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1.
Artigo em Inglês | MEDLINE | ID: mdl-34598085

RESUMO

Direct oral anticoagulants are widely used to treat and prevent thromboembolic disorders. With rising clinical application, monitoring concentrations of direct oral anticoagulants are necessary in certain clinical conditions. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of dabigatran etexilate, dabigatran, rivaroxaban, edoxaban, and apixaban, in human plasma. Protein precipitation with methanol was performed for sample preparation. The direct oral anticoagulants and internal standards were separated under gradient conditions using a C18 column, at an analytical run time of 8 min. The mobile phase was composed of 0.1% (v/v) formic acid in water (solvent A) and 0.1% (v/v) formic acid in acetonitrile (solvent B) at a flow rate of 0.3 mL/min. Mass detection was performed in multiple reaction monitoring using positive ionization mode. The method was validated over a range of 1.0-500 ng/mL for dabigatran etexilate, 0.1-500 ng/mL for dabigatran, and 0.5-500 ng/mL for edoxaban, rivaroxaban, and apixaban. The method detection limits of five analytes were in the range of 0.05-0.5 ng/mL. The lower limits of quantification of five analytes ranged from 0.1 to 1 ng/mL. The linearity (r2 values) was higher than 0.997. The accuracy of the low, medium, and high quality control samples were between 85.9 and 114%, and intra- and inter-day precision were below 9.47%. This validated method was successfully used to determine the plasma concentrations of rivaroxaban in 32 patients, and of dabigatran etexilate and dabigatran in 1 patient.

2.
Expert Opin Drug Saf ; : 1-7, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581647

RESUMO

Objectives:Real world studies have started to emerged on occurrence of venous thromboembolism (VTE) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but still deserve constant surveillance and evaluation. This study was to analyze this association. Methods: Adverse event cases were acquired from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database betweenJanuary 1st 2015 and December 31st 2020.Signals indicating association between CDK 4/6 inhibitors and VTE were identified by reporting odds ratio (ROR). Results: CDK 4/6 inhibitors had a total of 631 reports of VTE (ROR 1.44, 95% CI 1.33-1.55) compared with non-CDK 4/6 inhibitors. Palbociclib (ROR 1.42, 95% CI 1.09-1.88) demonstratedthe highest number of VTE reports, followed by ribociclib (ROR 1.41, 95% CI 1.29-1.54) and abemaciclib (ROR 0.92, 95% CI 0.72-1.17). Conclusions:Although it is not able to confirm the casual relationship between VTE and CDK4/6 inhibitors, this study suggested signal of VTE reporting in patients receiving CDK4/6 inhibitors, which is likely to reflect a potential association. The results may enhance physicians' awareness of the potential side effect of VTE associated with CDK 4/6 inhibitors. An early recognition of VTE signs/symptoms could decrease the morbidity and severity of such adverse events.

3.
Front Immunol ; 12: 611711, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763062

RESUMO

Background and Aims: There is a controversy regarding whether fingolimod is associated with an increased risk of infection in patients with multiple sclerosis (MS). We performed a systematic review and meta-analysis of data from randomized controlled trials (RCTs) to determine the risk of infection in these patients. Methods: We systematically searched PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov from inception to April 8, 2020, to identify RCTs that reported the occurrence of infection in patients with MS treated with fingolimod. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated using the random-effects model. Results: Twelve RCTs including 8,448 patients were eligible. Compared with the control (placebo and other active treatments), fingolimod significantly increased the risk of infection (RR, 1.16; 95% CI, 1.07-1.27; I 2, 81%), regardless of whether the infection was a general infection (RR, 1.14; 95% CI, 1.05-1.25; I 2, 78%), or a serious infection (RR, 1.49; 95% CI, 1.06-2.10; I 2, 0%). Analyses of subgroups found that fingolimod significantly increased the risk of lower respiratory infection (RR, 1.48; 95% CI, 1.19-1.85; I 2, 0%) and herpes virus infection (RR, 1.34; 95% CI, 1.01-1.78; I 2, 9%). There appears to be no dose-dependent increase in the risk of infection associated with fingolimod (0.5 mg: RR, 1.15; 95% CI, 1.07-1.25; I 2, 91%; 1.25 mg: RR, 1.11; 95% CI, 0.97-1.28; I 2, 81%; Pinteraction = 0.66). Conclusions: Compared with a placebo and other active treatments, fingolimod was associated with a 16% increase in the risk of infection, especially lower respiratory infection and herpes virus infection. The risk of infection associated with fingolimod might not be dose related.


Assuntos
Cloridrato de Fingolimode/efeitos adversos , Imunossupressores/efeitos adversos , Infecções/epidemiologia , Infecções/etiologia , Esclerose Múltipla/complicações , Esclerose Múltipla/epidemiologia , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/uso terapêutico , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Incidência , Infecções/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Razão de Chances , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco
4.
Gene ; 771: 145359, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33333223

RESUMO

PURPOSE: Drug-resistant epilepsy is a problem worldwide. Xenobiotic receptors may play a significant role in the establishment of resistance to antiepileptic agents. Previous studies have confirmed that the metabolism and efficacy of carbamazepine (CBZ) can be influenced by xenobiotic receptors, especially pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AHR). Therefore, this study intends to elucidate the pharmacogenomic associations of polymorphisms of these xenobiotic receptors with the CBZ response in epilepsy patients, and these genetic data may be useful for the treatment of clinical prophylaxis and individualized treatment of intractable epilepsy. METHODS: Adult patients with epilepsy who were on CBZ-based monotherapy and combination therapy (n = 257) were genotyped, and the patients were divided into drug-responsive and drug-resistant groups according to the International League Against Epilepsy criteria. We sought to tag single-nucleotide polymorphisms (SNPs) of PXR, CAR and AHR that principally represent alleles associated with drug resistance risk; in addition, a gene interaction analysis reference panel was constructed for SNP-based imputation. RESULTS: No significant effects of PXR or AHR polymorphisms were observed. However, an interaction between the CAR rs2502815 variant and CBZ response was observed: in CBZ-based monotherapy and combination therapy patients, the GG genotype of the CAR rs2502815 variant (vs. wild-type homozygous) was independently associated with CBZ response after adjusting for variables [odds ratio (OR) = 0.389, 95% confidence interval (CI) 0.203-0.743, p = 0.004]. The results of the haplotype and gene interaction case-control analyses of the CBZ response were negative. Our results provide clinical data regarding the genetic possibilities of drug responses related to CAR variation in epilepsy patients. CONCLUSION: This study is the first to indicate a potentially relevant interaction between the CAR rs2502815 polymorphism and the CBZ response in epilepsy patients.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carbamazepina/administração & dosagem , Resistência a Medicamentos , Epilepsia/tratamento farmacológico , Receptor de Pregnano X/genética , Receptores de Hidrocarboneto Arílico/genética , Receptores Citoplasmáticos e Nucleares/genética , Adolescente , Adulto , Carbamazepina/farmacologia , Estudos de Casos e Controles , Criança , Epilepsia/genética , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Resultado do Tratamento , Adulto Jovem
5.
Curr Neuropharmacol ; 18(2): 153-166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31660836

RESUMO

An epigenetic effect mainly refers to a heritable modulation in gene expression in the short term but does not involve alterations in the DNA itself. Epigenetic molecular mechanisms include DNA methylation, histone modification, and untranslated RNA regulation. Antiepileptic drugs have drawn attention to biological and translational medicine because their impact on epigenetic mechanisms will lead to the identification of novel biomarkers and possible therapeutic strategies for the prevention and treatment of various diseases ranging from neuropsychological disorders to cancers and other chronic conditions. However, these transcriptional and posttranscriptional alterations can also result in adverse reactions and toxicity in vitro and in vivo. Hence, in this review, we focus on recent findings showing epigenetic processes mediated by antiepileptic drugs to elucidate their application in medical experiments and shed light on epigenetic research for medicinal purposes.


Assuntos
Anticonvulsivantes/farmacologia , Epigênese Genética/efeitos dos fármacos , Anticonvulsivantes/uso terapêutico , Doenças Cardiovasculares , Metilação de DNA , Epigenômica , Histonas/genética , Humanos , Nefropatias , Neoplasias , Doenças do Sistema Nervoso , Processamento de Proteína Pós-Traducional , RNA não Traduzido/genética , RNA não Traduzido/metabolismo
6.
Chin J Nat Med ; 17(3): 218-226, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30910058

RESUMO

This study developed a population pharmacokinetic model for sodium tanshinone IIA sulfonate (STS) in healthy volunteers and coronary heart disease (CHD) patients in order to identify significant covariates for the pharmacokinetics of STS. Blood samples were obtained by intense sampling approach from 10 healthy volunteers and sparse sampling from 25 CHD patients, and a population pharmacokinetic analysis was performed by nonlinear mixed-effect modeling. The final model was evaluated by bootstrap and visual predictive check. A total of 230 plasma concentrations were included, 137 from healthy volunteers and 93 from CHD patients. It was a two-compartment model with first-order elimination. The typical value of the apparent clearance (CL) of STS in CHD patients with total bilirubin (TBIL) level of 10 µmol(L-1 was 48.7 L(h-1 with inter individual variability of 27.4%, whereas that in healthy volunteers with the same TBIL level was 63.1 L(h-1. Residual variability was described by a proportional error model and estimated at 5.2%. The CL of STS in CHD patients was lower than that in healthy volunteers and decreased when TBIL levels increased. The bootstrap and visual predictive check confirmed the stability and validity of the final model. These results suggested that STS dosage adjustment might be considered based on TBIL levels in CHD patients.


Assuntos
Bilirrubina/sangue , Doença das Coronárias/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Fenantrenos/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença das Coronárias/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Fenantrenos/administração & dosagem , Fenantrenos/sangue
7.
Basic Clin Pharmacol Toxicol ; 124(4): 456-465, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30346663

RESUMO

Lopinavir (LPV) is a protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infections. Current studies on LPV are mainly focused on Caucasians, and none have investigated the population pharmacokinetics (PPK) of LPV in Chinese population. The present study aimed to develop a PPK model for oral LPV in Chinese adults who are HIV-infected. A total of 460 LPV concentrations from 174 Chinese patients who received LPV/ritonavir (LPV/r) 400/100 mg orally every 12 hours (q12h) were analysed using the non-linear mixed-effects modelling approach. Simulations of the LPV concentration profile were performed with different dosing regimens. A one-compartment model with first-order absorption and elimination process described the data. The estimated apparent clearance (CL/F) and volume of distribution (V/F) (% relative standard error [RSE]) for oral LPV were 5.9 L/h (3%) and 117 L (8%), respectively. Body-weight was identified as a covariate on CL/F. In patients who weighed between 45 and 115 kg and received the standard 400/100 mg q12h regimen, the probability of achieving target trough concentration (Ctrough ) of 1 mg/L was >98% for PI-naïve patients and the probability of achieving target Ctrough of 4 mg/L was <80% for PI-pretreated patients. This is the first population pharmacokinetic study to characterise the PK of LPV in Chinese patients with HIV infection. There were no obvious ethnic differences in the PK of LPV between the Chinese population and Caucasian population. The simulations demonstrated that the standard dosing regimen of 400/100 mg q12h (LPV/r tablets) appears to be sufficient for PI-naïve patients but suboptimal for PI-pretreated patients. Therefore, the regimen of 800/200 mg q12h was recommended for PI-pretreated patients. Further investigation of dosage recommendation could be helpful in optimising LPV therapy for HIV infections.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Lopinavir/administração & dosagem , Modelos Biológicos , Administração Oral , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Inibidores da Protease de HIV/farmacocinética , Humanos , Lopinavir/farmacocinética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ritonavir/administração & dosagem , Distribuição Tecidual , Adulto Jovem
8.
SAGE Open Med ; 6: 2050312118798278, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30345053

RESUMO

Objectives: Acute muscle injury and potentially fatal rhabdomyolysis may occur with the use of statins and certain enzyme inhibitors, but data on this topic from China are quite limited. This study aimed to measure the concomitant exposure of patients to different statins and their enzyme inhibitors or interacting medications in 76 hospitals in six Chinese cities. Methods: Prescription database was retrieved from Hospital Prescription Analysis Cooperation Project from January 2015 to December 2015, covering 76 tertiary facilities in six cities in China. Every evidence-based enzyme inhibitor was included, and labeled enzyme inhibitors and other relevant information were identified and obtained using the Drug Safety Update from the UK Medicines and Healthcare Products Regulatory Agency. The proportions of different statin types among all patients and those co-medicated with their inhibitors were examined. Results: A total of 296,765 patients exposed to statins were included in this study. 80% of patients (n = 144,863, 80.5%) were concomitantly prescribed a CYP3A4-metabolized statin with an interacting drug during the study period. Among those prescribed a non-CYP3A4-metabolized statin, 40.0% of patients were concomitantly given an interacting drug, and approximately 20% of patients were concomitantly given a labeled inhibitor, predominantly calcium channel blockers, other statins, and fibrates. Rates of co-prescription were higher in patients aged over 65 years and in patients taking high-dose statins. Conclusion: Statins were frequently co-prescribed with metabolic inhibitors in China, where drug safety strategy on highlighting warnings and contraindications of statins are still lacking. For high-dose statins patients who are over 65 years and co-administered with any metabolic inhibitors, prescribers and pharmacists should be more concerned in order to prevent adverse drug reactions.

9.
Br J Clin Pharmacol ; 84(1): 153-171, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28891596

RESUMO

AIMS: Several population pharmacokinetic (popPK) models for ciclosporin (CsA) in adult renal transplant recipients have been constructed to optimize the therapeutic regimen of CsA. However, little is known about their predictabilities when extrapolated to different clinical centres. Therefore, this study aimed to externally evaluate the predictive ability of CsA popPK models and determine the potential influencing factors. METHODS: A literature search was conducted and the predictive performance was determined for each selected model using an independent data set of 62 patients (471 predose and 500 2-h postdose concentrations) from our hospital. Prediction-based diagnostics and simulation-based normalized prediction distribution error were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. Additionally, potential factors influencing model predictability were investigated. RESULTS: Seventeen models extracted from 17 published popPK studies were assessed. Prediction-based diagnostics showed that ethnicity potentially influenced model transferability. Simulation-based normalized prediction distribution error analyses indicated misspecification in most of the models, especially regarding variance. Bayesian forecasting demonstrated that the predictive performance of the models substantially improved with 2-3 prior observations. The predictability of nonlinear Michaelis-Menten models was superior to that of linear compartmental models when evaluating the impact of structural models, indicating the underlying nonlinear kinetics of CsA. Structural model, ethnicity, covariates and prior observations potentially affected model predictability. CONCLUSIONS: Structural model is the predominant factor influencing model predictability. Incorporation of nonlinear kinetics in CsA popPK modelling should be considered. Moreover, Bayesian forecasting substantially improved model predictability.


Assuntos
Ciclosporina/farmacocinética , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Modelos Biológicos , Adulto , Área Sob a Curva , Teorema de Bayes , Ciclosporina/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Estudos Retrospectivos , Transplantados/estatística & dados numéricos , Adulto Jovem
10.
Gene ; 644: 93-100, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29101067

RESUMO

AIM: The present study was conducted to determine the effect of FOXP3 single nucleotide polymorphisms (SNPs) on clinical outcomes in CsA-treated renal transplant patients. METHODS: A total of 166 renal transplant patients with at least 5years of follow-up were included. SNPs of FOXP3 gene (rs3761547, rs3761548, rs3761549, rs2232365 and rs2280883) were detected by Taqman probe technique. The associations of SNPs with acute rejection, CsA-induced nephrotoxicity, pneumonia and post-transplantation estimated glomerular filtration rate (eGFR) were explored. RESULTS: Patients with rs3761549 T/TT genotype showed a more rapid decline in the eGFR level during the 5years following transplantation than those with the C/CC genotype (24.0% vs. 6.3%, P=0.004). All the SNPs and site-site interaction were not related to the occurrence of acute rejection, nephrotoxicity, and pneumonia. CONCLUSIONS: FOXP3 rs3761549 was significantly correlated with the renal allograft function. It could be used to predict and improve the outcome of renal transplant patients taking CsA as an immunosuppressant.


Assuntos
Ciclosporina/uso terapêutico , Fatores de Transcrição Forkhead/genética , Rejeição de Enxerto/genética , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Adulto , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/genética , Humanos , Transplante de Rim/métodos , Masculino
11.
Eur J Pharmacol ; 769: 167-76, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26586335

RESUMO

The human estrogen related receptor α (ERRα) is a pivotal regulator involved in energy homeostasis and mitochondrial biogenesis. It has been demonstrated that activation of ERRα in various breast cancer cells results in a significant increase of vascular endothelial growth factor (VEGF) mRNA and protein secretion. However, little is known about the relationship between ERRα and angiogenesis. Thus, the present study is aimed to investigate the effects and mechanism of ERRα suppression on the angiogenesis in human umbilical vein endothelial cells (HUVECs). Here we show that ERRα suppression powerfully inhibits proliferation, migration and capillary-like structures formation of HUVECs. Importantly, we demonstrate that these inhibitory effects are associated with the significantly reduced expression and production of VEGF. Results from further experiments using western blot and luciferase reporter assay exhibit that ERRα suppression inhibits hypoxia-inducible factor 1α (HIF-1α) expression, and phosphorylation of protein kinase B (Akt) and signal transducer and activator of transcription (STAT3) which up-regulated VEGF expression. In summary, we show that ERRα suppression inhibits angiogenesis in HUVECs and deserves further studies for application of rationale therapeutic target for patient with diseases related with aberrant angiogenesis.


Assuntos
Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana/citologia , Neovascularização Fisiológica , Receptores de Estrogênio/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Movimento Celular , Proliferação de Células , Embrião de Galinha , Membrana Corioalantoide/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição/genética , Ativação Transcricional , Fator A de Crescimento do Endotélio Vascular/genética
12.
Pharmacogenomics ; 16(13): 1499-512, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26314341

RESUMO

AIM: To evaluate the association between the major genetic variants involved in the pharmacokinetic/pharmacodynamic (PK/PD) properties of carbamazepine (CBZ) and its maintenance doses and concentrations. PATIENTS & METHODS: The genotypes of 166 patients receiving CBZ monotherapy were detected using high-resolution melting curve (HRM) and TaqMan methods. RESULTS: Both univariate and multiple regression analyses revealed that carriers of the SCN1A IVS5-91G>A or EPHX1 c.337T>C allele tended to require a higher CBZ dose and a lower CBZ natural logarithmic concentration-dose ratio (lnCDR) than noncarriers (p < 0.05). Furthermore, two interactions between these genes were associated with the lnCDR and the maintenance dosage of CBZ, respectively. CONCLUSION: SCN1A IVS5-91G>A gene polymorphism is potential genetic biomarker associated with the PK of CBZ.


Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Carbamazepina/farmacocinética , Carbamazepina/uso terapêutico , Polimorfismo Genético/genética , Adulto , Alelos , Anticonvulsivantes/administração & dosagem , Carbamazepina/administração & dosagem , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Epóxido Hidrolases/genética , Feminino , Estudos de Associação Genética , Variação Genética , Genótipo , Glucuronosiltransferase/genética , Humanos , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Medicina de Precisão , Adulto Jovem
13.
Pharmacogenomics ; 16(4): 347-60, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25823783

RESUMO

AIM: Associations between the effects of SCN1A, SCN2A, ABCC2 and UGT2B7 genetic polymorphisms and oxcarbazepine (OXC) maintenance doses in Han Chinese epileptic patients were investigated. PATIENTS & METHODS: Genetic polymorphisms were detected in 184 epileptic patients receiving OXC monotherapy by high-resolution melting curve and TaqMan method. RESULTS: Carriers of the SCN1A IVS5-91G>A, UGT2B7 c.802T>C and ABCC2 c.1249G>A variant alleles required significantly higher OXC maintenance doses than noncarriers (p < 0.05). Corresponding relative ln (concentration-dose ratios) values for SCN1A IVS5-91 variants differed by the genotypic order GG > GA > AA. CONCLUSION: SCN1A, UGT2B7 and ABCC2 genetic polymorphisms are associated with OXC maintenance doses and may be useful for the personalization of OXC therapy in epileptic patients. Further studies are needed. Original submitted 6 June 2014; Revision submitted 5 September 2014.


Assuntos
Epilepsia/tratamento farmacológico , Glucuronosiltransferase/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adulto , Alelos , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Carbamazepina/administração & dosagem , Carbamazepina/efeitos adversos , Carbamazepina/análogos & derivados , Relação Dose-Resposta a Droga , Epilepsia/genética , Epilepsia/patologia , Feminino , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Oxcarbazepina , Polimorfismo de Nucleotídeo Único
14.
Pharm Biol ; 53(11): 1567-75, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25856699

RESUMO

CONTEXT: Obesity is associated with a number of diseases with metabolic abnormalities such as type 2 diabetes (T2D). OBJECTIVE: We investigate the effects of tectorigenin on 3T3-L1 preadipocyte differentiation and adipocytokines secretion. MATERIALS AND METHODS: The effects of tectorigenin on adipocyte differentiation were studied using Oil Red O staining. Effects of tectorigenin on adipogenesis-related genes expression and adipocytokines secretion were measured by the real-time quantitative RT-PCR and ELISA method, respectively. Reporter gene assays were performed to determine the PPARγ and NF-κB transactivation. We also used [(3)H]-2-deoxy-d-glucose to study the glucose uptake, and the IKK/NF-κB signaling pathway was assessed by western blot analysis. HFD/STZ rats were used to evaluate the therapeutic efficacies of tectorigenin. RESULTS: Tectorigenin 10, 25, 50, and 75 µM inhibited 3T3-L1 adipogenesis and related genes transcription. TNF-α-induced changes of IL-6, MCP-1, as well as adiponectin in 3T3-L1 were markedly reversed by tectorigenin at 75 µM. Further investigation using reporter gene revealed that tectorigenin was a partial PPARγ agonist with an IC50 value of 13.3 µM. Tectorigenin improved basal and insulin-stimulated glucose uptake in mature 3T3-L1 adipocytes. Moreover, tectorigenin antagonized TNF-α-induced NF-κB transactivation and p65 nuclear translocation. Although tectorigenin (50 and 100 mg/kg) displayed the ability to promote insulin sensitivity and improve glucose metabolism in HFD/STZ rats, it did not cause significant side effects such as body weight gain, fluid retention, or cardiac hypertrophy. DISCUSSION AND CONCLUSION: These results suggest that tectorigenin may ameliorate hyperglycemia by blocking preadipocyte differentiation and adipocytokines secretion in which PPARγ and NF-κB signaling pathways were involved.


Assuntos
Adipogenia/fisiologia , Adipocinas/metabolismo , Diferenciação Celular/fisiologia , Isoflavonas/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
15.
Eur J Pharmacol ; 751: 81-8, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25666384

RESUMO

Chlorogenic acid (CGA), abundant in coffee and particular fruits, can modulate hypertension and vascular dysfunction. Hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation has been tightly linked to vascular remodeling in pulmonary arterial hypertension (PAH). Thus, the present study was designed to investigate the effect of CGA on hypoxia-induced proliferation in cultured rat PASMCs. The data showed that CGA potently inhibited PASMCs proliferation and DNA synthesis induced by hypoxia. These inhibitory effects were associated with G1 cell cycle arrest and down-regulation of cell cycle proteins. Treatment with CGA reduced hypoxia-induced hypoxia inducible factor 1α (HIF-1α) expression and trans-activation. Furthermore, hypoxia-evoked c-Src phosphorylation was inhibited by CGA. In vitro ELISA-based tyrosine kinase assay indicated that CGA was a direct inhibitor of c-Src. Moreover, CGA attenuated physical co-association of c-Src/Shc/Grb2 and ERK2 phosphorylation in PASMCs. These results suggest that CGA inhibits hypoxia-induced proliferation in PASMCs via regulating c-Src-mediated signaling pathway. In vivo investigation showed that chronic CGA treatment inhibits monocrotaline-induced PAH in rats. These findings presented here highlight the possible therapeutic use of CGA in hypoxia-related PAH.


Assuntos
Ácido Clorogênico/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Liso Vascular/citologia , Inibidores de Proteínas Quinases/farmacologia , Artéria Pulmonar/citologia , Animais , Proteína Tirosina Quinase CSK , Proteínas de Ciclo Celular/genética , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácido Clorogênico/uso terapêutico , DNA/biossíntese , Regulação para Baixo/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Proteína Adaptadora GRB2/metabolismo , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Monocrotalina/efeitos adversos , Músculo Liso Vascular/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transcrição Genética/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo
16.
Pharmacogenomics ; 15(10): 1323-36, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25155934

RESUMO

AIM: The purpose of this study was to investigate the potential impact of SCN1A, SCN2A and ABCC2 gene polymorphisms on the response to antiepileptic drugs in Chinese Han patients with epilepsy. PATIENTS & METHODS: Genetic polymorphisms in the candidate genes were detected in 453 Chinese epileptic patients by high-resolution melting curve and TaqMan methods. RESULTS: The SCN1A IVS5-91G>A AA genotype and the ABCC2 c.1249G>A GA genotype were significantly associated with carbamazepine/oxcarbamazepine (CBZ/OXC)-resistant epilepsy (p =0.002 and p = 0.036, respectively). The frequencies of haplotypes AA (SCN1A gene) and AC (ABCC2 gene) in drug-resistant patients were significantly higher than those in responsive patients (p = 0.002 and p = 0.005, respectively). CONCLUSION: This study suggested that SCN1A and ABCC2 polymorphisms may be associated with the response to CBZ/OXC in the Chinese Han population, indicating that they could serve as predictors of drug response. Original submitted 29 January 2014; Revision submitted 30 May 2014.


Assuntos
Epilepsia/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Carbamazepina/administração & dosagem , Carbamazepina/efeitos adversos , Carbamazepina/análogos & derivados , Resistência a Medicamentos , Epilepsia/genética , Epilepsia/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
17.
Br J Clin Pharmacol ; 78(4): 718-26, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24645974

RESUMO

AIM: Injury to bone is a significant clinical challenge, due to its limited regenerative capacity. The current methods of repairing bone defect are surgical, highly invasive and not always successful. A systematic review and meta-analysis of preclinical studies involving large animals with bone defects were conducted to determine the treatment outcomes with stem cell therapies. METHODS: A random effects meta-analysis of the available studies was conducted to assess the treatment outcomes including the rate of new bone formation and new bone mineral density (BMD). Stratified analyses were also conducted by separating studies based on each characteristic independently. RESULTS: Pooled analysis of 20 preclinical studies showed a significant beneficial effect of stem cell therapy in increasing new bone formation (17.79%, 95% confidence interval [CI], 10.54, 25.03; P < 0.001) and BMD (276.94 mg cm(-2) , 95% CI, 62.71, 491.17; P < 0.001) for disease amelioration. Regarding new bone formation, a statistical improvement was similarly detected from randomized controlled trial groups (17.06%, 95% CI, 8.87, 25.24; P < 0.001) and cohort groups (17.43%, 95% CI, 10.79, 24.07; P < 0.001). Exploratory stratified analysis yielded significant predictors of new bone formation including cell number (<10(7) vs. ≥10(7) ; P = 0.048) and the route of cell delivery (combining with matrix scaffold showed more effect than direct cell injection, P = 0.041). The effect of stem cell therapy diminished after 12 weeks. CONCLUSION: The study results suggest that stem cell therapy improves new bone formation and BMD in bone defect models. Future trials should focus on the transplantation of ≥10(7) stem cells, especially using slow release biodegradable scaffolds or repetitive cell injections.


Assuntos
Densidade Óssea , Osteogênese , Transplante de Células-Tronco , Animais , Células-Tronco Mesenquimais/fisiologia , Modelos Animais , Viés de Publicação
18.
J Ethnopharmacol ; 151(1): 287-91, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24269776

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: San-Huang formula is a popular traditional Chinese medicine (TCM) preparation to replenish Qi, resolve phlegm, dissipate blood stasis, and therapy metabolic syndrome in China. Metabolic syndrome, which is accompanied by Qi and blood stasis, mainly arises from spleen deficiency in essence. There is limited information available for differences of pharmacokinetic properties of San-Huang formula between normal and metabolic syndrome rats. The present study was conducted to compare the pharmacokinetics of berberine as well as palmatine in normal and metabolic syndrome rats following oral administration of San-Huang formula extract. MATERIALS AND METHODS: The animals were orally administered with San-Huang formula extract with the equivalent dose of 60.4 and 12.5mg/kg for berberine and palmatine, respectively. The blood samples were collected according to the time schedule. The concentrations of berberine and palmatine in rat plasma were determined by LC-ESI/MS. Various pharmacokinetic parameters were estimated from the plasma concentration versus time data using non-compartmental methods. RESULTS: It was found that AUC0-t, Cmax, Vd and CL of berberine and palmatine in metabolic syndrome rats were significantly different (P<0.05) from normal rats. CONCLUSIONS: The results indicated that berberine and palmatine have higher uptake and slower elimination in the rats with metabolic syndrome, which suggests that the rate and extent of drug metabolism were altered in metabolic syndrome rats.


Assuntos
Alcaloides de Berberina/farmacocinética , Berberina/farmacocinética , Síndrome Metabólica/metabolismo , Administração Oral , Animais , Área Sob a Curva , Medicamentos de Ervas Chinesas/química , Meia-Vida , Masculino , Estrutura Molecular , Distribuição Aleatória , Ratos
19.
Pharmazie ; 68(6): 459-64, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23875255

RESUMO

Delay in the initiation of appropriate antifungal therapy is associated with substantial morbidity and mortality. The aim of this study was to derive a risk score system for the development of invasive fungal infections in an intensive care unit (ICU). We retrospectively evaluated 1812 patients who stayed in the ICU for > or = 4 days, used univariate and multivariable logistic regression to identify potential risk factors associated with invasive fungal infections (IFI), and created a risk score system. Seven variables were identified as important predictors of ICU-IFI (diabetes mellitus, gastrointestinal surgery, hematological malignancies, mechanical ventilation > or = 2 days, central venous catheter, total parenteral nutrition, broad-spectrum antibiotic use > or = 4 days). The area under the receiver operating characteristic curve was 0.807 and was similar in the validation set. The percentages of patients with ICU-IFI in the low, intermediate, and high risk groups were 5.2%, 31.6%, and 63.2% in the derivation cohort and 4.2%, 30.1%, and 66.7% in the validation cohort, respectively. A new risk score was developed to predict ICU-IFI and was validated in an independent cohort. The new risk score may help clinicians identify patients who are at high risk of developing ICU-IFI and increase their odds of survival.


Assuntos
Infecção Hospitalar/diagnóstico , Infecção Hospitalar/epidemiologia , Unidades de Terapia Intensiva , Micoses/diagnóstico , Micoses/epidemiologia , Idoso , Antifúngicos/uso terapêutico , Estudos de Coortes , Infecção Hospitalar/prevenção & controle , Feminino , Mortalidade Hospitalar , Humanos , Tempo de Internação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Micoses/prevenção & controle , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Sobrevida
20.
Clin Chim Acta ; 413(7-8): 683-90, 2012 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-22227166

RESUMO

BACKGROUND: This study aimed to evaluate the effect of UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A polymorphisms on the pharmacokinetics (PKs) of mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) in healthy Chinese volunteers and in stable renal transplant patients. METHODS: The data were extracted from comparative bioavailability studies conducted in 42 healthy individuals and 37 renal transplant patients. A complete PK profile was obtained over 48 h for healthy volunteers and over 12h for the transplant patients. The MPA/MPAG plasma concentrations were measured by HPLC. The genotypes were determined using either the Taqman probe technique or direct sequencing. A multivariate analysis was used to assess the effect of the genotypes (UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A) and other covariates (age, weight, height, calculated creatinine clearance, serum albumin, haemoglobin and drug comedication) on the AUC(4-12) and AUC(0-12) for MPA and MPAG in the healthy volunteers and patients. RESULTS: In the healthy volunteers, the dose-adjusted geometric means (GM) of the MPA AUC(4-12) in individuals with the SLCO1B3 334T allele were 30.4% lower than those values in the 334G homozygote carriers (P<0.05); in the transplant patients, the steroid dose was associated with a negative effect on the AUC of MPAG (P<0.03) and weight was associated with a negative effect on the AUC for MPA in the healthy volunteers and patients (P<0.03). No other significant effect of genotype or of the other studied variables on AUC(4-12) or AUC(0-12) of MPA/MPAG was found in the healthy volunteers or patients. CONCLUSIONS: The PKs of MPA is affected by the SLCO1B3 polymorphism in healthy Chinese individuals. The absence of an effect of SLCO1B3 polymorphisms in transplant patients may be due to the co-administration of cyclosporine (CsA). Concomitant steroid dose and weight are two important covariates of the AUC of MPA and MPAG, which should be taken into account in clinical use. Further confirmatory in vivo studies are needed.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Glucuronídeos/farmacocinética , Glucuronosiltransferase/genética , Imunossupressores/farmacocinética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Ácido Micofenólico/farmacocinética , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Polimorfismo de Nucleotídeo Único , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Área Sob a Curva , Sequência de Bases , Estudos de Casos e Controles , China , Primers do DNA , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
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