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1.
J Clin Psychiatry ; 81(5)2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32857933

RESUMO

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. METHODS: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. RESULTS: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. CONCLUSIONS: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818751.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Citalopram/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Área Sob a Curva , Criança , Citalopram/análogos & derivados , Citalopram/sangue , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/farmacocinética , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(29): e20582, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702814

RESUMO

The morbidity of coronary artery disease (CAD) in the Uygur population of Xinjiang was much higher than the national average. Clopidogrel is the most commonly used medication worldwide in dual antiplatelet therapy for CAD, and the response of clopidogrel is affected by CYP2C19, PON1, and ABCB1 genetic polymorphisms. The distribution of CYP2C19*17, ABCB1, and PON1 genetic polymorphisms in Han and Uygur populations with CAD of Xinjiang has not been investigated.This study aimed to investigate the frequencies of CYP2C19, PON1, and ABCB1 genetic polymorphisms, and to identify the metabolizer phenotype of CYP2C19 in Han and Uygur populations with CAD in Northwestern Xinjiang, China. We identified 602 Han and 527 Uygur patients from 2014 through 2019 and studied genotypes for selected allele polymorphisms using sequencing by hybridization.There were significantly different allele frequencies and genotype frequencies between the 2 ethnic groups in terms of CYP2C19*2, *3, *17, ABCB1 and PON1, (P < .05). For CYP2C19*17, the frequency of TT genotype was 2.5% in Uygur patients, but it was undetectable in Han patients. In both the intermediate and poor metabolizer groups, the genotypes polymorphisms CYP2C19*2, *3, *17 were significantly less common in Uygur patients than in Han patients (P < .001). By contrast, the proportion of ultra-metabolizers as defined by CYP2C19*2, *3, *17 polymorphisms significantly higher in Uygur patients (18.6%) than in Han patients (1.7%, P < .001). The CYP2C19*2 frequency was significantly different between Han patients and Han healthy groups (P < .001), while the CYP2C19*3 frequency was significantly different between Uygur patients and Uygur healthy groups (P < .001).Our study supports the notion of interethnic differences in terms of CYP2C19, PON1, and ABCB1 polymorphisms and CYP2C19 genotype-defined clopidogrel metabolic groups. These finding could provide valuable data and insights into personalized CAD treatment for the Uygur and Han populations in Xinjiang.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Arildialquilfosfatase/genética , China/etnologia , Clopidogrel/uso terapêutico , Comorbidade , Doença da Artéria Coronariana/mortalidade , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Grupos Étnicos/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico
3.
J Stroke Cerebrovasc Dis ; 29(7): 104877, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414579

RESUMO

OBJECTIVES: To assess the prevalence of high on-clopidogrel platelet reactivity (HCPR) in patients with ischaemic stroke or transient ischaemic attack (IS/TIA), their outcome and genetic basis of on-treatment response variability in IS/TIA patients. METHODS: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to March 9, 2019. Studies that reported absolute numbers/percentages of HCRP at any time point after IS/TIA onset evaluated with any type of platelet function tests, clinical outcomes and genotyping data were included. RESULTS: Among 21 studies of 4312 IS/TIA patients treated with clopidogrel, the pooled prevalence of HCPR was 28% (95%CI: 24-32%; high heterogeneity: I2 = 88.2%, p < 0.001). Heterogeneity degree diminished across groups defined by the HCPR testing method. Clopidogrel non-responder IS/TIA patients had poorer outcome compared to responders (RR = 2.09, 95%CI: 1.61-2.70; p = 0.036; low heterogeneity across studies: I2 = 27.4%, p = 0.210). IS/TIA carriers of CYP2C19*2 or CYP2C19*3 loss of function alleles had a higher risk of HCPR compared to wild type (RR = 1.69, 95%CI: 1.47-1.95; p < 0.001; I2 = 0.01%, p = 0.475). CONCLUSIONS: This systematic review shows a high prevalence of clopidogrel resistance in IS/TIA and poor outcome in these patients. CYP2C19 polymorphisms may potentially influence clopidogrel resistance.


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/uso terapêutico , Resistência a Medicamentos , Ataque Isquêmico Transitório/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Plaquetas/metabolismo , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos/genética , Humanos , Ataque Isquêmico Transitório/sangue , Ataque Isquêmico Transitório/diagnóstico , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Polimorfismo Genético , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Resultado do Tratamento
4.
Psychiatry Res ; 288: 112984, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32315880

RESUMO

Cytochrome P450 C19 (CYP2C19) metabolizes exogenous and endogenous compounds. Although CYP2C19 is highly expressed in the liver, it is also expressed in the brain during early life. Previous human and animal studies have linked CYP2C19 genotype-predicted enzyme activity to hippocampal volumes, depressive symptoms, and anxiety-like behaviors. We examined these promising associations in a general community sample comprising 386 Caucasian adults with no history of psychiatric or neurological illnesses. Contrary to previous findings, CYP2C19 genotype-predicted enzyme activity was not associated with hippocampal volumes, nor depressive and anxiety symptoms. Interstudy differences in CYP2C19 frequencies and/or study methodology may explain this discrepancy.


Assuntos
Ansiedade/diagnóstico por imagem , Citocromo P-450 CYP2C19/metabolismo , Depressão/diagnóstico por imagem , Genótipo , Hipocampo/diagnóstico por imagem , Adulto , Animais , Ansiedade/enzimologia , Ansiedade/genética , Estudos Transversais , Citocromo P-450 CYP2C19/genética , Depressão/enzimologia , Depressão/genética , Ativação Enzimática/fisiologia , Feminino , Hipocampo/enzimologia , Humanos , Masculino , Tamanho do Órgão/fisiologia
5.
JACC Cardiovasc Interv ; 13(5): 606-617, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32139218

RESUMO

OBJECTIVES: The aim of this study was to develop a risk score integrating cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes. BACKGROUND: Clopidogrel is the most broadly used platelet P2Y12 inhibitor. However, a considerable number of patients achieve inadequate platelet inhibition, with persistent HPR, an established marker of increased thrombotic risk, underscoring the need for tools to help identify these subjects. Although carriers of loss-of-function alleles of the cytochrome P450 2C19 enzyme have reduced clopidogrel metabolism leading to increased rates of HPR and thrombotic complications, this explains only a fraction of the pharmacodynamic response to clopidogrel, and a number of clinical factors have also been shown to have contributing roles. METHODS: Three prospective and independent studies were used to: 1) develop a risk score integrating genetic and clinical factors to identify patients with HPR while on clopidogrel; 2) investigate the external validity of the risk score; and 3) define clinical outcomes associated with the risk score in a cohort of patients with myocardial infarction treated with clopidogrel. RESULTS: A risk score ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) was developed incorporating 5 independent predictors of HPR: 4 clinical (age >75 years, body mass index >30 kg/m2, chronic kidney disease [glomerular filtration rate <60 ml/min], and diabetes mellitus) and 1 genetic (cytochrome P450 2C19 loss-of-function alleles). The C-statistics for the score as an integer variable were 0.71 (95% confidence interval [CI]: 0.68 to 0.75) and 0.64 (95% CI: 0.60 to 0.67) in the pharmacodynamic derivation and validation cohorts, respectively. A cutoff score ≥10 was associated with the best sensitivity and specificity to identify HPR status. The C-statistics for the score were 0.67 (95% CI: 0.64 to 0.71) for all-cause death and 0.66 (95% CI: 0.63 to 0.69) for the composite of all-cause death, stroke, or myocardial infarction at 1 year. Using multiple models for adjustment, the ABCD-GENE score consistently and independently correlated with all-cause death, as well as with the composite of all-cause death, stroke, or myocardial infarction, both as a continuous variable and by using the cutoff of ≥10. The score did not predict bleeding. CONCLUSIONS: The ABCD-GENE score is a simple tool to identify patients with HPR on clopidogrel and who are at increased risk for adverse ischemic events, including mortality, following an acute myocardial infarction. In patients with a high ABCD-GENE score, long-term oral P2Y12 inhibitors other than clopidogrel should be considered.


Assuntos
Regras de Decisão Clínica , Clopidogrel/uso terapêutico , Trombose Coronária/prevenção & controle , Resistência a Medicamentos , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Fatores Etários , Idoso , Índice de Massa Corporal , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Trombose Coronária/diagnóstico por imagem , Trombose Coronária/etiologia , Trombose Coronária/mortalidade , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Bases de Dados Factuais , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Obesidade/complicações , Obesidade/diagnóstico , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Valor Preditivo dos Testes , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
6.
JACC Cardiovasc Interv ; 13(5): 621-630, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32139220

RESUMO

OBJECTIVES: The aim of this study was to evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-segment elevation myocardial infarction with primary percutaneous coronary intervention. BACKGROUND: Response to clopidogrel differs widely among patients, notably because of CYP2C19 genetic polymorphisms. METHODS: CYP2C19 genotype (6 alleles) was determined centrally and communicated within 4.1 ± 1.9 days of primary percutaneous coronary intervention in 1,445 patients with ST-segment elevation myocardial infarction recruited at 57 centers in France. CYP2C19 metabolic status was predicted from genotype and served to adjust thienopyridine treatment. The primary endpoint was differences in 12-month outcomes (death, myocardial infarction, and stent thrombosis) between patients with the wild-type genotype or gain-of-function allele (class 1, n = 1,118) and those with loss-of-function (LOF) alleles (class 2, n = 272) who received optimized thienopyridine treatment. RESULTS: Detection of LOF alleles resulted in adjustment of P2Y12 inhibition in 85% of patients, with significantly higher use of prasugrel or double-dose clopidogrel. The primary endpoint did not differ between class 1 and class 2 patients (3.31% vs. 3.04%, respectively; p = 0.82). In contrast, carriers of LOF alleles without treatment adjustment had significantly worse outcomes (15.6%; p < 0.05). Bleeding rates were not different between groups. CONCLUSIONS: In a real-world setting, a complete CYPC2C19 genotype can be mostly determined in <7 days using analysis of saliva deoxyribonucleic acid collected during the in-hospital phase among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Genotype information led to stronger platelet inhibition treatment in the vast majority of LOF allele carriers and to similar clinical outcomes as in patients carrying the wild-type genotype or gain-of-function allele. (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment [GIANT]; NCT01134380).


Assuntos
Clopidogrel/administração & dosagem , Trombose Coronária/prevenção & controle , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/administração & dosagem , Polimorfismo Genético , Cloridrato de Prasugrel/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Idoso , Tomada de Decisão Clínica , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Trombose Coronária/etiologia , Trombose Coronária/mortalidade , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/farmacocinética , Medicina de Precisão , Estudos Prospectivos , Recidiva , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Fatores de Tempo , Resultado do Tratamento
8.
J Cardiovasc Pharmacol Ther ; 25(3): 201-211, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32027168

RESUMO

BACKGROUND AND OBJECTIVES: Clopidogrel is widely used after the percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and requires activation by cytochrome P450 (CYP), primarily CYP2C19. Patients with CYP2C19 loss-of-function alleles are at increased risk of major adverse cardiovascular events, while more expensive novel antiplatelet agents (ticagrelor and prasugrel) are unaffected by the CYP2C19 mutations. This systematic review aims to answer the question about whether overall evidence supports the genotype-guided selection of antiplatelet therapy as a cost-effective strategy in post-PCI ACS. METHODS: A systematic literature search of PubMed, EMBASE, EconLit, and PharmGKB was done to identify all the economic evaluations related to genotype-guided therapy compared to the universal use of antiplatelets in ACS patients. Quality of Health Economic Studies tool was used for quality assessment. RESULTS: The search identified 13 articles, where genotype-guided treatment was compared to universal clopidogrel, ticagrelor, and/or prasugrel. Six studies showed that genotype-guided therapy was cost-effective compared to universal clopidogrel, while 5 studies showed that it was dominant. One study specified that genotype-guided with ticagrelor is cost-effective only in both CYP2C19 intermediate and poor metabolizers. Genotype-guided therapy was dominant when compared to universal prasugrel, ticagrelor, or both in 5, 1, and 3 studies, respectively. Only 2 studies reported that universal ticagrelor was cost-effective compared to genotype-guided treatment. All the included articles had good quality. CONCLUSION: Based on current economic evaluations in the literature, implementing CYP2C19 genotype-guided therapy is a cost-effective approach in guiding the selection of medication in patients with ACS undergoing PCI.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/economia , Citocromo P-450 CYP2C19/genética , Custos de Medicamentos , Testes Farmacogenômicos/economia , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/economia , Inibidores da Agregação de Plaquetas/uso terapêutico , Medicina de Precisão/economia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Tomada de Decisão Clínica , Clopidogrel/economia , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/metabolismo , Humanos , Seleção de Pacientes , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Cloridrato de Prasugrel/economia , Cloridrato de Prasugrel/uso terapêutico , Valor Preditivo dos Testes , Ticagrelor/economia , Ticagrelor/uso terapêutico , Resultado do Tratamento
9.
Life Sci ; 245: 117364, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32001263

RESUMO

AIMS: To investigate the impact of microRNA target SNPs (mirSNPs) and their interaction with miRNAs on important drug-metabolizing enzymes, transporters and target genes for prediction of clopidogrel drug response in cardiovascular disease individuals. MAIN METHODS: A prospective cross-sectional study was conducted on 292 individuals undergoing clopidogrel drug therapy. All the enrolled participants were administered 300 mg loading dose followed by 75 mg dose of maintenance therapy. Platelet aggregations were measured before administration of the loading dose and 2 h post fifth day dose of clopidogrel maintenance therapy. Clopidogrel carboxylic acid metabolite from plasma and urine were analyzed post maintenance therapy using the RP-HPLC method. Genotyping of mirSNP's shortlisted through in silico analysis was performed by tetra ARMS PCR and validated by Sanger DNA sequencing. The levels of selected miRNAs were estimated by the TaqMan-PCR assay. Functional validation of mirSNPs was performed in HepG2 cells after transfecting with the selected gene and miRNA mimics. Protein expressions were analyzed by western blot. KEY FINDINGS: 23% of enrolled individuals showed resistance to clopidogrel therapy. Out of 13 mirSNP's analyzed, CYP2C19 rs4244285 was associated with clopidogrel drug resistance and clopidogrel carboxylic acid metabolite in urine and plasma. hsa-miR-1343-3p and hsa-miR-6783-3p levels were significantly high in individuals with CYP2C19 rs4244285 mutant genotype and these miRNAs down-regulated the protein expression of CYP2C19. SIGNIFICANCE: We demonstrated the role of coding mirSNP (rs4244285) in the regulation of the CYP2C19 gene through miRNAs and its implications to clopidogrel drug response prediction in the Indian population.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Clopidogrel/farmacologia , Citocromo P-450 CYP2C19/genética , MicroRNAs/genética , Agregação Plaquetária/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Western Blotting , Clopidogrel/metabolismo , Clopidogrel/uso terapêutico , Estudos Transversais , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos/genética , Feminino , Células Hep G2 , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sequência de DNA
10.
Xenobiotica ; 50(8): 929-938, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32065000

RESUMO

We assessed the contribution of CYP2C19 and CYP3A4 metabolic activity to the ADP-induced platelet aggregation 1h and 24h after a loading dose of 60 mg prasugrel or 180 mg ticagrelor in patients with ST-elevation myocardial infarction (STEMI). Further, we assessed the contribution of CYP2C19 polymorphisms and medication to the CYP enzymatic activity.Patients with STEMI were randomly assigned to the treatment with prasugrel (n = 51) or ticagrelor (n = 46). Metabolic activity of CYP2C19 and CYP3A4 was assessed by the rate of 5-hydroxylation and sulfoxidation of lansoprazole. Further, patients were genotyped for CYP2C19 *2 and *17 alleles.In prasugrel-treated patients, high ADP-induced platelet reactivity 1h after the loading dose positively correlated with 5OH-lansoprazole/lansoprazole ratio (r = 0.44, p = 0.002), a marker of CYP2C19 metabolic activity, and negatively with lansoprazole-sulfone/lansoprazole ratio, which reflects CYP3A4 metabolic activity (r = -0.35, p = 0.018).CYP2C19 poor metabolizers had lower 5OH-lansoprazole/lansoprazole ratio and higher lansoprazole-sulfone/lansoprazole ratio, but without any effect on the ADP-induced platelet reactivity. The treatment with amiodarone, a CYP3A4 inhibitor, influenced neither the metabolic ratios nor the ADP-induced platelet reactivity.The CYP3A4 and CYP2C19 metabolic activity is associated with ADP-induced platelet reactivity in prasugrel-treated, but not ticagrelor-treated patients with STEMI.


Assuntos
Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/metabolismo , Cloridrato de Prasugrel/farmacologia , Ticagrelor/farmacologia , Difosfato de Adenosina/metabolismo , Feminino , Humanos , Masculino , Cloridrato de Prasugrel/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Ticagrelor/uso terapêutico
11.
PLoS One ; 15(2): e0229654, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106262

RESUMO

Human hepatocytes are essential materials in pharmaceutical researches. Not only primary human hepatocytes (PHH) but also human iPS cell-derived hepatocyte-like cells (human iPS-HLCs) are expected to be applied as materials for pharmaceutical researches. To date, several culture media have been developed for culturing human hepatocytes. However, there have been no reports comparing these media to determine which is most suitable for culturing human hepatocytes. In this study, we compared five commercial media (Hepatocyte Culture Medium (HCM), HepatoZYME-SFM, Cellartis Power Primary HEP Medium, DMEM/F12, and William's E Medium (WEM)) to determine which is most suitable for culturing PHH and human iPS-HLCs. In hepatic differentiation of human iPS cells (day 14-25 of differentiation), albumin (ALB) and urea secretion abilities and CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM or WEM. During maintenance of human iPS-HLCs, ALB and urea producing abilities and CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM. Importantly, we found that human iPS-HLCs cultured in HCM were maintained for 3 weeks or more without impairment of their hepatic functions. These results suggest that it is necessary to select an optimal medium for hepatic differentiation and maintenance of human iPS-HLCs. In the case of PHH culture, there was little difference in hepatic functions among the five media. However, the CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM and WEM. In conclusion, it is important to select the optimal medium for specific application when carrying out pharmaceutical researches using human hepatocytes.


Assuntos
Técnicas de Cultura de Células/métodos , Meios de Cultura , Hepatócitos/citologia , Hepatócitos/metabolismo , Albuminas/metabolismo , Diferenciação Celular , Linhagem Celular , Células Cultivadas , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Ureia/metabolismo
12.
Biochem Pharmacol ; 171: 113725, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31758923

RESUMO

In conditions of acute and chronic inflammation hepatic detoxification capacity is severely impaired due to coordinated downregulation of drug metabolizing enzymes and transporters. Using global transcriptome analysis of liver tissue from donors with pathologically elevated C-reactive protein (CRP), we observed comparable extent of positive and negative acute phase response, where the top upregulated gene sets included immune response and defense pathways while downregulation occurred mostly in metabolic and catabolic pathways including many important drug metabolizing enzymes and transporters. We hypothesized that microRNAs (miRNA), which usually act as negative regulators of gene expression, contribute to this process. Microarray and quantitative real-time PCR analyses identified differentially expressed miRNAs in liver tissues from donors with elevated CRP, cholestasis, steatosis, or non-alcoholic steatohepatitis. Using luciferase reporter constructs harboring native and mutated 3'-untranslated gene regions, several predicted miRNA binding sites on RXRα (miR-130b-3p), CYP2C8 (miR-452-5p), CYP2C9 (miR-155-5p), CYP2C19 (miR-155-5p, miR-6807-5p), and CYP3A4 (miR-224-5p) were validated. HepaRG cells transfected with miRNA mimics showed coordinate reductions in mRNA levels and several cytochrome P450 enzyme activities particularly for miR-155-5p, miR-452-5p, and miR-6807-5p, the only miRNA that was deregulated in all four pathological conditions. Furthermore we observed strong negative correlations between liver tissue miRNA levels and hepatic CYP phenotypes. Since miR-155 is well known for its multifunctional roles in immunity, inflammation, and cancer, our data suggest that this and other miRNAs contribute to coordinated downregulation of drug metabolizing enzymes and transporters in inflammatory conditions.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Regulação para Baixo , Inflamação/genética , MicroRNAs/genética , Neoplasias/genética , Linhagem Celular Tumoral , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Inativação Metabólica , Inflamação/enzimologia , Inflamação/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Neoplasias/enzimologia , Neoplasias/metabolismo
13.
Psychiatr Genet ; 30(1): 30-33, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31842058

RESUMO

OBJECTIVE: Major depressive disorder (MDD) is a global mental health problem. As a serotonin-noradrenaline reuptake inhibitor (SNRI), the antidepressant venlafaxine is used to alleviate MDD clinically. Recent research has shown that Cytochrome P450 (CYP) enzymes affect venlafaxine efficacy by mediating its metabolism. The present study investigates genetic polymorphisms of cytochrome P450 family 2 subfamily C member 19 (CYP2C19) are associated with remission after venlafaxine treatment for MDD. METHODS: A total of 175 Han Chinese patients with depression were recruited to accept a 6-week treatment with venlafaxine. Three single-nucleotide polymorphisms of CYP2C19 were selected from dbSNP and previous literature to compare the allele and genotype frequencies between patients in remission and nonremission. Seventeen items Hamilton Depression Scale (17-HAMD) was used to access the outcomes of patients' depressive symptoms through the study. Our results denied the role of CYP2C19 polymorphisms for remission after venlafaxine treatment in MDD patients. RESULT & CONCLUSION: CYP2C19 genetic polymorphism may not have association with SNRI venlafaxine treatment remission in the Han Chinese population.


Assuntos
Citocromo P-450 CYP2C19/genética , Transtorno Depressivo Maior/genética , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Antidepressivos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Farmacológicos/sangue , China , Citocromo P-450 CYP2C19/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica , Inibidores de Captação de Serotonina/uso terapêutico , Resultado do Tratamento
15.
Heart Vessels ; 35(3): 312-322, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31549178

RESUMO

Dual antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitor is administered following percutaneous coronary intervention (PCI) with coronary stent implantation. Several studies have reported the effects of switching between P2Y12 inhibitors on platelet reactivity (P2Y12 reaction units: PRU), from acute to late phase after PCI. However, the effect of switching at very late phase is unknown. This study examined the effect on PRU in Japanese coronary heart disease patients with long-term DAPT (aspirin + clopidogrel) when switching from clopidogrel to prasugrel. Ninety-six patients were enrolled in this study. The median DAPT duration at enrollment was 1824.0 days. Twenty-three patients with PRU ≥ 208 at enrollment were randomly assigned into either continuing to receive clopidogrel (Continued Group; n = 11) or switching to prasugrel (Switched Group; n = 12). The primary endpoint was the rate of patients who achieved PRU < 208 at the end of 12 weeks of treatment, which was significantly higher in Switched Group relative to Continued Group (90.0% vs. 36.4%; P = 0.024). The secondary endpoint was the PRU at week 12 in groups subdivided according to cytochrome P450 (CYP) 2C19 genotypes. At week 12, extensive metabolizers (EM Group) had 202.3 ± 60.0 and 174.5 ± 22.3 in Continued Group and Switched Group (P = 0.591), respectively; intermediate and poor metabolizers (non-EM Group) had 229.4 ± 36.9 and 148.4 ± 48.4 in Continued Group and Switched Group (P = 0.002), respectively. The PRU for non-EM Group was significantly reduced in Switched Group. Thus, for patients with long-term DAPT (aspirin + clopidogrel) after PCI with coronary stent implantation, switching from clopidogrel to prasugrel resulted in a stable reduction in PRU, regardless of CYP2C19 polymorphism.


Assuntos
Clopidogrel/administração & dosagem , Doença da Artéria Coronariana/terapia , Citocromo P-450 CYP2C19/genética , Substituição de Medicamentos , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Cloridrato de Prasugrel/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspirina/administração & dosagem , Clopidogrel/efeitos adversos , Clopidogrel/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos/genética , Substituição de Medicamentos/efeitos adversos , Terapia Antiplaquetária Dupla , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Agregação Plaquetária/genética , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/metabolismo , Cloridrato de Prasugrel/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
16.
Xenobiotica ; 50(2): 209-222, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30902024

RESUMO

1. Meperidine is an opioid analgesic that undergoes N-demethylation to form the neurotoxic metabolite normeperidine. Previous studies indicate that meperidine N-demethylation is catalyzed by cytochrome P450 2B6 (CYP2B6), CYP3A4, and CYP2C19.2. The purpose of this study was to examine the relative P450 contributions to meperidine N-demethylation and to evaluate the effect of CYP2C19 polymorphism on normeperidine generation. Experiments were performed using recombinant P450 enzymes, selective chemical inhibitors, enzyme kinetic assays, and correlation analysis with individual CYP2C19-genotyped human liver microsomes.3. The catalytic efficiency (kcat/Km) for meperidine N-demethylation was similar between recombinant CYP2B6 and CYP2C19, but markedly lower by CYP3A4.4. In CYP2C19-genotyped human liver microsomes, normeperidine formation was significantly correlated with CYP2C19 activity (S-mephenytoin 4´-hydroxylation).5. CYP2C19 inhibitor (+)-N-3-benzylnirvanol and CYP3A inhibitor ketoconazole significantly reduced microsomal normeperidine generation by an individual donor with high CYP2C19 activity, whereas donors with lower CYP2C19 activity were sensitive to inhibition by ketoconazole but not benzylnirvanol.6. These findings demonstrate that the relative CYP3A4, CYP2B6, and CYP2C19 involvement in meperidine N-demethylation depends on the enzyme activities in individual human liver microsomal samples. CYP2C19 is likely an important contributor to normeperidine generation in individuals with high CYP2C19 activity, but additional factors influence inter-individual metabolite accumulation.


Assuntos
Inibidores da Colinesterase/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Meperidina/análogos & derivados , Citocromo P-450 CYP2C19/metabolismo , Desmetilação , Humanos , Meperidina/metabolismo , Mefenitoína
17.
Catheter Cardiovasc Interv ; 95(1): E8-E16, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30983087

RESUMO

OBJECTIVE: The aim of this study was to compare how prasugrel and clopidogrel affect platelet aggregation reactivity, cardiac enzyme release, cardiac remodeling, and the formation of in-stent thrombi after primary percutaneous coronary intervention (PCI). BACKGROUND: The advantages of using prasugrel over clopidogrel in cardiac injury following acute coronary syndrome (ACS) remain unclear. METHODS: A total of 78 ACS patients were randomly allocated into clopidogrel (300 mg loading/75 mg maintenance) or prasugrel (20 mg loading/3.75 mg maintenance) treatment groups, followed by undergoing primary PCI. Platelet reactivity and cardiac enzymes were measured before and after primary PCI. Moreover, cardiac function was measured by ultrasound echocardiography and coronary angioscopic observation was after primary PCI up to 8 months later. RESULTS: Antiplatelet reactivity in the prasugrel treatment group reached optimal levels (P2Y12 reaction units [PRU] less than 262) immediately after the administration and was maintained even at 8 months, independently of the CYP2C19 genotype. Prasugrel treatment significantly suppressed creatine kinase elevation compared to clopidogrel treatment (median value 404 IU/L to 726 IU/L vs. 189 IU/L to 1,736 IU/L, p = 0.018 for maximum values) and reduced left ventricular mass (217.2-168.8 g in prasugrel, p = 0.045; 196.9-176.4 g in clopidogrel, p = 0.061). There were no significant differences in the incidence of in-stent attached thrombi between the two groups. CONCLUSIONS: Compared to clopidogrel, prasugrel produced a stable platelet aggregation inhibitory effect in patients with ACS regardless of CYP2C19 genotype, reduced cardiac enzyme release, and prevented cardiac remodeling after ACS.


Assuntos
Síndrome Coronariana Aguda/terapia , Clopidogrel/administração & dosagem , Trombose Coronária/prevenção & controle , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Inibidores da Agregação de Plaquetas/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Cloridrato de Prasugrel/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/fisiopatologia , Idoso , Clopidogrel/efeitos adversos , Clopidogrel/sangue , Trombose Coronária/diagnóstico por imagem , Trombose Coronária/etiologia , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/sangue , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/sangue , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/sangue , Fatores de Risco , Fatores de Tempo , Tóquio , Resultado do Tratamento
18.
Cardiovasc Ther ; 2019: 3470145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772608

RESUMO

Objective: The objective of this study is to explore the relationships of the effects of CYP2C19 and PON1 Q192R polymorphism on the activity of clopidogrel and the risk of high platelet responsiveness (HPR) by thrombelastography in patients with acute coronary syndrome (ACS). Methods: 459 ACS patients with aspirin and clopidogrel were enrolled in this observational case control study from July 13, 2015, to November 11, 2017. The patients with <30% platelet inhibition were defined as HPR group, while the others were defined as normal platelet responsiveness (NPR) group. The genotypes distribution between the groups was assessed, and the clinical impact of genetic variants was investigated by comparing the relationship between the risk of HPR and genotypes including CYP2C19⁎2, CYP2C19⁎3, CYP2C19⁎17, ABCB1, and PON1. Results: Compared with CYP2C19⁎1/⁎1 wild type carriers, CYP2C19⁎2 and ⁎3 carriers showed a significant association with the lower platelet inhibition (P=0.048). The platelet inhibition in carriers of at least one CYP2C19 loss-of-function (LOF) alleles was obviously higher than noncarriers (P=0.031). The platelet inhibition of PON1 192R carriers was lower than PON1 192Q carriers (P=0.044). Patients with the CYP2C19⁎2 and ⁎3 alleles had a greater risk of HPR than CYP2C19 wild type carriers (adjusted P=0.018 and adjusted P=0.005). At least one PON1 192R carrier predicted a significantly higher risk of HPR than PON1 192Q carriers (adjusted P=0.021). Individual CYP2C19⁎17 and ABCB1 variants did not differ significantly between the two groups. Conclusions: CYP2C19 and PON1 Q192R variants influence ADP-induced platelet inhibition by thrombelastography (TEG) in ACS patients with clopidogrel. In addition, both LOF CYP2C19 and PON1 192R variants are independent risk factors of HPR, which is measured by the relative platelet inhibition.


Assuntos
Síndrome Coronariana Aguda/terapia , Arildialquilfosfatase/genética , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Tromboelastografia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Idoso , Arildialquilfosfatase/metabolismo , Aspirina/uso terapêutico , Estudos de Casos e Controles , China , Clopidogrel/efeitos adversos , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos/genética , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Agregação Plaquetária/genética , Inibidores da Agregação de Plaquetas/efeitos adversos , Valor Preditivo dos Testes , Fatores de Risco , Resultado do Tratamento
19.
Biochem J ; 476(23): 3661-3685, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31750875

RESUMO

In this study, we investigate the ability of ethanol-inducible CYP2E1 to interact with other cytochrome P450 species and affect the metabolism of their substrates. As a model system, we used CYP2E1-enriched human liver microsomes (HLM) obtained by the incorporation of purified CYP2E1. Using a technique based on homo-FRET in oligomers of CYP2E1 labeled with BODIPY 577/618 maleimide we demonstrated that the interactions of CYP2E1 with HLM result in the formation of its mixed oligomers with other P450 species present in the microsomal membrane. Incorporation of CYP2E1 results in a multifold increase in the rate of metabolism of CYP2E1-specific substrates p-Nitrophenol and Chlorzaxozone. The rate of their oxidation remains proportional to the amount of incorporated CYP2E1 up to the content of 0.3-0.4 nmol/mg protein (or ∼50% CYP2E1 in the P450 pool). The incorporated CYP2E1 becomes a fully functional member of the P450 ensemble and do not exhibit any detectable functional differences with the endogenous CYP2E1. Enrichment of HLM with CYP2E1 results in pronounced changes in the metabolism of 7-ethoxy-4-cyanocoumarin (CEC), the substrate of CYP2C19 and CYP1A2 suggesting an increase in the involvement of the latter in its metabolism. This effect goes together with an augmentation of the rate of dealkylation of CYP1A2-specific substrate 7-ethoxyresorufin. Furthermore, probing the interactions of CYP2E1 with model microsomes containing individual P450 enzymes we found that CYP2E1 efficiently interacts with CYP1A2, but lacks any ability to form complexes with CYP2C19. This finding goes inline with CYP2E1-induced redirection of the main route of CEC metabolism from CYP2C19 to CYP1A2.


Assuntos
Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Microssomos Hepáticos/metabolismo , Membrana Celular/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Remoção de Radical Alquila , Escherichia coli/metabolismo , Feminino , Humanos , Fígado/citologia , Masculino , Espectrometria de Massas , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Oxazinas/metabolismo , Oxirredução , Espectrometria de Fluorescência , Especificidade por Substrato , Doadores de Tecidos
20.
Eur J Pharm Sci ; 139: 105061, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31479720

RESUMO

Understanding the influence of ethnicity on drug exposure is key to patient safety and could minimize repetitive clinical studies. This analysis aimed to evaluate the ability of physiologically-based pharmacokinetic modelling to predict exposure of CYP2C19 substrates (lansoprazole, (es)citalopram, voriconazole) across Caucasian and East Asian populations. CYP2C19 abundance levels in Japanese and Chinese populations have been re-assessed based on clinical evidence. Model performance in each population was evaluated by predicted-over-observed AUC ratios and comparison of observed data with simulated plasma concentration profiles. Exposures in 84.4% (76 out of 90) of the clinical studies were predicted within 1.5-fold of observed values. The reported concentration-time profiles were well-captured within the 90% prediction intervals. With specified CYP2C19 phenotype, PBPK modelling is capable to predict systemic exposure of drugs largely metabolized by CYP2C19 in different ethnic populations. This study demonstrated PBPK modelling can be applied to assess genotype-dependent exposure difference across ethnicities.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Grupo com Ancestrais do Continente Europeu/genética , Lansoprazol/farmacocinética , Modelos Biológicos , Voriconazol/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Feminino , Humanos , Masculino , Polimorfismo Genético
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