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1.
Support Care Cancer ; 28(1): 395-403, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31056713

RESUMO

PURPOSE: Asthenia, myalgia, arthralgia, mucositis, abdominal pain, diarrhea, and neutropenia are adverse reactions commonly reported by women undergoing chemotherapy. Traditional approaches do not take into account the effect that chemotherapeutic changes and variable interactions can cause in adverse reactions. We aimed to identify the impact of the change of a chemotherapy protocol within the same treatment in profiles associated with adverse reactions. METHODS: A total of 166 women admitted to the Brazilian National Institute of Cancer (INCA) were followed. Polymorphisms, clinical variables, and FAC-D protocols (3 cycles of cyclophosphamide, 5-fluorouracil, and doxorubicin followed by 3 cycles of docetaxel) composed the set of independent variables analyzed. Reaction levels were recorded at the end of each chemotherapy cycle via interviews. Marginal models were fitted. RESULTS: The results of marginal models for non-hematological reactions revealed that the docetaxel phase was associated with increased reaction levels compared with the FAC phase. In addition, the set of factors associated with the reactions changed in each protocol. The post-menopausal status was related to high levels of asthenia in docetaxel protocol whereas CYP2B6 polymorphism (rs3745274) was related to high levels in FAC protocol. Regarding the docetaxel phase, high levels of abdominal pain and mucositis were related to CBR3 gene (rs8133052) polymorphism and diabetes respectively. CONCLUSION: The results suggest the need for monitoring non-hematological reactions during the docetaxel phase of FAC-D treatment. The factors related to more severe reactions depend on the chemotherapy protocol used.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Docetaxel/administração & dosagem , Substituição de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Dor Abdominal/induzido quimicamente , Dor Abdominal/epidemiologia , Dor Abdominal/genética , Adulto , Idoso , Oxirredutases do Álcool/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brasil/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citocromo P-450 CYP2B6/genética , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Diarreia/genética , Docetaxel/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Substituição de Medicamentos/métodos , Substituição de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Testes Farmacogenômicos , Polimorfismo de Nucleotídeo Único
2.
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
3.
Medicina (Kaunas) ; 55(8)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398888

RESUMO

Background and objectives: Assessment of drugs toxicity and associated biomarker genes is one of the most important tasks in the pre-clinical phase of drug development pipeline as well as in toxicogenomic studies. There are few statistical methods for the assessment of doses of drugs (DDs) toxicity and their associated biomarker genes. However, these methods consume more time for computation of the model parameters using the EM (expectation-maximization) based iterative approaches. To overcome this problem, in this paper, an attempt is made to propose an alternative approach based on hierarchical clustering (HC) for the same purpose. Methods and materials: There are several types of HC approaches whose performance depends on different similarity/distance measures. Therefore, we explored suitable combinations of distance measures and HC methods based on Japanese Toxicogenomics Project (TGP) datasets for better clustering/co-clustering between DDs and genes as well as to detect toxic DDs and their associated biomarker genes. Results: We observed that Word's HC method with each of Euclidean, Manhattan, and Minkowski distance measures produces better clustering/co-clustering results. For an example, in the case of the glutathione metabolism pathway (GMP) dataset LOC100359539/Rrm2, Gpx6, RGD1562107, Gstm4, Gstm3, G6pd, Gsta5, Gclc, Mgst2, Gsr, Gpx2, Gclm, Gstp1, LOC100912604/Srm, Gstm4, Odc1, Gsr, Gss are the biomarker genes and Acetaminophen_Middle, Acetaminophen_High, Methapyrilene_High, Nitrofurazone_High, Nitrofurazone_Middle, Isoniazid_Middle, Isoniazid_High are their regulatory (associated) DDs explored by our proposed co-clustering algorithm based on the distance and HC method combination Euclidean: Word. Similarly, for the peroxisome proliferator-activated receptor signaling pathway (PPAR-SP) dataset Cpt1a, Cyp8b1, Cyp4a3, Ehhadh, Plin5, Plin2, Fabp3, Me1, Fabp5, LOC100910385, Cpt2, Acaa1a, Cyp4a1, LOC100365047, Cpt1a, LOC100365047, Angptl4, Aqp7, Cpt1c, Cpt1b, Me1 are the biomarker genes and Aspirin_Low, Aspirin_Middle, Aspirin_High, Benzbromarone_Middle, Benzbromarone_High, Clofibrate_Middle, Clofibrate_High, WY14643_Low, WY14643_High, WY14643_Middle, Gemfibrozil_Middle, Gemfibrozil_High are their regulatory DDs. Conclusions: Overall, the methods proposed in this article, co-cluster the genes and DDs as well as detect biomarker genes and their regulatory DDs simultaneously consuming less time compared to other mentioned methods. The results produced by the proposed methods have been validated by the available literature and functional annotation.


Assuntos
Biomarcadores , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Perfilação da Expressão Gênica/métodos , Animais , Análise por Conglomerados , Modelos Animais de Doenças , Ratos
4.
Epileptic Disord ; 21(4): 330-336, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31403464

RESUMO

Adverse drug reactions are a leading cause of treatment failure with antiepileptic drugs. Adverse drug reactions are also a major source of morbidity and mortality, and a substantial burden on the use and costs of health care. Recent pharmacogenetic studies have shown that some adverse drug reactions are associated with genetic variants, which has changed how we select antiepileptic drugs for individual patients. This article, beginning with a case of an adverse drug reaction induced by carbamazepine, will answer four key questions about pharmacogenetics of adverse drug reactions: (1) What types of adverse drug reactions can be caused by antiepileptic drugs? (2) What is pharmacogenetics? (3) How does pharmacogenetics play a role in the adverse drug reactions of antiepileptic drugs? and (4) How do we apply pharmacogenetic testing in clinical practice? Our goal is to increase awareness of the contributions of genetic variation to adverse drug reactions of antiepileptic drugs.


Assuntos
Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Farmacogenética , Carbamazepina/efeitos adversos , Carbamazepina/uso terapêutico , Humanos , Alfabetização , Organização Mundial da Saúde
5.
Transl Psychiatry ; 9(1): 177, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346157

RESUMO

Antipsychotic drugs fail to achieve adequate response in 30-50% of treated patients and about 50% of them develop severe and lasting side effects. Treatment failure results in poorer prognosis with devastating repercussions for the patients, carers and broader society. Our study evaluated the clinical benefits of a pharmacogenetic intervention for the personalisation of antipsychotic treatment. Pharmacogenetic information in key CYP polymorphisms was used to adjust clinical doses in a group of patients who started or switched treatment with antipsychotic drugs (PharmG+, N = 123), and their results were compared with those of a group of patients treated following existing clinical guides (PharmG-, N = 167). There was no evidence of significant differences in side effects between the two arms. Although patients who had their antipsychotic dose adjusted according to CYPs polymorphisms (PharmG+) had a bigger reduction in side effects than those treated as usual (PharmG-), the difference was not statistically significant (p > 0.05 for all comparisons). However, PharmG+ patients treated with CYP2D6 substrates that were carriers of CYP2D6 UMs or PMs variants showed a significantly higher improvement in global, psychic and other UKU side effects than PharmG- patients (p = 0.02, p = 0.05 and p = 0.01, respectively). PharmG+ clozapine treated patients with CYP1A2 or CYP2C19 UM and PMs variants also showed higher reductions in UKU scores than PharmG- clozapine patients in general. However, those differences were not statistically significant. Pharmacogenetic interventions may improve the safety of antipsychotic treatments by reducing associated side effects. This intervention may be particularly useful when considering treatment with antipsychotics with one major metabolic pathway, and therefore more susceptible to be affected by functional variants of CYP enzymes.


Assuntos
Antipsicóticos/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Farmacogenética , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/efeitos adversos , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Medicina de Precisão , Esquizofrenia Paranoide/tratamento farmacológico
6.
PLoS One ; 14(7): e0220071, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31329634

RESUMO

BACKGROUND: Knowledge of risk factors for drug-related hospitalizations (DRHs) is limited. AIM: To examine the prevalence of DRHs and the relationships between DRHs and various variables in multimorbid patients admitted to an internal medicine ward. METHODS: Multimorbid patients ≥ 18 years, using minimum of four regular drugs from minimum two therapeutic classes, were included from the Internal Medicine ward, Oslo University Hospital, Norway, from August 2014 to March 2016. Clinical pharmacists prospectively conducted medicines reconciliations and reviews to reveal drug-related problems (DRPs). Blinded for identified DRPs, an interdisciplinary group retrospectively made comprehensive, clinical assessments of each patient case to classify hospitalizations as drug-related (DRH) or non-drug-related (non-DRH). Age, sex distribution, Charlson Comorbidity Index (CCI), renal function, aberrant genotype frequencies, body-mass index, number of drugs, proportion of patients which received assistance for drug administration from the home care service, and/or through multidose-dispensed drugs, and occurrence of specific DRP subgroups, were compared separately between patients with DRHs versus non-DRHs, followed by multiple logistic regression analysis. RESULTS: Hospitalizations were classified as drug-related in 155 of the 404 included patients (38%). Factors significantly associated with DRHs were occurrence of adverse effect DRPs (adjusted odds ratio (OR) 3.3, 95% confidence interval (CI) 1.4-8.0), adherence issues (OR 2.9, 1.1-7.2), home care (OR 1.9, 1.1-3.5), drug monitoring DRPs (OR 1.9, 1.2-3.0), and CCI score ≥6 (OR 0.33, 0.14-0.77). Frequencies of aberrant genotypes did not differ between the patient groups, but in 41 patients with DRHs (26.5%), gene-drug interactions influenced the assessments of DRHs. CONCLUSION: DRHs are prevalent in multimorbid patients with adverse effect DRPs and adherence issues as the most important risk factors.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hospitalização/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Multimorbidade , Prevalência
7.
World J Gastroenterol ; 25(21): 2539-2548, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210708

RESUMO

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Gastroenterologia/métodos , Imunossupressores/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Medicina de Precisão/métodos , Variação Biológica da População/genética , Medula Óssea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Gastroenterologia/normas , Testes Genéticos , Antígenos HLA/genética , Antígenos HLA/imunologia , Hematopoese/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Metiltransferases/genética , Metiltransferases/metabolismo , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Medicina de Precisão/normas , Prognóstico , Pirofosfatases/genética , Pirofosfatases/metabolismo , Medição de Risco/métodos , Resultado do Tratamento
8.
Biomed Res Int ; 2019: 1283824, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119149

RESUMO

Drug-induced liver injury (DILI) is a major concern in clinical studies as well as in postmarketing surveillance. It is necessary to establish an animal model of DILI for thorough investigation of mechanisms of DILI and searching for protective medications. This article reviews the current status and future perspective on establishment of DILI models based on different hepatotoxic drugs, as well as the underlying mechanisms of liver function damage induced by specific medicine. Therefore, information from this article can help researchers make a suitable selection of animal models for further study.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Imunossupressão/efeitos adversos , Fígado/patologia , Tetraciclina/efeitos adversos , Tetraciclina/uso terapêutico
9.
Nat Commun ; 10(1): 1579, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952858

RESUMO

Only a small fraction of early drug programs progress to the market, due to safety and efficacy failures, despite extensive efforts to predict safety. Characterizing the effect of natural variation in the genes encoding drug targets should present a powerful approach to predict side effects arising from drugging particular proteins. In this retrospective analysis, we report a correlation between the organ systems affected by genetic variation in drug targets and the organ systems in which side effects are observed. Across 1819 drugs and 21 phenotype categories analyzed, drug side effects are more likely to occur in organ systems where there is genetic evidence of a link between the drug target and a phenotype involving that organ system, compared to when there is no such genetic evidence (30.0 vs 19.2%; OR = 1.80). This result suggests that human genetic data should be used to predict safety issues associated with drug targets.


Assuntos
Ensaios Clínicos como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Fenótipo , Análise de Regressão , Estudos Retrospectivos
10.
PLoS One ; 14(3): e0213860, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921347

RESUMO

In this era of clinical genomics, the accumulation of knowledge of pharmacogenomics (PGx) is rising dramatically and attempts to utilize it in clinical practice are also increasing. However, this advanced knowledge and information have not yet been sufficiently utilized in the clinical field due to various barriers including physician factors. This study was conducted to evaluate the attitudes of physicians to PGx services by providing them their own genomic data analysis report focusing on PGx. We also tried to evaluate the clinical applicability of whole exome sequencing (WES)-based functional PGx test. In total 88 physicians participated in the study from September 2015 to August 2016. Physicians who agreed to participate in the study were asked to complete a pre-test survey evaluating their knowledge of and attitude toward clinical genomics including PGx. Only those who completed the pre-test survey proceeded to WES and were provided with a personal PGx analysis report in an offline group meeting. Physicians who received these PGx reports were asked to complete a follow-up survey within two weeks. We then analyzed changes in their knowledge and attitude after reviewing their own PGx analysis results through differences in their pre-test and post-test survey responses. In total, 70 physicians (79.5%) completed the pre-test and post-test surveys and attended an off-line seminar to review their personal PGx reports. After physicians reviewed the report, their perception of and attitude towards the PGx domain and genomics significantly changed. Physician' awareness of the likelihood of occurrence of adverse drug reactions and genetic contribution was also changed significantly. Overall, physicians were very positive about the value and potential of the PGx test but maintained a conservative stance on its actual clinical use. Results revealed that physicians' perception and attitude to the utility of PGx testing was significantly changed after reviewing their own WES results.


Assuntos
Atitude , Testes Farmacogenômicos , Médicos/psicologia , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Sequenciamento Completo do Exoma
11.
Expert Rev Clin Pharmacol ; 12(5): 407-442, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30916581

RESUMO

INTRODUCTION: Adverse drug reactions (ADRs) are a major health concern worldwide. There are multiple causes of ADRs, some of which are preventable. Pharmacogenomics accounts for ≈80% variability in drug efficacy and safety. Over 400 genes are clinically relevant in drug metabolism, and ≈200 pharmagenes are associated with ADRs. The condition of extensive metabolizer in the Caucasian population is lower than 20%, and about 60% of patients are exposed to potential ADRs. Areas covered: Important topics related to pharmacogenomics in drug efficacy and safety are covered, including: (i) major components of the pharmacogenomic machinery; (ii) epigenetic regulation of pharmagene expression; and (iii) pharmacogenomics-related ADRs of different drug categories. Expert opinion: The Regulatory Agencies should make recommendations to the pharmaceutical industry in favor of the introduction of pharmacogenomics in drug development and the inclusion of pharmacogenomic information on drug labels, with specific warnings for the population at risk. Educational programs are fundamental for drug prescribers to become familiar with personalized treatments. Pharmacogenetic testing should be gradually introduced into medical practice. ADRs can be reduced not only by adherence to prescribing guidelines, suitable monitoring and regular medication review, but also by the implementation of pharmacogenomic procedures in the clinical setting.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Farmacogenética , Guias de Prática Clínica como Assunto , Desenvolvimento de Medicamentos/métodos , Indústria Farmacêutica/métodos , Rotulagem de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Epigênese Genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Preparações Farmacêuticas/administração & dosagem , Padrões de Prática Médica/normas
12.
Tumori ; 105(3): 243-252, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30857495

RESUMO

AIMS: BEAWARE investigated the pattern of first-line bevacizumab early interruption in the Italian real-world setting of metastatic colorectal cancer. METHODS: A total of 386 patients were followed for 15 months after first-line chemotherapy + bevacizumab start. The rate of bevacizumab interruption for progression or adverse drug reactions (ADRs) constituted the primary endpoint. RESULTS: A total of 78.2% of patients interrupted bevacizumab: 56.6% for progression, 7.3% for ADRs, and 36.1% for other reasons. Median treatment duration was 6.7, 2.5, and 4.6 months, respectively. Median progression-free survival was 10.3 months; however, 35.8% of patients were not progressed and were thus censored at the data cutoff of 15 months, while 21.8% were still receiving bevacizumab. Patients discontinuing for progression/ADRs more frequently had metastases in >1 site (p = .0001), and a shorter median progression-free survival (6.9 vs 13.9 months, p < .0001). CONCLUSIONS: In Italy, first-line bevacizumab is interrupted mainly for progression, only 7.3% due to adverse events, and about one third of cases for other reasons. In clinical practice, the attitude to treat until progression as per guidelines might be implemented. ClinicalTrials.gov Identifier: NCT01609075.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Bevacizumab/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Genótipo , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas p21(ras)/genética
13.
Genet Med ; 21(9): 2145-2150, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30728528

RESUMO

PURPOSE: Severe hematotoxicity in patients with thiopurine therapy has been associated with genetic polymorphisms in the thiopurine S-methyltransferase (TPMT). While TPMT genetic testing is clinically implemented for dose individualization, alterations in the nudix hydrolase 15 (NUDT15) emerged as independent determinant of thiopurine-related hematotoxicity. Because data for European patients are limited, we investigated the relevance of NUDT15 in Europeans. METHODS: Additionally to TPMT phenotyping/genotyping, we performed in-depth Sanger sequencing analyses of NUDT15 coding region in 107 European patients who developed severe thiopurine-related hematotoxicity as extreme phenotype. Moreover, genotyping for NUDT15 variants in 689 acute lymphoblastic leukemia (ALL) patients was performed. RESULTS: As expected TPMT was the main cause of severe hematotoxicity in 31% of patients, who were either TPMT deficient (10%) or heterozygous carriers of TPMT variants (21%). By comparison, NUDT15 genetic polymorphism was identified in 14 (13%) patients including one novel variant (p.Met1Ile). Six percent of patients with severe toxicity carried variants in both TPMT and NUDT15. Among patients who developed toxicity within 3 months of treatment, 13% were found to be carriers of NUDT15 variants. CONCLUSION: Taken together, NUDT15 and TPMT genetics explain ~50% of severe thiopurine-related hematotoxicity, providing a compelling rationale for additional preemptive testing of NUDT15 genetics not only in Asians, but also in Europeans.


Assuntos
Hipersensibilidade a Drogas/genética , Metiltransferases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Pirofosfatases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Erros Inatos do Metabolismo da Purina-Pirimidina/patologia
14.
Drug Saf ; 42(6): 743-750, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30762164

RESUMO

INTRODUCTION: It is important to monitor the safety profile of drugs, and mining for strong associations between drugs and adverse events is an effective and inexpensive method of post-marketing safety surveillance. OBJECTIVE: The objective of our work was to compare the accuracy of both common and innovative methods of data mining for pharmacovigilance purposes. METHODS: We used the reference standard provided by the Observational Medical Outcomes Partnership, which contains 398 drug-adverse event pairs (165 positive controls, 233 negative controls). Ten methods and algorithms were applied to the US FDA Adverse Event Reporting System data to investigate the 398 pairs. The ten methods include popular methods in the pharmacovigilance literature, newly developed pharmacovigilance methods as at 2018, and popular methods in the genome-wide association study literature. We compared their performance using the receiver operating characteristic (ROC) plot, area under the curve (AUC), and Youden's index. RESULTS: The Bayesian confidence propagation neural network had the highest AUC overall. Monte Carlo expectation maximization, a method developed in 2018, had the second highest AUC and the highest Youden's index, and performed very well in terms of high specificity. The regression-adjusted gamma Poisson shrinkage model performed best under high-sensitivity requirements. CONCLUSION: Our results will be useful to help choose a method for a given desired level of specificity. Methods popular in the genome-wide association study literature did not perform well because of the sparsity of data and will need modification before their properties can be used in the drug-adverse event association problem.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Algoritmos , Área Sob a Curva , Teorema de Bayes , Mineração de Dados/estatística & dados numéricos , Bases de Dados Factuais/estatística & dados numéricos , Estudo de Associação Genômica Ampla/métodos , Humanos , Aprendizado de Máquina , Farmacovigilância , Curva ROC , Estados Unidos , United States Food and Drug Administration
15.
Eur J Pharm Sci ; 130: 65-77, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684656

RESUMO

Understanding and predicting inter-individual differences related to the success of drug therapy is of tremendous importance, both during drug development and for clinical applications. Importantly, while seminal twin studies indicate that the majority of inter-individual differences in drug disposition are driven by hereditary factors, common genetic polymorphisms explain only less than half of this genetically encoded variability. Recent progress in Next Generation Sequencing (NGS) technologies has for the first time allowed to comprehensively map the genetic landscape of human pharmacogenes. Importantly, these projects have unveiled vast numbers of rare genetic variants, which are estimated to contribute substantially to the missing heritability of drug metabolism phenotypes. However, functional interpretation of these rare variants remains challenging and constitutes one of the important frontiers of contemporary pharmacogenomics. Furthermore, NGS technologies face challenges in the interrogation of genes residing in complex genomic regions, such as CYP2D6 and HLA genes. We here provide an update of the implementation of pharmacogenomic variations in the clinical setting and present emerging strategies that facilitate the translation of NGS data into clinically useful information. Importantly, we anticipate that these developments will soon result in a paradigm shift of pre-emptive genotyping away from the interrogation to candidate variants and towards the comprehensive profiling of an individuals genotype, thus allowing for a true individualization of patient drug treatment regimens.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Preparações Farmacêuticas , Polimorfismo Genético/genética , Estudos em Gêmeos como Assunto/métodos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/tendências , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Previsões , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Preparações Farmacêuticas/metabolismo , Farmacogenética/métodos , Farmacogenética/tendências , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Estudos em Gêmeos como Assunto/tendências
16.
Lung Cancer ; 128: 20-25, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30642448

RESUMO

OBJECTIVES: Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations. MATERIALS AND METHODS: DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher's exact test. RESULTS: We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs. CONCLUSION: Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Neoplasias Pulmonares/genética , Variantes Farmacogenômicos/genética , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Feminino , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/uso terapêutico
17.
Sci Data ; 6: 180306, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30620345

RESUMO

To achieve therapeutic goals, many cancer chemotherapeutics are used at doses close to their maximally tolerated doses. Thus, it may be expected that when therapies are combined at therapeutic doses, toxicity profiles may change. In many ways, prediction of synergistic toxicities for drug combinations is similar to predicting synergistic efficacy, and is dependent upon building hypotheses from molecular mechanisms of drug toxicity. The key objective of this initiative was to generate and make publicly available key high-content data sets for mechanistic hypothesis generation as it pertains to a unique toxicity profile of a drug pair for several anticancer drug combinations. The expectation is that tissue-based genomic information that are derived from target tissues will also facilitate the generation and testing of mechanistic hypotheses. The view is that availability of these data sets for bioinformaticians and other scientists will contribute to analysis of these data and evaluation of the approach.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Perfilação da Expressão Gênica , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Especificidade de Órgãos , Ratos , Análise Serial de Tecidos
19.
Clin Pharmacol Ther ; 105(3): 625-640, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29498032

RESUMO

Older persons may particularly benefit from pharmacogenetic diagnostics, but there is little clinical evidence on that question. We quantitatively analyzed the effects of age and genotype in drugs with consensus on a therapeutically relevant impact of a genotype. Assuming additive effects of age and genotype, drugs may be classified in groups with different priorities to consider either age, or genotype, or both, in therapy. Particularly interesting were those studies specifically analyzing the age-by-genotype interaction.


Assuntos
Envelhecimento/metabolismo , Variação Genética/fisiologia , Genômica/métodos , Genótipo , Preparações Farmacêuticas/metabolismo , Farmacogenética/métodos , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Variação Genética/efeitos dos fármacos , Humanos , Testes Farmacogenômicos/métodos
20.
Drug Res (Stuttg) ; 69(1): 23-31, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29791922

RESUMO

BACKGROUND AND STUDY AIM: Some studies have reported an association between P2Y12 gene polymorphisms and clopidogrel adverse outcomes with inconsistent results. We aimed to explore the relationship between P2Y12 polymorphisms and the risk of adverse clinical events in patients treated with clopidogrel through a meta-analysis. METHODS: A systematic search of PubMed, Web of Science and the Cochrane Library was conducted. Retrieved articles were comprehensively reviewed and eligible studies were included, and the relevant data was extracted for this meta-analysis. All statistical tests were performed by the Review Manager 5.3 software. RESULTS: A total of 14 studies involving 8,698 patients were included. In the Han Chinese population, ischemic events were associated with P2Y12 T744C polymorphism in the CC vs TT+CT genetic model (OR=3.32, 95%CI=1.62-6.82, P=0.001), and the events were associated with P2Y12 C34T polymorphism in the TT+TC vs CC genetic model (OR=1.70, 95%CI=1.22-2.36, P=0.002). However, ischemic events were not related to P2Y12 G52T polymorphism (TT+TG vs GG: OR=1.13, 95%CI=0.76-1.68, P=0.56; TT vs GG+TG: OR=2.02, 95%CI=0.65-6.28, P=0.22). The associations between the P2Y12 polymorphism and ischemic events were not significant in T744C, G52T and C34T genotype for another subgroup of the Caucasian population (P>0.05). Only two studies referring to bleeding events were included in this analysis of C34T polymorphism, and no significant association was found (TT+TC vs CC: OR=1.07, 95%CI=0.37-3.15, P=0.90). CONCLUSIONS: In the Caucasian population, P2Y12 gene polymorphisms are not associated with clinical events. However, in the Chinese Han population, P2Y12 T744C and C34T polymorphisms are significantly associated with adverse clinical events.


Assuntos
Clopidogrel/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Inibidores da Agregação de Plaquetas/efeitos adversos , Polimorfismo Genético/genética , Receptores Purinérgicos P2Y12/genética , Estudos de Casos e Controles , Genótipo , Humanos , Risco
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