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1.
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.

2.
Eur J Pharm Sci ; 167: 105986, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474119

RESUMO

BACKGROUND: Efavirenz is a vital component used to treat HIV-1 infection. Nevertheless, it shows large between-subject variability, which affects both its therapeutic response and adverse effects. OBJECTIVE: To investigate the impact of gene polymorphisms and non-genetic factors on the variability of efavirenz pharmacokinetics and to propose the optimal dose regimens. METHODS: A total of 769 plasma samples from 376 HIV-infected Han Chinese outpatients were collected to develop a population pharmacokinetic model using NONMEM software. The impact of patient demographics, laboratory tests, concomitant medication, and genetic polymorphisms of CYP2B6 and ABCB1 on efavirenz pharmacokinetics were explored. According to the final model, the model-informed dose optimization was conducted. RESULTS: The pharmacokinetics of efavirenz was characterized by a one-compartment model with first-order absorption and elimination. The typical values of the estimated apparent oral clearance, volume of distribution, and absorption rate constant in the final model were 9.44 L/h, 200 L, and 0.727 h - 1, respectively. Efavirenz clearance was significantly influenced by CYP2B6 variants, including rs2099361, rs3745274, and rs2279343, along with albumin and weight. The volume of distribution was affected by albumin and weight. Based on the CYP2B6 polymorphisms of patients, the recommended daily doses of efavirenz were 100 mg for CYP2B6 slow metabolizers, 400 or 600 mg for intermediate metabolizers, and 800 or 1000 mg for extensive metabolizers. CONCLUSIONS: Polymorphisms of CYP2B6, along with albumin and weight, resulted as the predictors of efavirenz pharmacokinetic variability, which could be used in prescribing optimal efavirenz doses.

3.
Clin Endocrinol (Oxf) ; 92(5): 461-467, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31943291

RESUMO

OBJECTIVE: A differential diagnosis between malignant and benign parathyroid lesions is difficult due to their overlapping clinicopathological characteristics. As such, molecular markers are urgently needed. Cancer-derived immunoglobulin G (CIgG) is a novel molecule playing important roles in carcinogenesis. The present study aimed to investigate the clinical significance of CIgG in parathyroid neoplasms. PATIENTS: Fifty patients with parathyroid carcinoma (PC), 50 patients with parathyroid adenoma (PA) and 9 patients with parathyroid hyperplasia (PH) were retrospectively enrolled in the current study. MEASUREMENTS: Immunohistochemistry was used to assess CIgG expression in these patients. The performance of CIgG expression in the differential diagnosis between parathyroid lesions was assessed by receiver operating characteristic (ROC) curves. The associations between CIgG expression and clinical outcomes were also analysed by Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS: The expression level of CIgG was significantly higher in PC patients than in PA or PH patients (P < .001). CIgG expression discriminated PC from PA or PH, with an area under the ROC curve of 0.84 (76% sensitivity and 88% specificity). High CIgG expression was significantly associated with worse disease-free survival (DFS) in PC patients (P = .018) and was validated as an independent risk factor for DFS in the multivariable Cox regression analysis (P = .002). CONCLUSIONS: The ability of CIgG expression both in the differential diagnosis between malignant and benign parathyroid lesions and in the prognosis prediction for PC was shown in the present study. CIgG might be used as a novel biomarker of parathyroid lesions in future clinical practice.

4.
J Asian Nat Prod Res ; 22(2): 144-152, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30526081

RESUMO

Two oleanane-type triterpenoid saponins named pedunsaponin D (1) and pedunsaponin E (2) were isolated from the roots of Pueraria peduncularis. The structures of the new compounds were elucidated based on chemical and physicochemical evidence as follows: pedunsaponin D, 3-O-ß-glucopyranosyl-(1-3)-ß-glucuronopyranosyl-3ß,15α,23α-trihydroxy-11,13(18)-oleanadien-16-one (1); pedunsaponin E, 3-O-ß-glucopyranosyl-(1-2)-ß-glucopy ranosyl(1-2)[ß-glucopyranosyl(1-3)-ß-glucuronopyranosyl]-3ß-hydroxy-16-oxoolean-12-en-30-oic acid (2). The two compounds showed moderate molluscicidal activity.[Formula: see text].


Assuntos
Pueraria , Saponinas , Triterpenos , Estrutura Molecular , Raízes de Plantas
5.
Clin Lab ; 65(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31307168

RESUMO

BACKGROUND: MicroRNA molecules have been identified to play key roles in a broad range of physiological and pathological processes. Polymorphisms in the corresponding sequence space are likely to make a significant con-tribution to phenotypic variation. The aim of this study was to evaluate the pre-miR-146a C/G (rs2910164) and pre-miR-499 T/C (rs3746444) polymorphisms and their putative association with inflammatory markers in AF in Han Chinese. METHODS: A total of 123 participants were enrolled, 65 AF patients were confirmed with electrocardiogram (ECG) or dynamic electrocardiography, 58 normal individuals were assigned to the control group. RESULTS: Genotypes of the pre-miR-146a C/G (rs2910164) and pre-miR-499 T/C (rs3746444) polymorphisms were distinguished using the method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The distribution of the pre-miR-146a C/G (rs2910164) genotypes CC, CG, and GG was 33.85%, 52.31%, and 13.84% in the AF group and 37.93%, 51.72%, and 10.35% in the controls, respectively. There was no significant difference in either genotype frequency distributions (p = 0.7973) or allele frequency distributions (p = 0.5411) between these two groups. The distribution of the pre-miR-499 T/C (rs3746444) genotypes TT, TC, and CC was 72.41%, 22.41%, and 5.18% in the controls and 49.23%, 38.46%, and 12.31% in AF subjects, respec-tively (p = 0.0296). The frequency of the C allele in the AF group was significantly higher than that in the control group (31.54% vs. 16.38%, p = 0.0057). Compared with the TT genotype, the C allele carriers (TC+CC genotypes) had a 2.7070-fold increased risk of AF. After being adjusted for age, gender, leucocytes, left atrial dimension, left ventricular ejection fraction, serum levels of lipids, and inflammatory markers, the association persisted (adjusted OR = 2.3387, 95% CI =1.1094 - 4.9300, p = 0.0280). Individuals with TC+CC genotype in pre-miR-499 T/C (rs3746444) had greater serum levels of IL-6 and hs-CRP than did patients with the TT genotype. CONCLUSIONS: Our data support that the pre-miR-499 T/C (rs3746444) polymorphism is associated with AF, and the C allele has increased risk for AF in Han Chinese.


Assuntos
Fibrilação Atrial/genética , Predisposição Genética para Doença/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Fibrilação Atrial/sangue , Fibrilação Atrial/etnologia , Biomarcadores/sangue , Proteína C-Reativa/análise , China , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade
6.
World J Gastrointest Oncol ; 11(3): 195-207, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30918593

RESUMO

BACKGROUND: There is growing evidence proving that many human carcinomas, including colon cancer, can overexpress immunoglobulin (Ig); the non B cancer cell-derived Ig usually displayed unique V(D)J rearrangement pattern that are distinct from B cell-derived Ig. Especially, the cancer-derived Ig plays important roles in cancer initiation, progression, and metastasis. However, it still remains unclear if the colon cancer-derived Ig can display unique V(D)J pattern and sequencing, which can be used as novel target for colon cancer therapy. AIM: To investigate the Ig repertoire features expressed in human colon cancer cells. METHODS: Seven cancerous tissue samples of colon adenocarcinoma and corresponding noncancerous tissue samples were sorted by fluorescence-activated cell sorting using epithelial cell adhesion molecule as a marker for epithelial cells. Ig repertoire sequencing was used to analyze the expression profiles of all 5 classes of Ig heavy chains (IgH) and the Ig repertoire in colon cancer cells and corresponding normal epithelial cells. RESULTS: We found that all 5 IgH classes can be expressed in both colon cancer cells and normal epithelial cells. Surprisingly, unlike the normal colonic epithelial cells that expressed 5 Ig classes, our results suggested that cancer cells most prominently express IgG. Next, we found that the usage of Ig in cancer cells caused the expression of some unique Ig repertoires compared to normal cells. Some VH segments, such as VH3-7, have been used in cancer cells, and VH3-74 was frequently present in normal epithelial cells. Moreover, compared to the normal cell-derived Ig, most cancer cell-derived Ig showed unique VHDJH patterns. Importantly, even if the same VHDJH pattern was seen in cancer cells and normal cells, cancer cell-derived IgH always displayed distinct hypermutation hot points. CONCLUSION: We found that colon cancer cells could frequently express IgG and unique IgH repertoires, which may be involved in carcinogenesis of colon cancer. The unique IgH repertoire has the potential to be used as a novel target in immune therapy for colon cancer.

7.
Ther Drug Monit ; 40(5): 572-580, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29847459

RESUMO

BACKGROUND: The aim of this study was to characterize the pharmacokinetics of mycophenolic acid (MPA) and MPA glucuronide (MPAG) in Chinese renal transplant patients taking enteric-coated mycophenolate sodium (EC-MPS). Limited sampling strategies (LSSs) were developed to estimate the area under the concentration curve from 0 to 12 hours (AUC0-12h) of total and free MPA. Another objective was to investigate the correlation between high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay technology (EMIT) for total MPA determination. METHODS: Serial blood samples were collected over 12 hours from 15 patients who were administered multiple doses of EC-MPS. LSS was developed by multiple stepwise regression analysis. Measurement by HPLC and EMIT was compared using Passing-Bablok regression and Bland-Altman analysis. RESULTS: Normalized to 720 mg twice daily, the AUC0-12h of total MPA and MPAG was 43.0 ± 17.4 and 653 ± 329 mg·h/L, respectively, whereas the free MPA AUC0-12h was 1.368 ± 0.988 mg·h/L. The free fraction of MPA was 3.01% ± 3.15%. The combination of C2h-C4h-C6h and C2h-C4h-C6h-C8h was found to be superior to estimate total and free MPA simultaneously. The EMIT showed an acceptable correlation with HPLC, with an AUC0-12h overestimation of 11.32% ± 15.77%. CONCLUSIONS: The pharmacokinetic profile of total and free MPA and its main metabolite MPAG was examined in Chinese adult renal transplant patients receiving EC-MPS. The use of LSS to estimate individual free and total MPA exposure could be useful in optimizing patient care.


Assuntos
Glucuronídeos/farmacocinética , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacocinética , Técnica de Imunoensaio Enzimático de Multiplicação , Feminino , Glucuronídeos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/sangue , Comprimidos com Revestimento Entérico/farmacocinética , Adulto Jovem
8.
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
9.
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
10.
Oncol Lett ; 14(4): 4491-4498, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29085446

RESUMO

Cancer cell-derived immunoglobulin G (cancer-IgG) has been implicated in the pathogenesis and progression of various types of cancer. However, its role in salivary adenoid cystic carcinoma (SACC) remains unclear. The present study aimed to investigate the effects of cancer-IgG on metastasis and prognosis in 96 patients with SACC. Immunohistochemical staining showed that cancer-IgG expression was present in all 96 individual SACC tissues. Additionally, high cancer-IgG expression was significantly correlated with metastasis, nerve invasion and recurrence in SACC (P<0.05). Moreover, cancer-IgG expression was significantly correlated with the survival duration of patients with SACC (P<0.05). Proliferation, cell motility and invasion all decreased significantly following knockdown of cancer-IgG in SACC cells (P<0.05) through population-doubling time, wound healing and transwell invasion assays. Additionally, cancer-IgG-knockdown in SACC cells induced the increased expression of E-cadherin and matrix metalloproteinase 9, and promoted the epithelial-mesenchymal transition, but decreased the expression of F-actin filaments. Taken together, these results showed that the high expression of cancer-IgG was strongly associated with metastasis, recurrence and invasion in SACC, suggesting that cancer-IgG expression could serve as a useful biomarker to predict the prognosis of the disease.

11.
Arch Oral Biol ; 81: 15-20, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28460248

RESUMO

OBJECTIVE: Cancer-IgG is a newly-discovered molecule, mainly derived from epithelial carcinoma cells and is significantly correlated with differentiation, metastasis, local invasion, and poor prognosis of many cancers. In our previous study we detected IgG expression in oral epithelial carcinoma, including salivary adenoid cystic carcinoma (SACC), using an IgG-specific commercial antibody. Here, we explored the correlation between cancer-IgG and clinicopathological features of SACC. DESIGN: A total of 68 human SACC tissue specimens and 2 siRNAs were used to analyze the correlation between cancer-IgG and extra domain A (EDA+)-containing fibronectin using the cancer-IgG-specific monoclonal antibody, RP215. RESULTS: We found an unexpected correlation between cancer-IgG and EDA+ fibronectin, both of which showed aberrant expression in SACC tissue samples. Both were highly expressed in SACC with nerve invasion. In our previous study, EDA+ fibronectin overexpression in SACC cells decreased N-cadherin expression. In the present study, we used SACC-83 cells, wherein EDA+ fibronectin is overexpressed and cancer-IgG is knocked down. EDA+ fibronectin expression was reduced with cancer-IgG knockdown, while cancer-IgG expression did not affect EDA+ fibronectin overexpression. Furthermore, knockdown of non-B cell-derived IgG in SACC cells decreased cellular motility (P<0.05) as well as increased E-cadherin and alpha-smooth muscle actin levels. CONCLUSION: The results suggest that cancer IgG potentially regulates EDA+ fibronectin expression, thereby suggesting possible new therapeutic approaches for SACC.


Assuntos
Carcinoma Adenoide Cístico/metabolismo , Fibronectinas/metabolismo , Imunoglobulina G/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Adulto , Idoso , Western Blotting , Linhagem Celular Tumoral , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Reação em Cadeia da Polimerase em Tempo Real
12.
Artigo em Chinês | MEDLINE | ID: mdl-30124271

RESUMO

Objective: To investigate the effect of excreted/secreted antigens (ESAs) from Toxoplasma gondii RH strain and TgCtwh3 strain on apoptosis of CD4+CD25+ regulatory T cells and interferon-γ (IFN-γ) secretion. Methods: ESAs of Toxoplasma gondii RH strain and TgCtwh3 strain were prepared. Splenic mononuclear cells were isolated from C57BL/6 mice and randomly divided into RH ESA group(2×106 cells/well with addition of 10 µg/ml RH ESA), TgCtwh3 ESA group (2×106 cells/well with addition of 10 µg/ml TgCtwh3 ESA) and control group(2×106 cells/well with addition of 10 µg/ml ovalbumin). Flow cytometry was performed to examine the early apoptosis of CD4+CD25+ regulatory T cells after treatment for 48 h and 72 h. ELISA was conducted to determine the level of IFN-γ in the supernatant after treatment for 72 h. In another experiment, the 3 groups of splenic mononuclear cells were added with 10 µg/ml anti-IFN-γ antibody for 72 h and flow cytometry was performed to examine the early apoptosis of CD4+CD25+ regulatory T cells. Meanwhile, splenic mononuclear cells from IFN-γ knockout and wild-type C57BL/6 mice were also divided into the above-described 3 groups, and flow cytometry was performed to examine the early apoptosis of CD4+CD25+ regulatory T cells after treatment for 72 h. Results: The concentrations of RH ESA and TgCtwh3 ESA were 0.54 mg/ml and 2.14 mg/ml, respectively. Flow cytometry showed that the early apoptosis rate of CD4+CD25+ regulatory T cells in the RH ESA group and the TgCtwh3 ESA group after 48 h treatment was (12.90±1.26)% and (9.71±1.04)%, respectively (P<0.05), both significantly higher than that in control group (4.48±0.48)% (P<0.01) . The early apoptosis rate of CD4+CD25+ regulatory T cells after 72 h in the RH ESA group was(15.21±1.11)%, significantly higher than that in the TgCtwh3 ESA group[(11.02±0.92)%] (P<0.05) and the control group[(10.10±1.49)%](P<0.01). ELISA showed that the level of interferon-γ in the RH ESA group and the TgCtwh3 ESA group after 72 h was(4 764.0±118.7) pg/ml and (3 629.0±33.6) pg/ml, respectively (P<0.01), both significantly higher than that in the control[(679.4±30.6) pg/ml](P<0.01). Flow cytometry revealed lower early apoptosis rate of CD4+CD25+ regulatory T cells in the RH ESA group added with anti-IFN-γ antibody[(10.44±1.44)%ï¼½ compared with that without the addition of the antibody[(14.96±0.83)](P<0.05). But this difference was not observed for the TgCtwh3 ESA group. Moreover, the RH ESA-induced apoptosis rate of regulatory T cells from IFN-γ knockout mice[(10.64±0.55)%ï¼½ was significantly lower than that from the wild-type mice [(15.21±1.11)%](P<0.01). But this difference was not found for the TgCtwh3 ESA treatment. Conclusion: T. gondii RH ESA induces apoptosis of CD4+CD25+ regulatory T cells and IFN-γ secretion, and these effects are stronger than those of TgCtwh3 ESA. The T. gondii ESA-induced IFN-γ stimulates generation of anti-Toxoplasma immunity during acute Toxoplasma infection through mediation of regulatory T cell apoptosis.


Assuntos
Linfócitos T Reguladores , Toxoplasma , Animais , Apoptose , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interferon gama , Camundongos , Camundongos Endogâmicos C57BL , Baço
13.
Yao Xue Xue Bao ; 51(11): 1666-73, 2016 11.
Artigo em Chinês | MEDLINE | ID: mdl-29908108

RESUMO

Inosine 5'-monophosphate dehydrogenase(IMPDH) is a rate-limiting enzyme in de novo biosynthesis of guanine and plays an important role in cell proliferation. In clinic, IMPDH inhibitors are mainly used in fields of anticancer, antiviral, anti-parasitic, and immunosuppressive chemotherapy. However, since there are usually great inter- and intra-individual variability between drug concentration and clinical effect of IMPDH inhibitors, the enzyme activity of IMPDH may be applied as a specific biomarker and combined with the pharmacokinetics (PK) monitoring to improve efficacy and safety of IMPDH inhibitors. This review aims to discuss the assay of IMPDH activity measurement and its clinical application in recent years and provide valuable insights and theoretical basis for the development of IMPDH inhibitors' pharmacodynamics monitoring.


Assuntos
Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/metabolismo , Antineoplásicos/farmacologia , Antiparasitários/farmacologia , Antivirais/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Imunossupressores/farmacologia
14.
Br J Clin Pharmacol ; 81(5): 891-907, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26574188

RESUMO

AIM: Several tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualization. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyze potential influencing factors. METHODS: Published models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction-based prediction error (PE%), (2) simulation-based prediction- and variability-corrected visual predictive check (pvcVPC) and normalized prediction distribution error (NPDE) tests and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated. RESULTS: Sixteen published models were evaluated. In prediction-based diagnostics, the PE% within ±30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation-based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2-3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time and haematocrit) and whether non-linear kinetics were used. CONCLUSIONS: The published models were unsatisfactory in prediction- and simulation-based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of non-linear pharmacokinetics in modelling might be a promising approach to improving model predictability.


Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Modelos Biológicos , Tacrolimo/farmacocinética , Área Sob a Curva , Teorema de Bayes , Estudos de Coortes , Citocromo P-450 CYP3A/genética , Hematócrito , Humanos , Polimorfismo Genético , Período Pós-Operatório , Estudos Retrospectivos , Transplantados
15.
Parasitol Res ; 113(6): 2087-94, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24667973

RESUMO

Angiostrongylus cantonensis is a neurotropic parasite which can cause injury to central nervous system and eosinophilic meningitis to human. Natural killer (NK) cells are specialized innate lymphocytes important in early defense against pathogens as in a variety of intracellular bacterial, viral, and protozoan infections. However, the number and function of NK cells in extracellular parasitic infection of A. cantonensis are unclear. In this study, on A. cantonensis infected mice which may mimic the human's infection, we found that the percentage of splenic NK cells and the absolute number of peripheral blood NK cells were decreased at 21-day post infection compared with that of controls. When administrating with albendazole treatment at early stage of the infection, the changes of NK cells could be avoided. Further analysis confirmed that the reduction of NK cells was due to their apoptosis manifested as increased expressions of annexin V and activated caspase-3 after 16-day post infection. Moreover, both activated and inhibitory receptors such as CD16, CD69, NKG2D, and Ly49a on NK cells were down-regulated after 16-day post infection. Interestingly, NK cells isolated from mice of 21-day post infection showed enhanced IFN-γ production when stimulated with IL-12 for 24 h and cytotoxicity to YAC-1 cells, as well as elevated CD107a expression. It is evident that NK cell population and its function were changed in A. cantonensis infected mice, suggesting their involvement in pathogenesis of the infection.


Assuntos
Angiostrongylus cantonensis/fisiologia , Células Matadoras Naturais/fisiologia , Infecções por Strongylida/parasitologia , Albendazol/farmacologia , Animais , Anti-Helmínticos/farmacologia , Feminino , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/patologia
16.
PLoS One ; 8(7): e69012, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874852

RESUMO

Toxoplasma gondii is an opportunistic intracellular parasite that is highly prevalent in human and warm-blooded animals throughout the world, leading to potentially severe congenital infections. Although the abortion caused by T. gondii is believed to be dependent on the timing of maternal infection during pregnancy, the mechanism remains unclear. This study was focused on the effects of T. gondii excreted-secreted antigens on pregnant outcomes and CD4(+)CD25(+) Foxp3(+) regulatory T cells at different stages of pregnancy. The results showed that in mice the frequency and suppressive function of CD4(+)CD25(+) regulatory cells were diminished after injection of T. gondii excreted-secreted antigens at early and intermediate stages of pregnancy. The abortion caused by T. gondii excreted-secreted antigens at early pregnancy could be partly prevented by adoptively transferring of CD4(+)CD25(+) cells from the mice injected with T. gondii excreted-secreted antigens at late pregnancy, but not from the mice with the same treatment at early pregnancy. Furthermore, T. gondii excreted-secreted antigens induced apoptosis of CD4(+)CD25(+) regulatory cells of mice in early and intermediate stages of pregnancy by down-regulating their Bcl-2 expressions and Bcl-2/Bax ratio. This study provides new insights into the mechanism that T. gondii infection is the high risk factor for abortion in early pregnancy.


Assuntos
Aborto Espontâneo , Antígenos de Protozoários/imunologia , Antígenos CD4/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Toxoplasma/imunologia , Animais , Sequência de Bases , Primers do DNA , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Resultado da Gravidez , Reação em Cadeia da Polimerase em Tempo Real
17.
Huan Jing Ke Xue ; 34(3): 1204-10, 2013 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-23745435

RESUMO

A peroxiredoxin6 (PRDX6)-like gene segment has been found in up-regulated cDNA libraries of earthworm Eisenia fetida exposed to benzo[a]pyrene(BaP). Analysis with basic local alignment search tool (BLAST) and phylogenetic analysis revealed that the gene segment contains a characteristic motif which was encoded by Cys, illustrating that this gene segment belongs to PRDX. To verify the response of PRDX in E. feitida exposed to poly aromatic hydrocarbons (PAHs), four-week pollution experiments were conducted following the methods recommended by the Organization for Economic Co-operation and Development (OECD). The results showed that the expression of PRDX was up-regulated in earthworm exposed to 1.0 mg x kg(-1) Pyrene and BaP. It was indicated that PRDX in E. fetida was the potential molecular biomarkers of antioxidative stress caused by soil contamination.


Assuntos
Monitoramento Ambiental/métodos , Oligoquetos/genética , Peroxirredoxina VI/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes do Solo/toxicidade , Sequência de Aminoácidos , Animais , Benzo(a)pireno/análise , Benzo(a)pireno/toxicidade , Dados de Sequência Molecular , Oligoquetos/efeitos dos fármacos , Oligoquetos/fisiologia , Peroxirredoxina VI/genética , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes do Solo/análise , Estresse Fisiológico/fisiologia
18.
Chin Med J (Engl) ; 125(23): 4233-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23217392

RESUMO

BACKGROUND: Cyclosporin A (CsA) is a substrate of both cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), some of the single nucleotide polymorphisms (SNPs) in these genes are associated with interindividual variations in CsA pharmacokinetics. We studied the influence of these SNPs on the incidence of rejection and CsA nephrotoxicity, as well as pneumonia within one year after renal transplant and post-transplantation diabetes mellitus (PTDM), in order to find whether genetic evaluation may help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes. METHODS: A total of 208 renal transplant recipients receiving CsA were genotyped for ABCB1 (C1236T, G2677T/A, and C3435T), CYP3A4 1G, and CYP3A5 3 by direct sequencing method. Retrospective case control study was utilized to identify the association between CYP3A4 1G, CYP3A5 3, ABCB1 genetic polymorphisms and CsA-related outcomes. RESULTS: The patients with a CYP3A4 1G/ 1G genotype were found to have a higher incidence of acute rejection compared with those with CYP3A4 1/1. CONCLUSION: CYP3A4 1G/1G genotype predict increased risk of acute rejection, so genetic evaluation may partly help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes.


Assuntos
Ciclosporina/efeitos adversos , Citocromo P-450 CYP3A/genética , Imunossupressores/efeitos adversos , Transplante de Rim , Polimorfismo Genético/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Ciclosporina/uso terapêutico , Genótipo , Humanos , Imunossupressores/uso terapêutico , Estudos Retrospectivos
19.
Nephrology (Carlton) ; 17(4): 423-30, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22239151

RESUMO

AIM: FOXP3 gene is known to be important for regulatory T cell development and function, and is associated with the rejection of human kidney transplants. The present study was therefore conducted to determine the effect of FOXP3 polymorphisms on allograft rejection in renal transplant recipients. METHODS: A total of 166 adult patients were categorized into either a Rejection group (65 patients) or a No rejection group (101 patients). Rs3761547, rs3761548 and rs2232365 variant alleles in the FOXP3 gene were genotyped using a TaqMan probe technique, and their relationships with rejection were investigated. RESULTS: There was no significant difference in the genotype frequencies of rs3761547 and rs2232365 variants between patients with and without rejection history (P > 0.05). Binary logistic regression analysis showed that the rs3761548 AA genotype carriers were associated with about a fourfold greater risk for rejection compared with CC genotype (5 years post-transplant: odds ratio 3.95, 95% confidence interval 1.27-12.29, P = 0.018). Kaplan-Meier analysis revealed a lower mean time to the first rejection in rs3761548 AA compared with CC genotype patients (Log rank = 4.303, P = 0.038). Multivariate Cox regression analysis indicated that rs3761548 AA genotype carriers have up to about a twofold (hazard ratio 2.37, 95% confidence interval 1.17-4.80, P = 0.017) higher risk for rejection than CC carriers. CONCLUSION: Our study suggests an association between FOXP3 rs3761548 polymorphisms and allograft rejection in renal transplantation. This association should be further proven in large prospective studies because of the small sample size and confounding factors in this retrospective study.


Assuntos
Fatores de Transcrição Forkhead/genética , Rejeição de Enxerto/genética , Sobrevivência de Enxerto/genética , Transplante de Rim/imunologia , Polimorfismo de Nucleotídeo Único , Adulto , Distribuição de Qui-Quadrado , China , Feminino , Frequência do Gene , Predisposição Genética para Doença , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
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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