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1.
Sci Rep ; 8(1): 7342, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743634

RESUMO

About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as ΔDAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to ΔDAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response.


Assuntos
Artrite Reumatoide/genética , Metotrexato/uso terapêutico , Adulto , Idoso , Alelos , Antirreumáticos/uso terapêutico , Biomarcadores Farmacológicos/sangue , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/fisiologia , Frequência do Gene/genética , Humanos , Masculino , Metotrexato/farmacologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Índice de Gravidade de Doença , Resultado do Tratamento
2.
PLoS One ; 13(5): e0196793, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29734345

RESUMO

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Marcadores Genéticos/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
3.
Pharmacogenomics J ; 18(4): 539-545, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29520081

RESUMO

Variability of response to treatment hinders successful management of rheumatoid arthritis (RA). Consequently, a clinical pharmacogenetics model for predicting response to methotrexate (CP-MTX) has been previously proposed that includes four clinical variables (disease activity, sex, the presence of rheumatoid factor and smoking status) and four SNPs (rs2236225, rs17602729, rs1127354, and rs2372536) in genes of the folate pathway. It showed good performance, but failed to attract attention, likely, in relation with lack of clear clinical benefit. Here, we have revised the value of the CP-MTX model directly addressing its clinical benefit by focusing on the expected benefit-cost of the predictions. In addition, our study included a much larger number of RA patients (n = 720) in MTX monotherapy than previous studies. Benefit of CP-MTX prediction was defined as the patients that would have received combination therapy as first treatment because they were correctly predicted as non-responders to MTX monotherapy. In contrast, cost of CP-MTX prediction was defined as the responder patients that were wrongly predicted as non-responders. Application of CP-MTX predictions to our patients showed a good benefit-cost relationship, with half of the 66.7% non-responders to MTX monotherapy rightly directed to alternative treatments (a benefit of 33.3%) at the cost of 8.5% wrongly predicted non-responders. These benefits-costs were consistent with reanalysis of the previously published studies. Therefore, predictions of CP-MTX showed a good benefit-cost relationship for informing MTX prescription.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Análise Custo-Benefício , Metotrexato/administração & dosagem , Farmacogenética , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/economia , Artrite Reumatoide/epidemiologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Metotrexato/economia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Resultado do Tratamento
4.
Basic Clin Pharmacol Toxicol ; 122(5): 501-511, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29136336

RESUMO

Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5-hydroxytryptamine receptor 2A (HTR2A) and 5-hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half-life (T1/2 ). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2 . No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate-lowering effect, directly related to maximum concentration (Cmax ) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals.


Assuntos
Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C19/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Inibidores de Captação de Serotonina/farmacocinética , Sertralina/farmacocinética , Administração Oral , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Feminino , Genótipo , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Medição de Risco , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/efeitos adversos , Sertralina/administração & dosagem , Sertralina/efeitos adversos , Adulto Jovem
5.
PLoS One ; 12(7): e0180927, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28704535

RESUMO

INTRODUCTION: Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. METHODS: NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. RESULTS: Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). CONCLUSION: The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.


Assuntos
Hepatite C Crônica/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , 2',5'-Oligoadenilato Sintetase/genética , Adulto , Idoso , Aspartato Aminotransferases/sangue , Endorribonucleases/genética , Feminino , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Humanos , Interferons , Janus Quinase 1/genética , Masculino , Pessoa de Meia-Idade , Proteína 1 Supressora da Sinalização de Citocina/genética , TYK2 Quinase/genética
6.
Liver Int ; 37(8): 1148-1156, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28027429

RESUMO

BACKGROUND & AIMS: Chronic hepatitis C (CHC) is a major cause of cirrhosis and hepatocellular carcinoma and angiogenesis is closely related to the pathogenesis and progression of different chronic liver diseases (CLD). Thus, the intrahepatic expression of angiopoietins 1 and 2 (Ang1 and Ang2), as relevant mediators of pathological angiogenesis in several CLD, was investigated. In addition, the differential influence of structural and non-structural genomic regions of HCV on the expression of angiopoietins and the possible signalling involved were studied. METHODS: Ang1 and Ang2 expression was evaluated by western blotting and enzyme-linked immunosorbent assay (ELISA) in liver homogenates of CHC patients (n=47) and uninfected subjects (n=8). Their association with disease progression (according to METAVIR classification) was assessed by Spearman's correlation. Statistical differences among the expression of angiopoietins at different CHC stages were calculated by Mann-Whitney U-test. Finally, the in vitro expression of Angiopoietins in HCV replicons (complete or non-structural subgenomic) and the main signalling pathways involved were also examined. RESULTS: Ang2 levels were significantly higher in the liver of CHC patients compared to controls and significantly correlated with inflammation and fibrosis. Accordingly, an increased expression of Ang2 was found in all HCV replicons tested. Interestingly, the inhibition of MEK and PI3K signalling pathways exerted differential effects on Ang2 expression concerning to the genomic region of HCV. CONCLUSIONS: Hepatitis C virus induces Ang2 expression in hepatocytes through different signalling routes which may lead to the disregulation of vascular homeostasis in the liver. Thus, pharmacologic intervention on Ang2 signalling might constitute an important therapeutic tool.


Assuntos
Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Hepacivirus/fisiologia , Hepatite C Crônica/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular , Progressão da Doença , Feminino , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Replicon , Transdução de Sinais , Proteínas Virais/metabolismo
7.
World J Gastroenterol ; 22(44): 9744-9751, 2016 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-27956798

RESUMO

AIM: To evaluate the efficacy of peripheral blood concentrations of angiopoietins (Ang) as cirrhosis biomarkers of chronic hepatitis C (CHC). METHODS: Ang1 and Ang2 serum levels were measured by enzyme-linked immunosorbent assays (ELISA) in samples from 179 cirrhotic and non-cirrhotic CHC patients, classified according to the METAVIR system. Groups were compared by non-parametric Mann-Whitney U test. Subsequently, the association of peripheral concentrations of angiopoietins with the stage of fibrosis was analyzed using Spearman correlation test. Finally, the accuracy, sensitivity and specificity of circulating angiopoietins for cirrhosis diagnosis were determined by the study of the respective area under the curve of receiver operator characteristics (AUC-ROC). RESULTS: Peripheral blood concentrations of Ang1 and Ang2 in CHC patients were significantly related to fibrosis. While Ang1 was decreased in cirrhotic subjects compared to non-cirrhotic (P < 0.0001), Ang2 was significantly increased as CHC progressed to the end stage of liver disease (P < 0.0001). Consequently, Ang2/Ang1 ratio was notably amplified and significantly correlated with fibrosis (P < 0.0001). Interestingly, the individual performance of each angiopoietin for the diagnosis of cirrhosis reached notable AUC-ROC values (above 0.7, both), but the Ang2/Ang1 ratio was much better (AUC-ROC = 0.810) and displayed outstanding values of sensitivity (71%), specificity (84%) and accuracy (82.1%) at the optimal cut-off (10.33). Furthermore, Ang2/Ang1 ratio improved the performance of many other previously described biomarkers or scores of liver cirrhosis in CHC. CONCLUSION: Ang2/Ang1 ratio might constitute a useful tool for monitoring the progression of chronic liver disease towards cirrhosis and play an important role as therapeutic target.


Assuntos
Angiopoietina-1/sangue , Angiopoietina-2/sangue , Hepatite C Crônica/complicações , Cirrose Hepática/sangue , Adulto , Idoso , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Hepatite C Crônica/diagnóstico , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Adulto Jovem
9.
PLoS One ; 11(4): e0153140, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27050469

RESUMO

Response to treatment of rheumatoid arthritis shows large inter-individual variability. This heterogeneity is observed with all the anti-rheumatic drugs, including the commonly used TNF inhibitors. It seems that drug-specific and target-specific factors lead individual patients to respond or not to a given drug, although this point has been challenged. The search of biomarkers distinguishing responders from non-responders has included shotgun proteomics of serum, as a previous study of response to infliximab, an anti-TNF antibody. Here, we have used the same study design and technology to search biomarkers of response to a different anti-TNF antibody, adalimumab, and we have compared the results obtained for the two anti-TNF drugs. Search of biomarkers of response to adalimumab included depletion of the most abundant serum proteins, 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) labeling, two-dimensional liquid chromatography fractionation and relative quantification with a hybrid Orbitrap mass spectrometer. With this approach, 264 proteins were identified in all the samples with at least 2 peptides and 95% confidence. Nine proteins showed differences between non-responders and responders (P < 0.05), representing putative biomarkers of response to adalimumab. These results were compared with the previous study of infliximab. Surprisingly, the non-responder/responder differences in the two studies were not correlated (rs = 0.07; P = 0.40). This overall independence with all the proteins showed two identifiable components. On one side, the putative biomarkers of response to either adalimumab or infliximab, which were not shared and showed an inverse correlation (rs = -0.69; P = 0.0023). On the other, eight proteins showing significant non-responder/responder differences in the analysis combining data of response to the two drugs. These results identify new putative biomarkers of response to treatment of rheumatoid arthritis and indicate that they are notably drug-specific.


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Proteínas Sanguíneas/metabolismo , Infliximab/uso terapêutico , Adulto , Idoso , Artrite Reumatoide/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
J Clin Microbiol ; 53(1): 219-26, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25378574

RESUMO

Hepatitis C virus (HCV) is classified into seven major genotypes and 67 subtypes. Recent studies have shown that in HCV genotype 1-infected patients, response rates to regimens containing direct-acting antivirals (DAAs) are subtype dependent. Currently available genotyping methods have limited subtyping accuracy. We have evaluated the performance of a deep-sequencing-based HCV subtyping assay, developed for the 454/GS-Junior platform, in comparison with those of two commercial assays (Versant HCV genotype 2.0 and Abbott Real-time HCV Genotype II) and using direct NS5B sequencing as a gold standard (direct sequencing), in 114 clinical specimens previously tested by first-generation hybridization assay (82 genotype 1 and 32 with uninterpretable results). Phylogenetic analysis of deep-sequencing reads matched subtype 1 calling by population Sanger sequencing (69% 1b, 31% 1a) in 81 specimens and identified a mixed-subtype infection (1b/3a/1a) in one sample. Similarly, among the 32 previously indeterminate specimens, identical genotype and subtype results were obtained by direct and deep sequencing in all but four samples with dual infection. In contrast, both Versant HCV Genotype 2.0 and Abbott Real-time HCV Genotype II failed subtype 1 calling in 13 (16%) samples each and were unable to identify the HCV genotype and/or subtype in more than half of the non-genotype 1 samples. We concluded that deep sequencing is more efficient for HCV subtyping than currently available methods and allows qualitative identification of mixed infections and may be more helpful with respect to informing treatment strategies with new DAA-containing regimens across all HCV subtypes.


Assuntos
Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Filogenia , Proteínas não Estruturais Virais/genética , Técnicas de Genotipagem , Hepatite C/diagnóstico , Humanos , Kit de Reagentes para Diagnóstico
11.
Int Clin Psychopharmacol ; 30(2): 82-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25025989

RESUMO

Quetiapine is an atypical antipsychotic used for treatment of schizophrenia. Variability in response to this drug may be associated with pharmacogenetics. The aim of this study was to identify genetic markers related to the pharmacokinetics, pharmacodynamics, and adverse effects of quetiapine. The study population comprised 79 healthy volunteers from two bioequivalence trials who were genotyped to identify polymorphisms in genes encoding enzymes, receptors, and transporters. Quetiapine plasma levels were quantified using high-performance liquid chromatography/mass spectrometry. Prolactin plasma levels were detected by indirect chemiluminescence. Possible adverse effects were recorded throughout the study. Factors with P value of 0.1 or less in the univariate analysis were included in a multiple regression analysis (logistic regression for adverse reactions). The area under the curve and clearance of quetiapine were affected by polymorphisms in CYP1A2 and DRD3, respectively. Men had a lower quetiapine area under the curve compared with women. Prolactin iC(max) was higher in volunteers harboring polymorphisms in CYP2C19 and AGT. An association was detected between polymorphisms in CYP1A1 and CYP2C9 and somnolence. Several polymorphisms are responsible for differences in the pharmacokinetics, pharmacodynamics, and safety of quetiapine in healthy individuals.


Assuntos
Angiotensinogênio/genética , Sistema Enzimático do Citocromo P-450/genética , Dibenzotiazepinas/efeitos adversos , Dibenzotiazepinas/farmacocinética , Receptores de Dopamina D3/genética , Adolescente , Adulto , Antipsicóticos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Dibenzotiazepinas/sangue , Feminino , Estudos de Associação Genética , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Prolactina/sangue , Fumarato de Quetiapina , Caracteres Sexuais , Adulto Jovem
12.
Basic Clin Pharmacol Toxicol ; 116(2): 124-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24975366

RESUMO

Within-subject coefficient of variation (CVw ) plays a decisive role in the determination of sample size in bioequivalence clinical trials. Highly variable drugs may require the participation of a large number of subjects. The aim of this study was to investigate whether gender and polymorphisms in CYP2D6 affect the CVw of risperidone. Two single-dose, two-period crossover studies of risperidone (n = 70) were reanalysed to calculate CVw for AUCt and Cmax . Subjects were classified into four different CYP2D6 phenotype groups [poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM)]. The effect of gender was evaluated in EM and IM. CVw was lower in PM (13.3% for AUCt and 10.9% for Cmax ) and UM (17.4% and 8.7%) than in EM (28.7% and 34.7%) and IM (33.2% and 27.3%). Variability was slightly lower in women (27.9% for AUCt and 25.7% for Cmax ) than in men (33.3% and 37.2%, respectively). Genetic polymorphisms affect within-subject variability more than gender and could considerably affect sample size calculation. Therefore, subjects participating in bioequivalence trials should be genotyped.


Assuntos
Antipsicóticos/farmacocinética , Citocromo P-450 CYP2D6/genética , Polimorfismo Genético , Risperidona/farmacocinética , Adulto , Área Sob a Curva , Estudos Cross-Over , Feminino , Genótipo , Humanos , Masculino , Fatores Sexuais , Adulto Jovem
13.
PLoS One ; 9(10): e106958, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25302785

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease (CLD) and is frequently linked to intrahepatic microvascular disorders. Activation of hepatic stellate cells (HSC) is a central event in liver damage, due to their contribution to hepatic renewal and to the development of fibrosis and hepatocarcinoma. During the progression of CLDs, HSC attempt to restore injured tissue by stimulating repair processes, such as fibrosis and angiogenesis. Because HSC express the key vascular receptor Tie2, among other angiogenic receptors and mediators, we analyzed its involvement in the development of CLD. METHODS: Tie2 expression was monitored in HSC cultures that were exposed to media from HCV-expressing cells (replicons). The effects of Tie2 blockade on HSC activation by either neutralizing antibody or specific signaling inhibitors were also examined. RESULTS: Media from HCV-replicons enhanced HSC activation and invasion and upregulated Tie2 expression. Notably, the blockade of Tie2 receptor (by a specific neutralizing antibody) or signaling (by selective AKT and MAPK inhibitors) significantly reduced alpha-smooth muscle actin (α-SMA) expression and the invasive potential of HCV-conditioned HSC. CONCLUSIONS: These findings ascribe a novel profibrogenic function to Tie2 receptor in the progression of chronic hepatitis C, highlighting the significance of its dysregulation in the evolution of CLDs and its potential as a novel therapeutic target.


Assuntos
Hepacivirus/fisiologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/virologia , Hepatite C Crônica/patologia , Receptor TIE-2/antagonistas & inibidores , Anticorpos Neutralizantes/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Estreladas do Fígado/enzimologia , Células Estreladas do Fígado/patologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/enzimologia , Humanos , Fígado/patologia , Fígado/virologia , Inibidores de Proteínas Quinases/farmacologia , Receptor TIE-2/análise
14.
Hum Psychopharmacol ; 29(5): 459-69, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25042870

RESUMO

OBJECTIVE: To identify genetic markers capable of predicting the pharmacokinetics, pharmacodynamics, and adverse effects of risperidone. METHODS: Genotyping was performed in 70 healthy volunteers receiving a single 1mg oral dose of risperidone. Risperidone and hydroxyrisperidone plasma levels were measured using high-performance liquid chromatography combined with tandem mass spectrometry.Prolactin concentration was quantified by direct chemiluminescence. RESULTS: Poor CYP2D6 metabolizers showed higher risperidone Cmax, area under the curve (AUC), and t1/2, as well as lower clearance. They also showed lower Cmax and AUC and higher t1/2 for hydroxyrisperidone. Furthermore, individuals with a mutant VKORC1 genotype had a lower risperidone AUC and t1/2 and higher clearance. The hydroxyrisperidone AUC was lower in individuals with the COMT mutant genotype. Risperidone increased prolactin levels (iAUC and iCmax), which were higher in women than in men. The most frequent reactions were somnolence (47.1%), headache (21.4%), and dizziness (17.1%). Women had neurological effects and headache more frequently than men. The incidence of headache was associated with polymorphisms in the AGTR1 and NAT2; neurological effects were associated with CYP2C19. CONCLUSIONS: Differences in the pharmacokinetics of risperidone are due to polymorphisms in CYP2D6, COMT, and VKORC1. Differences in adverse reactions can be explained by gender and polymorphisms in CYP2C19, AGTR1, and NAT2.


Assuntos
Antipsicóticos/farmacologia , Polimorfismo Genético , Risperidona/farmacocinética , Adolescente , Adulto , Antipsicóticos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Biomarcadores Farmacológicos , Catecol O-Metiltransferase/genética , Estudos Cross-Over , Citocromo P-450 CYP2D6/genética , Feminino , Humanos , Masculino , Prolactina/sangue , Receptor Tipo 1 de Angiotensina/genética , Risperidona/efeitos adversos , Fatores Sexuais , Vitamina K Epóxido Redutases/genética , Adulto Jovem
15.
PLoS One ; 9(6): e99426, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24927414

RESUMO

The aim of this study was to analyse the distribution of KIR haplotypes and the KIR2DL2/3 alleles in chronic HCV-infected patients in order to establish the influence on the response to pegylated interferon plus ribavirin classical treatment. The alleles study of previously associated KIR2DL2/3 showed that KIR2DL2*001 was more frequent in non-SVR (NSVR) (42.2% vs. 27.5%, p<0.05) and KIR2DL3*001 was associated with sustained viral response (SVR) (41.6% vs. 61.2%, p<0.005). The KIR2DL3*001-HLA-C1 association was also significant (24.5% vs. 45.7%, p<0.001). From the frequencies of KIR obtained, 35 genotypes were assigned on the basis of previous studies. The centromeric A/A genotype was more frequent in SVR (44.1% vs. 34.5%, p<0.005) and the centromeric B/B genotype was found to be significantly more frequent in NSVR (20.9% vs. 11.2%, p<0.001). The logic regression model showed the importance of KIR genes in predicting the response to combined treatment, since the positive predictive value (PPV) was improved (from 55.9% to 75.3%) when the analysis of KIR was included in addition to the IFNL3 rs12979860 polymorphism. The study of KIR receptors may be a powerful tool for predicting the combined treatment response in patients with chronic HCV infection in association with the determination of IFNL3 polymorphism.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Ribavirina/uso terapêutico , Quimioterapia Combinada , Genótipo , Haplótipos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Humanos , Interferons , Interleucinas/genética , Células Matadoras Naturais/imunologia , Modelos Logísticos , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento
16.
Pharmacogenomics ; 14(10): 1203-14, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23859574

RESUMO

AIM: Clinical trials with healthy volunteers are a useful model for evaluating safety and tolerability, without the interference of concomitant diseases and drugs. The present study aims to improve our understanding of antipsychotic-related adverse reactions (ARs) and their possible association with common genetic variants of pharmacodynamic proteins such as neurotransmitter receptors/transporters. MATERIALS & METHODS: A total of eight polymorphisms located in seven pharmacodynamic-related genes (SCL6A4, MDR1, 5HT2A, DRD2, DRD3, COMT and GRIN2B) were genotyped in a cohort of 211 healthy volunteers who received a single dose of risperidone (1 mg), olanzapine (5 mg) or quetiapine (25 mg). RESULTS: Interestingly, a significant association was found between the incidence of neurological ARs and specific polymorphisms in key genes (DRD2 and SCL6A4). CONCLUSION: Genetic variants in pharmacodynamic genes could represent valuable markers of AR risk and antipsychotic safety. Original submitted 7 February 2013; Revision submitted 3 June 2013.


Assuntos
Antipsicóticos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Proteínas do Tecido Nervoso/genética , Receptores de Dopamina D2/genética , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacocinética , Biomarcadores Farmacológicos , Dibenzotiazepinas/administração & dosagem , Dibenzotiazepinas/efeitos adversos , Dibenzotiazepinas/farmacocinética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Proteína Huntingtina , Masculino , Olanzapina , Fumarato de Quetiapina , Risperidona/administração & dosagem , Risperidona/efeitos adversos , Risperidona/farmacocinética
17.
PLoS One ; 8(6): e66143, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23823085

RESUMO

AIMS: Accurate liver fibrosis staging is crucial for the management of chronic hepatitis C (CHC). The invasiveness and cost burden of liver biopsy have driven the search for new noninvasive biomarkers of fibrosis. Based on the link between serum angiopoietin-1 and 2 levels and CHC progression, we aimed to determine the value of these angiogenic factors as noninvasive biomarkers of liver fibrosis. METHODS: Serum levels of angiopoietin-1 and -2 were measured by ELISA in 108 CHC patients who underwent pretreatment liver biopsy. The correlation between angiopoietins and clinical and demographic variables with liver fibrosis was analyzed by univariate regression. Significant factors were then subjected to multivariate analysis, from which we constructed a novel noninvasive liver fibrosis index (AngioScore), whose performance was validated in an independent series of 71 CHC patients. The accuracy of this model was compared with other documented fibrosis algorithms by De Long test. RESULTS: Angiopoietins correlated significantly with hepatic fibrosis; however, only angiopoietin-2 was retained in the final model, which also included age, platelets, AST, INR, and GGT. The model was validated and behaved considerably better than other fibrosis indices in discriminating all, significant, moderate and severe liver fibrosis (0.886, 0.920, 0.923). Using clinically relevant cutoffs, we classified CHC patients by discarding significant fibrosis and diagnosing moderate and severe fibrosis with greater accuracy, sensitivity, and specificity. CONCLUSIONS: Our novel noninvasive liver fibrosis model, based on serum angiopoietin-2 levels, outperforms other indices and should help substantially in managing CHC and monitoring long-term follow-up prognosis.


Assuntos
Angiopoietina-2/sangue , Hepatite C Crônica/sangue , Cirrose Hepática/patologia , Neovascularização Patológica , Adulto , Idoso , Angiopoietina-1/sangue , Biópsia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Hepatite C Crônica/complicações , Humanos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade
18.
Hum Psychopharmacol ; 28(3): 205-14, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23559402

RESUMO

OBJECTIVE: The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug-metabolizing enzymes, transporters, or receptors. The aim of this study was to identify genetic markers predictive of pharmacokinetics, pharmacodynamics, and adverse effects of olanzapine. METHODS: Sixty-three healthy volunteers receiving a single 5-mg oral dose of olanzapine were genotyped for 39 genetic variants that could be related to the response to olanzapine. All genetic variants were analyzed by PharmaChip, but DRD2 Taq1A polymorphism was determined by real-time polymerase chain reaction. Olanzapine was measured using high-performance liquid chromatography combined with tandem mass spectrometry. The relationship of gender and polymorphisms with olanzapine pharmacokinetics, the change in prolactin levels, and the incidence of adverse effects were evaluated by multiple regression analysis. RESULTS: The pharmacokinetics of olanzapine was influenced by polymorphisms in CYP3A5, GSTM3, and GRIN2B. Prolactin levels were affected by gender and polymorphisms in DRD2 and 5-HTR2A. Polymorphisms in CYP2C9, TPMT, UGT1A1, MDR1, and 5-HTR2A were related to some adverse effects of olanzapine. CONCLUSIONS: Several polymorphisms can explain differences in the pharmacokinetics, pharmacodynamics, and safety of olanzapine in healthy subjects. Whether these genetic factors influence the risk of therapeutic failure or tolerability in patients remains to be established.


Assuntos
Antipsicóticos/farmacocinética , Benzodiazepinas/farmacocinética , Polimorfismo Genético , Prolactina/sangue , Adulto , Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Estudos Cross-Over , Feminino , Variação Genética , Humanos , Masculino , Olanzapina , Análise de Sequência com Séries de Oligonucleotídeos , Farmacogenética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Regressão , Fatores Sexuais , Espectrometria de Massas em Tandem , Adulto Jovem
19.
Liver Int ; 33(6): 864-70, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23419030

RESUMO

BACKGROUND: Monocytes are essential precursors of antigen-presenting cells, such as macrophages and dendritic cells, and contribute to the pathogenesis of chronic inflammatory diseases and cancer. AIMS: As Tie2-expressing monocytes (TEMs) are increased in the peripheral blood of patients with chronic hepatitis C (CHC), we aimed to examine the expression of Tie2 and angiopoietins (Ang1 and Ang2) during monocyte differentiation and maturation in CHC. METHODS: The expression of Tie2, CD11b, CD80, CD83, CD86 and MHC-II was measured by flow cytometry in peripheral blood monocytes and monocytes-derived cells (Mo-DCs) from nine healthy subjects and eight CHC patients whose HCV infection was unresolved after combination therapy. Ang1 and Ang2 levels were measured in cellular supernatants by ELISA. RESULTS: Mo-DCs from CHC patients expressed differential patterns of maturation markers compared with controls--primarily with regard to CD80. Tie2 was downregulated during monocyte differentiation in controls and CHC patients, whereas Ang1 expression was constant. However, Ang2 levels fell significantly during the differentiation of control monocytes, in contrast with those from CHC patients in whom Ang2 expression remained stable throughout differentiation. CONCLUSIONS: Altered expression of the Ang/Tie2 system in monocytes and Mo-DCs from CHC patients might account for the inflammatory and angiogenic disorders that are related to CHC. An increased understanding of Ang/Tie2 system regulation might be helpful in designing strategies to prevent CHC progression.


Assuntos
Angiopoietina-2/metabolismo , Diferenciação Celular , Células Dendríticas/metabolismo , Hepatite C Crônica/metabolismo , Monócitos/metabolismo , Adulto , Idoso , Angiopoietina-1/metabolismo , Antivirais/uso terapêutico , Biomarcadores/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/virologia , Receptor TIE-2/metabolismo
20.
Drug Metab Dispos ; 41(1): 224-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23118328

RESUMO

Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan C(max) than men (590.5 ± 75.8 ng/ml versus 282.1 ± 30.8 ng/ml; P ≤ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 ± 0.4 hours) than in volunteers with the wild-type genotype (2.3 ± 0.1 hours) (P ≤ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 ± 0.57 l/h·kg) than those with the wild-type genotype (0.48 ± 0.72 l/h·kg; P ≤ 0.01) and carriers of the *3 allele (0.35 ± 0.49 l/h·kg; P ≤ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Polimorfismo Genético , Fatores Sexuais , Alelos , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Feminino , Meia-Vida , Humanos , Masculino , Valores de Referência
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