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1.
Med Clin North Am ; 103(6): 977-990, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582008

RESUMO

Pharmacogenomics (PGx) is a powerful tool that can predict increased risks of adverse effects and sub-therapeutic response to medications. This article establishes the core principles necessary for a primary care provider to meaningfully and prudently use PGx testing. Key topics include in which patients PGx testing should be considered, how PGx tests are ordered, how the results are translated into clinical recommendations, and what further advancements are likely in the near future. This will provide clinicians with a foundational knowledge of PGx that can allow incorporation of this tool into their practice or support further personal investigation.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Farmacogenética/métodos , Medicina de Precisão , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Atenção Primária à Saúde/métodos
4.
Gene ; 718: 144050, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425740

RESUMO

Individual specific variable drug response against similar drugs raises a significant challenge for the effective and safe treatment of many human diseases. Pharmacogenomics is the branch which try to deal with these challenge by relating drug response to patient specific genome in order to better customize patient treatments. Pharmacogenomics based research focus on the whole genome, but since last few years after realizing the importance, it mainly centralized towards genes of pharmacological importance called pharmacogenes, and try to explore association between their variants and variable drug response in world's different population. This research was initiated with the resulted data from human genome based research projects and later on assisted by exome sequencing projects. Simultaneously, it was boost-up with the participation of various pharmacogenomics groups lead by PGRN. By realizing the significance of pharmacogenes, and their variant related information, in health science, scientific communities are already started to look for genes of pharmacogenomics importance with different aspect. This article aims to provide an inclusive insight on current state of knowledge of pharmacogenes, recent trends and progress in the understanding of the pharmacogenes and the implications for personalized medicine.


Assuntos
Genoma Humano , Farmacogenética/métodos , Farmacogenética/tendências , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Humanos
5.
Lancet ; 394(10197): 521-532, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31395440

RESUMO

Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy-the topic addressed here-is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics), available data from clinical trials, and ongoing efforts to implement pharmacogenetics in clinical practice.


Assuntos
Farmacogenética/métodos , Variantes Farmacogenômicos , Ensaios Clínicos como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos
6.
Vestn Oftalmol ; 135(3): 137-143, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31393458

RESUMO

In recent years, ß-adrenergic blockers have become the first choice drugs for glaucoma treatment. Timolol holds the main position among them, being a part of most combined antiglaucoma preparations. The use of timolol maleate in clinical practice may be accompanied by severe side effects affecting different organs and systems. The fact that cells with ß-adrenergic receptors are widely common within the human body explains pharmacodynamic effects of timolol maleate. Because of these undesirable side effects, timolol maleate often evokes negative reaction from doctors and patients, which to certain extent limits its usage in ophthalmological practice. Obviously, efficacy and safety of timolol administration depends on individual characteristics making personalized approach necessary for every patient. Such particular approach, being the foundation of personalized medicine, increases efficacy and safety of timolol while reducing costs by using targeted doses.


Assuntos
Farmacogenética , Timolol/farmacologia , Antagonistas Adrenérgicos beta , Humanos , Pressão Intraocular
7.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 36(4): 657-663, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31441268

RESUMO

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.


Assuntos
Farmacogenética , Software , Humanos , Medicina de Precisão
8.
Mol Biol (Mosk) ; 53(4): 574-599, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397433

RESUMO

Pharmacogenetics (PG) investigates the inherited variants of the human genome that underlie individual differences in drug metabolic transformation, delivery, and mechanism of action. Not only the contributions of individual genes, but also their cumulative effect should be considered in the case of polygenic diseases, which include the majority of human diseases. Multiple sclerosis (MS) is a severe autoimmune neurodegenerative disorder of the central nervous system (CNS) and is polygenic in nature. Understanding the role that the immune system plays in the pathogenesis of MS helped to design drugs for its pathogenetic therapy. These drugs are known as the disease-modifying treatments (DMTs). Among these are interferon ß (IFN-ß) and glatiramer acetate (GA), whose treatment efficacy and long-term safety have been proven in many clinical trials. However their efficacy on MS course varies from highly effective to lack of response. Prognostic genetic biomarkers of treatment efficacy can help to identify the MS patient groups where a particular drug is preferential or even strictly indicated to use. The review summarizes the findings from pharmacogenetic studies evaluating the efficacy of IFN-ß and GA in MS patients, including the author's original data.


Assuntos
Herança Multifatorial/genética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Farmacogenética , Medicina de Precisão , Marcadores Genéticos , Acetato de Glatiramer/uso terapêutico , Humanos , Interferon beta/uso terapêutico
9.
Psychiatr Danub ; 31(2): 162-171, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291220

RESUMO

In this project, we recruited a sample of 150 patients with first episode of psychosis with schizophrenia features (FEP) and 100 healthy controls. We assessed the differences between these two groups, as well as the changes between the acute phase of illness and subsequent remission among patients over 18-month longitudinal follow-up. The assessments were divided into four work packages (WP): WP1- psychopathological status, neurocognitive functioning and emotional recognition; WP2- stress response measured by saliva cortisol during a stress paradigm; cerebral blood perfusion in the resting state (with single photon emission computed tomography (SPECT) and during activation paradigm (with Transcranial Ultrasonography Doppler (TCD); WP3-post mortem analysis in histologically prepared human cortical tissue of post mortem samples of subjects with schizophrenia in the region that synaptic alteration was suggested by WP1 and WP2; WP4- pharmacogenetic analysis (single gene polymorphisms and genome wide association study (GWAS). We expect that the analysis of these data will identify a set of markers that differentiate healthy controls from patients with FEP, and serve as an additional diagnostic tool in the first episode of psychosis, and prediction tool which can be then used to help tailoring individualized treatment options. In this paper, we describe the project protocol including aims and methods and provide a brief description of planned post mortem studies and pharmacogenetic analysis.


Assuntos
Biomarcadores/análise , Transtornos Psicóticos/genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Hidrocortisona/análise , Masculino , Farmacogenética , Estudos Prospectivos , Transtornos Psicóticos/complicações , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/tratamento farmacológico , Saliva/química , Esquizofrenia/complicações
10.
Nat Commun ; 10(1): 2674, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209238

RESUMO

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biologia Computacional/métodos , Neoplasias/tratamento farmacológico , Farmacogenética/métodos , Proteína ADAM17/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benchmarking , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Biologia Computacional/normas , Conjuntos de Dados como Assunto , Antagonismo de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Genômica/métodos , Humanos , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias/genética , Farmacogenética/normas , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/genética , Resultado do Tratamento
11.
Expert Opin Drug Metab Toxicol ; 15(7): 553-564, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31162983

RESUMO

Introduction: Alcohol use disorder (AUD) is highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated. The low rate of utilization of medications with demonstrated (albeit modest) efficacy is particularly noteworthy. One approach to increasing the utility and safety of available medications is to use a precision medicine approach, which seeks to identify patients for whom specific medications are likely to be most efficacious and have the fewest adverse effects. Areas Covered: We review the literature on the pharmacogenetics of AUD treatment using both approved and off-label medications. We cover both laboratory studies and clinical trials, highlighting valuable mechanistic insights and underscoring the potential value of precision-based care for AUD. Expert Opinion: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, a precision medicine approach is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data provides important opportunities to develop this area of research.


Assuntos
Alcoolismo/tratamento farmacológico , Farmacogenética , Medicina de Precisão/métodos , Dissuasores de Álcool/administração & dosagem , Dissuasores de Álcool/efeitos adversos , Alcoolismo/genética , Alcoolismo/fisiopatologia , Humanos , Uso Off-Label
12.
Sr Care Pharm ; 34(6): 363-369, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164183

RESUMO

Pharmacogenomics (PGx), the study of how an individual's genetic makeup affects his or her response to drugs, is a fast-growing field that gives health care providers a valuable tool to help safely and effectively manage medication. However, few providers have experience in applying the results of PGx tests to their practices, and this can lead to disregarding the data or unnecessarily modifying medication regimens. Pharmacists are uniquely positioned to become wellversed in the interpretation of PGx data, critically evaluating the "green-yellow-red" result categories that seemingly signal "go, caution, stop" regarding the use of a particular medication. Pharmacists also can evaluate genotype and phenotype information, commonly included in PGx laboratory reports, to optimize therapy. Using a case-based approach, this primer is intended to provide consultant pharmacists with practical direction to aid in PGx interpretation that will provide contextappropriate recommendations that contributes to positive patient outcomes.


Assuntos
Farmacêuticos , Farmacogenética , Feminino , Genótipo , Pessoal de Saúde , Humanos , Masculino , Fenótipo
13.
Life Sci ; 231: 116540, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176778

RESUMO

MRP4 is an ABC membrane transporter involved in clinical outcomes as it is located in many tissues that manages the transport and the elimination of many drugs. This review explores the implication of MRP4 in clinical pharmacology and the importance of its genetic variability. Although there is no specific recommendation regarding the study of MRP4 in drug development, it should be considered when drugs are eliminated by the kidney or liver or when drug-drug interactions are expected.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Animais , Antineoplásicos/farmacocinética , Antivirais/farmacocinética , Interações de Medicamentos , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Farmacogenética , Farmacocinética , Farmacologia
15.
Expert Opin Drug Metab Toxicol ; 15(7): 541-552, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241371

RESUMO

Introduction: Pancreatic cancer (PC) remains a disease with a dismal prognosis. Despite accounting for only 3% of cancer diagnosis, 7% of all cancer deaths in the United States are from PC. This is explained by many being diagnosed with late-stage disease and the cancer's resistance to chemotherapy. Since 1996 there have only been two upfront regimens found to be superior to gemcitabine, FOLFIRINOX (5-fluorouracil/leucovorin and oxaliplatin) and gemcitabine plus nab-paclitaxel. Areas covered: Clinical pharmacology of newer agents that are either approved or being investigated in the management of PC. Knowledge of their pharmacokinetics, pharmacodynamics, and pharmacogenetics can be used to predict outcomes for specific patient populations. Drugs discussed include nanoliposomal irinotecan, pegvorhyaluronidase alfa, poly (ADP-ribose) polymerase enzyme inhibitors, larotrectinib, and napabucasin. Expert opinion: PC is a heterogeneous disease and outcomes are likely to improve as better predictive models of an individual's response to different therapies are developed. This may be best accomplished through phase 0 studies and the use of tumor organoid models grown from initial biopsies or resected tissue. The genetic and physical makeup of the tumor as well as the functional characterization in patient-derived organoids (PDOs), can help guide which agents may be most efficacious or toxic.


Assuntos
Antineoplásicos/administração & dosagem , Desenvolvimento de Medicamentos/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Estadiamento de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Farmacogenética , Prognóstico
16.
Expert Opin Drug Metab Toxicol ; 15(6): 437-447, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31100206

RESUMO

Introduction: Despite clinical efforts, pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The scarcity of effective therapies can be reflected by the lack of reliable biomarkers to adapt anticancer drugs prescription to tumors' and patients' features. Areas covered: Pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best matches individual and tumor genetic profile, but it has not yet led to gains in outcome. This review describes PDAC pharmacogenetics findings, critically reappraising studies on polymorphisms and -omics profiles correlated to response to gemcitabine, FOLFIRINOX, and nab-paclitaxel combinations, as well as limitations of targeted therapies. Further, we question whether personalized approaches will benefit patients to any significant degree, supporting the need of new strategies within well-designed trials and validated genomic tests for treatment decision-making. Expert opinion: A major challenge in PDAC is the identification of subgroups of patients who will benefit from treatments. Minimally-invasive tests to analyze biomarkers of drug sensitivity/toxicity should be developed alongside anticancer treatments. However, progress might fall below expectations because of tumor heterogeneity and clonal evolution. Whole-genome sequencing and liquid biopsies, as well as prospective validation in selected cohorts, should overcome the limitations of traditional pharmacogenetic approaches.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Farmacogenética/métodos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Seleção de Pacientes , Prognóstico
17.
Expert Opin Drug Metab Toxicol ; 15(6): 449-458, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31120800

RESUMO

Introduction: The inclusion of pharmacogenetics alongside clinical information in anticoagulant therapy offers the opportunity for a tailored approach to treatment according to individual patient characteristics. Areas covered: Literature was searched using PubMed database, focusing on pharmacogenetics of oral anticoagulants. Original research articles and review articles in English language were included in the literature reviewed. This article includes all information available for the genetic cause of inter-individual variability in anticoagulation response to oral anticoagulant drugs. The pharmacogenetics of VKAs and NOACs are described in detail. Expert opinion: There have been numerous studies focusing on the pharmacogenetics of VKAs, particularly warfarin. Current evidence suggests that known genetic and clinical factors explain a large proportion of the inter-individual variability in response to warfarin. Pharmacogenetic-based algorithms have been validated to determine their clinical utility with equivocal results. To date, only a limited number of mostly small studies on the pharmacogenetics of NOACs exists. The latter have highlighted genetic polymorphisms in specific genes that may affect clinical outcomes. Further evaluations of these polymorphisms are needed before firm conclusions can be drawn about the significance of pharmacogenetics on NOAC therapy.


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Farmacogenética , Administração Oral , Algoritmos , Animais , Fibrilação Atrial/complicações , Humanos , Polimorfismo Genético , Acidente Vascular Cerebral/prevenção & controle , Vitamina K/antagonistas & inibidores , Varfarina/administração & dosagem
18.
J Headache Pain ; 20(1): 56, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101004

RESUMO

Migraine is the most disabling and expensive chronic disorders, the etiology of which is still not fully known. The neuronal systems, (glutammatergic, dopaminergic, serotoninergic and GABA-ergic) whose functionality is partly attributable to genetically determined factors, has been suggested to play an important role. The treatment of acute attacks and the prophylactic management of chronic forms include the use of different category of drugs, and it is demonstrated that not each subject has the same clinical answer to them. The reason of this is to be searched in different functional capacity and quantity of phase I enzymes (such as different isoforms of CYP P450), phase II enzymes (such as UDP-glucuronosyltransferases), receptors (such as OPRM1 for opioids) and transporters (such as ABCB1) involved in the metabolic destiny of each drug, all of these dictated by DNA and RNA variations. The general picture is further exacerbated by the need for polytherapies, often also to treat comorbidities, which may interfere with the pharmacological action of anti-migraine drugs. Personalized medicine has the objective of setting the optimal therapies in the light of the functional biochemical asset and of the comorbidities of the individual patient, in order to obtain the best clinical response. Novel therapeutic perspectives in migraine includes biotechnological drugs directed against molecules (such as CGRP and its receptor) that cause vasodilatation at the peripheral level of the meningeal blood vessels and reflex stimulation of the parasympathetic system. Drug-drug interactions and the possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale. Drug-drug interactions and their possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Medicina de Precisão/métodos , Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Interações de Medicamentos , Humanos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Farmacogenética , Triptaminas/uso terapêutico
20.
Cancer Res ; 79(17): 4539-4550, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31142512

RESUMO

Identifying robust biomarkers of drug response constitutes a key challenge in precision medicine. Patient-derived tumor xenografts (PDX) have emerged as reliable preclinical models that more accurately recapitulate tumor response to chemo- and targeted therapies. However, the lack of computational tools makes it difficult to analyze high-throughput molecular and pharmacologic profiles of PDX. We have developed Xenograft Visualization & Analysis (Xeva), an open-source software package for in vivo pharmacogenomic datasets that allows for quantification of variability in gene expression and pathway activity across PDX passages. We found that only a few genes and pathways exhibited passage-specific alterations and were therefore not suitable for biomarker discovery. Using the largest PDX pharmacogenomic dataset to date, we identified 87 pathways that are significantly associated with response to 51 drugs (FDR < 0.05). We found novel biomarkers based on gene expressions, copy number aberrations, and mutations predictive of drug response (concordance index > 0.60; FDR < 0.05). Our study demonstrates that Xeva provides a flexible platform for integrative analysis of preclinical in vivo pharmacogenomics data to identify biomarkers predictive of drug response, representing a major step forward in precision oncology. SIGNIFICANCE: A computational platform for PDX data analysis reveals consistent gene and pathway activity across passages and confirms drug response prediction biomarkers in PDX.See related commentary by Meehan, p. 4324.


Assuntos
Neoplasias , Farmacogenética , Animais , Xenoenxertos , Humanos , Medicina de Precisão , Ensaios Antitumorais Modelo de Xenoenxerto
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