loci. The system infrastructure was built on a service-oriented architecture (SOA) design and Docker container virtualization approach to achieve a rapid and automatic interpretation of genetic results and best available drugs. The front end was established on HTML5 and JavaScript to realize visualization of analysis results and user interaction. The system was tested and validated to show robust performance which is reliable in clinical use. It will show high impact on the development of pharmacogenomics and clinical practice of patients with personalized medicine.


Subject(s)
Humans , Pharmacogenetics , Precision Medicine , Software
17.
Psychiatry Investigation ; : 645-653, 2019.
Article in English | WPRIM | ID: wpr-760984

ABSTRACT

Depression leads the higher personal and socio-economical burden within psychiatric disorders. Despite the fact that over 40 antidepressants (ADs) are available, suboptimal response still poses a major challenge and is thought to be partially a result of genetic variation. Pharmacogenetics studies the effects of genetic variants on treatment outcomes with the aim of providing tailored treatments, thereby maximizing efficacy and tolerability. After two decades of pharmacogenetic research, variants in genes coding for the cytochromes involved in ADs metabolism (CYP2D6 and CYP2C19) are now considered biomarkers with sufficient scientific support for clinical application, despite the lack of conclusive cost/effectiveness evidence. The effect of variants in genes modulating ADs mechanisms of action (pharmacodynamics) is still controversial, because of the much higher complexity of ADs pharmacodynamics compared to ADs metabolism. Considerable progress has been made since the era of candidate gene studies: the genomic revolution has made possible to assess genetic variance on an unprecedented scale, throughout the whole genome, and to analyze the cumulative effect of different variants. The results have revealed key information on the biological mechanisms mediating ADs effect and identified hypothetical new pharmacological targets. They also paved the way for future availability of polygenic pharmacogenetic panels to predict treatment outcome, which are expected to explain much higher variance in ADs response compared to CYP2D6 and CYP2C19 only. As the demand and availability of AD pharmacogenetic testing is projected to increase, it is important for clinicians to keep abreast of this evolving area to facilitate informed discussions with their patients.


Subject(s)
Antidepressive Agents , Biomarkers , Clinical Coding , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP2D6 , Cytochromes , Depression , Genetic Variation , Genome , Humans , Metabolism , Negotiating , Pharmacogenetics , Precision Medicine , Treatment Outcome
18.
In. Consolim-Colombo, Fernanda M; Saraiva, José Francisco Kerr; Izar, Maria Cristina de Oliveira. Tratado de Cardiologia: SOCESP / Cardiology Treaty: SOCESP. São Paulo, Manole, 4ª; 2019. p.122-127.
Monography in Portuguese | LILACS | ID: biblio-1009501
19.
Rev. colomb. cardiol ; 25(6): 396-404, nov.-dic. 2018. tab, graf
Article in Spanish | LILACS, COLNAL | ID: biblio-1058367

ABSTRACT

Resumen El estudio de las variaciones de las secuencias de ADN y ARN en relación con la respuesta a diferentes fármacos, se ha convertido en un área de estudio particularmente prometedora para la aplicación en genómica clínica y estudios de genomas personalizados. Medicamentos de uso diario en el tratamiento de enfermedades cardiovasculares han demostrado variaciones en la respuesta en función de las variantes genéticas de los individuos. Dos fármacos han concentrado el interés mundial: la warfarina, un anticoagulante oral, y el clopidogrel, un antiagregante plaquetario, los cuales actúan alterando diferentes vías que conforman la cascada de la coagulación, ya sea limitando directamente la producción de trombina o bloqueando otros activadores de la ruta. Los cambios genéticos que se han asociado a la reducción de la actividad enzimática de estos fármacos ocurren en los genes, CYP2C19 para clopidogrel y CYP2C9 y VKORC1 para warfarina. Las variaciones genéticas identificadas para estos genes se relacionan con perfiles genotípicos que determinan la dosis requerida para el paciente. Es allí donde ciencias como la farmacogenómica tienen como fin brindar una ayuda diagnóstica más objetiva al optimizar tiempo y recursos, así como disminuir el riesgo del paciente a sufrir complicaciones que comprometan su vida.


Abstract The study of the variations in DNA and RNA sequencing as regards the response to different drugs has become a particularly promising area for their application in clinical genomics and personalised genome studies. Drugs of daily use in the treatment of cardiovascular diseases have shown variations in the response depending on the genetic variations of the individuals. Two drugs have gathered worldwide interest: warfarin, an oral anticoagulant, and clopidogrel, an antiplatelet drug, which act by altering different pathways that constitute the clotting cascade either by directly limiting the production of thrombin, or by blocking other activators of the pathway. The genetic changes that have been associated with the reduction in the enzyme activity of these drugs occur in the genes, CYP2C19 for clopidogrel, and the genes, CYP2C9 and VKORC1 for warfarin. The genetic variations identified for these genes are associated with genotype profiles that determine the dose required by the patient. It is from there, sciences like pharmacogenomics have as their aim to provide a more objective diagnostic aid in order to optimise time and resources, as well as to reduce the risk of the patient suffering complications that may compromise their life.


Subject(s)
Pharmacogenetics , Warfarin , DNA , RNA , Clopidogrel , Nucleotides
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