Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
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 Dec 01.
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.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adulto , Albuminas , Alcinos/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas , China , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Humanos , Polimorfismo Genético
3.
Expert Rev Clin Pharmacol ; 14(9): 1153-1163, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34058934

RESUMO

BACKGROUND: Rivaroxaban is an oral anticoagulant widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. This study aimed to explore appropriate remedial dosing regimens for non-adherent rivaroxaban-treated patients. METHODS: Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic (PK/PD) model for patients with NVAF was employed to design remedial dosing regimens. The proposed regimens were compared with remedial strategies in the European Heart Rhythm Association (EHRA) guide by assessing deviation time in terms of drug concentration, factor Xa activity, and prothrombin time. RESULTS: The proposed remedial dosing regimens were dependent on delay duration. The missed dose should be taken immediately when the delay does not exceed 6 h; a half dose is advisable when the delay is between 6 and 20 h. A missed dose should be skipped if less than 4 h remains before the next dose. The proposed regimens resulted in shorter deviation time than that of the EHRA guide. CONCLUSION: PK/PD modeling and simulation provide valid evidence on the remedial dosing regimen of rivaroxaban, which could help to minimize the risk of bleeding and thromboembolism.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Modelos Biológicos , Rivaroxabana/administração & dosagem , Idoso , Fibrilação Atrial/complicações , Simulação por Computador , Relação Dose-Resposta a Droga , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Método de Monte Carlo , Rivaroxabana/efeitos adversos , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Fatores de Tempo
4.
Front Pharmacol ; 12: 673492, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122098

RESUMO

Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations. Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b. Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations. Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.

5.
Expert Rev Clin Pharmacol ; 14(7): 853-864, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33851561

RESUMO

INTRODUCTION: Oxcarbazepine is commonly used as first-line treatment for partial and generalized tonic-clonic seizures. Owing to the high pharmacokinetic variability, several population pharmacokinetic models have been developed for oxcarbazepine to explore potential covariates that affect its pharmacokinetic variation. AREAS COVERED: This review summarizes the published population pharmacokinetic studies of oxcarbazepine in children and adults available in PubMed and Embase databases. The quality of the retrieved studies was evaluated, and significant covariates that may have an impact on the dosage regimen of oxcarbazepine were explored. EXPERT OPINION: The pharmacokinetics of oxcarbazepine was founded to be affected by body weight and co-administration with enzyme inducers. Pediatric patients require a higher dose per kilogram than adults because children generally have a higher clearance than adults. Moreover, to maintain the target concentration, patients co-administrate with enzyme inducers need a higher dose than monotherapy due to higher clearance in those patients. Because limited information is available for exposure-response relationship, additional pharmacokinetic/pharmacodynamics investigations of oxcarbazepine need to be conducted to optimize the dosage regimen in clinical practice.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia/tratamento farmacológico , Oxcarbazepina/administração & dosagem , Adulto , Fatores Etários , Anticonvulsivantes/farmacocinética , Criança , Relação Dose-Resposta a Droga , Epilepsia/fisiopatologia , Humanos , Modelos Biológicos , Oxcarbazepina/farmacocinética
6.
Clin Pharmacokinet ; 60(3): 305-318, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33447943

RESUMO

BACKGROUND: Levetiracetam has been widely used as a treatment option for different types of epilepsy in both adults and children. Because of its large between-subject variability, several population pharmacokinetic studies have been performed to identify its pharmacokinetic covariates, and thus facilitate individualised therapy. OBJECTIVE: The aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore the identified influencing covariates. METHODS: We systematically searched the PubMed and Embase databases from inception to 30 June 2020. The information on study designs, target population, model characteristics, and identified covariates was summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults. RESULTS: Fourteen studies were included, among which two involved neonates, four involved children, two involved both children and adults, and six involved adults only. The median value of apparent clearance for children (0.074 L/h/kg [range 0.038-0.079]) was higher than that for adults (0.054 L/h/kg [range 0.039-0.061]). Body weight was found to significantly influence the apparent clearance and volume of distribution, whereas renal function influenced the clearance. Likewise, coadministration with enzyme-inducing antiepileptic drugs (such as carbamazepine and phenytoin) increased the drug clearance by 9-22%, whereas coadministration with valproate acid decreased it by 18.8%. CONCLUSION: Levetiracetam dose regimen is dependent on the body size and renal function of patients. Further studies are needed to evaluate levetiracetam pharmacokinetics in neonates and pregnant women.


Assuntos
Levetiracetam , Adulto , Anticonvulsivantes/uso terapêutico , Carbamazepina , Criança , Feminino , Humanos , Recém-Nascido , Fenitoína , Piracetam , Gravidez
7.
Clin Pharmacokinet ; 60(1): 53-68, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32960439

RESUMO

BACKGROUND AND OBJECTIVE: External evaluation is an important issue in the population pharmacokinetic analysis of antibiotics. The purpose of this review was to summarize the current approaches and status of external evaluations and discuss the implications of external evaluation results for the future individualization of dosing regimens. METHODS: We systematically searched the PubMed and EMBASE databases for external evaluation studies of population analysis and extracted the relevant information from these articles. A total of 32 studies were included in this review. RESULTS: Vancomycin was investigated in 17 (53.1%) articles and was the most studied drug. Other studied drugs included gentamicin, tobramycin, amikacin, amoxicillin, ceftaroline, meropenem, fluconazole, voriconazole, and rifampicin. Nine (28.1%) studies were prospective, and the sample size varied widely between studies. Thirteen (40.6%) studies evaluated the population pharmacokinetic models by systematically searching for previous studies. Seven (21.9%) studies were multicenter studies, and 27 (84.4%) adopted the sparse sampling strategy. Almost all external evaluation studies of antibiotics (93.8%) used metrics for prediction-based diagnostics, while relatively fewer studies were based on simulations (46.9%) and Bayesian forecasting (25.0%). CONCLUSION: The results of external evaluations in previous studies revealed the poor extrapolation performance of existing models of prediction- and simulation-based diagnostics, whereas the posterior Bayesian method could improve predictive performance. There is an urgent need for the development of standards and guidelines for external evaluation studies.


Assuntos
Antibacterianos , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Teorema de Bayes , Humanos , Estudos Prospectivos
8.
Eur J Drug Metab Pharmacokinet ; 45(4): 453-466, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32170643

RESUMO

BACKGROUND AND OBJECTIVES: Tacrolimus is a widely used immunosuppressive agent with narrow therapeutic window. Nowadays, tacrolimus has gained acceptance as a therapeutic option in myasthenia gravis (MG) treament, however, little is known about its pharmacokinetic characteristics in MG population. In this study, we aimed to investigate the population pharmacokinetic (PopPK) of tacrolimus in patients with MG and to develop model-informed dosing regimens. METHODS: Trough concentrations of tacrolimus (267 measurements) and cytochrome P450 (CYP) genotypes were determined in 97 Chinese adults. The non-linear mixed-effects model was used for PopPK modeling. Monte Carlo simulations based on the established model were employed to design dosing regimens. RESULTS: The PopPK model was described using a one-compartment model with first-order absorption and elimination. The mean apparent clearance (CL/F) of tacrolimus was 17.1 L/h, with a between-subject variability of 20.1%. Covariate screening of demographic characteristics, blood test results, co-medications, and CYP3A5*3 or CYP3A4*1G polymorphisms showed that the CYP3A5*3 genotype and co-administration of a Wuzhi capsule significantly affected tacrolimus CL/F. CONCLUSIONS: For patients with the CYP3A5*3*3 allele, the required tacrolimus dose for 75% of subjects to achieve target trough concentrations of 4.8-15 ng/mL was 2 mg every 12 h (q12h). For patients with the CYP3A5*1*1 allele, the required dose was 2 mg tacrolimus q12h with a Wuzhi capsule, and for patients with the CYP3A5*1*3 allele, the required dose was 3 mg of tacrolimus q12h or 4 mg q24h co-administered with a Wuzhi capsule. This model could be employed to optimize individualized therapies for patients with MG.


Assuntos
Imunossupressores/farmacocinética , Modelos Biológicos , Miastenia Gravis/tratamento farmacológico , Tacrolimo/farmacocinética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Miastenia Gravis/etnologia , Variantes Farmacogenômicos , Medicina de Precisão , Estudos Prospectivos , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Resultado do Tratamento , Adulto Jovem
9.
Plant Sci ; 278: 64-69, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30471730

RESUMO

RNA editing in chloroplasts and mitochondria is performed by hypothetical editosomes. The MORF family proteins are essential components of these editosomes. In Arabidopsis, MORF2 and MORF9 are involved in the editing of most sites in chloroplasts. In this work, we performed immunoprecipitation and mass spectrometry assays of transgenic lines expressing MORF2-4xMYC and MORF9-4xMYC to identify interacting proteins. We found that MORF2 and MORF9 are present in the same complex. Blue-Native PAGE analysis of chloroplast protein complexes also revealed that both MORF2 and MORF9 are part of a complex of approximately 140 kDa, suggesting the existence of tight MORF2-MORF9 interaction in chloroplasts. The editing of ndhD-1 (ndhD-C2) site was reported to be blocked in both morf2 and morf9. RNA immunoprecipitation assays showed that MORF2 and MORF9 are tightly associated with the editing site of ndhD-1. However, in an RNA-EMSA assay MORF2 and MORF9 could not directly bind to transcripts harboring the editing site of ndhD-1. Taken together, these results indicate that the MORF2-MORF9 heterodimer is the core members of editosomes in chloroplasts, while they are not responsible for RNA editing site recognition.


Assuntos
Proteínas de Arabidopsis/fisiologia , Arabidopsis/genética , Cloroplastos/genética , Proteínas Mitocondriais/fisiologia , Edição de RNA , Proteínas de Ligação a RNA/fisiologia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Eletroforese em Gel de Poliacrilamida , Imunoprecipitação , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Plantas Geneticamente Modificadas/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
10.
Plant J ; 92(4): 546-556, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28850756

RESUMO

The pentatricopeptide repeat-DYW protein AtECB2 affects plastid RNA editing at seven sites, including accD-794, accD-1568, ndhF-290, ndhG-50, petL-5, rpoA-200 and rpoC1-488. To understand the mechanism of its involvement in RNA editing, a transgenic line was constructed with AtECB2 fused to a 4xMYC tag that could complement the atecb2 phenotype. RNA immunoprecipitation analysis indicated that AtECB2 is associated with the transcripts of accD, ndhF, ndhG and petL. Co-immunoprecipitation and mass spectrometry experiments showed that multiple organelle RNA editing factor 2 (MORF2) and porphobilinogen deaminase HEMC are associated with AtECB2. Biochemical analysis showed that AtECB2 directly interacts with HEMC through its E domain, while HEMC interacts with MORF8/RIP1. Deletion analysis showed that the E domain is essential for RNA editing. The hemc-1 mutant showed an albino and seedling-lethal phenotype. Of the seven editing sites affected in atecb2, the editing of accD-794 and ndhF-290 was also reduced in hemc-1. RNA immunoprecipitation analysis suggested that HEMC is associated with the editing sites of ndhF transcripts. These results showed that both HEMC and multiple organellar RNA editing factor (MORF) proteins are associated with AtECB2 for RNA editing in plastids.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimologia , Proteínas de Cloroplastos/metabolismo , Hidroximetilbilano Sintase/metabolismo , Edição de RNA , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Clorofila/biossíntese , Proteínas de Cloroplastos/genética , Hidroximetilbilano Sintase/genética , Fator de Crescimento Insulin-Like II , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Fragmentos de Peptídeos , Fenótipo , Plastídeos/metabolismo , Precursores de Proteínas , RNA de Cloroplastos/genética , Plântula/enzimologia , Plântula/genética , Deleção de Sequência
11.
Photosynth Res ; 126(2-3): 311-21, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26123918

RESUMO

After transcription, most chloroplast precursor RNAs undergo further post-transcriptional processing including cleavage, editing, and splicing. Previous investigation has shown that the cleavage of the rpoA transcript and most editing sites, including accD-1, are defective in the knockout mutant of PDM1/SEL1, a PLS-type PPR protein, and that PDM1 is associated with the rpoA transcript. In this work, we found that the splicing of group II introns in trnK and ndhA is also affected in pdm1. Co-immunoprecipitation mass spectrometry experiments were performed to identify proteins that are associated with PDM1. We obtained 126 non-redundant proteins, of which MORF9 was reported to be involved in RNA editing in chloroplast. Yeast two-hybrid assays showed that PDM1 interacts directly with MORF9, MORF2, and MORF8. RNA immunoprecipitation showed that PDM1 associates with the transcripts of trnK and ndhA, as well as accD-1, suggesting that PDM1 is involved in RNA editing and splicing. Therefore, PDM1 is an important protein for post-transcriptional regulation in chloroplast.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de Cloroplastos/metabolismo , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Cloroplastos/genética , Modelos Biológicos , Plastídeos/genética , Edição de RNA , Splicing de RNA , RNA de Plantas/genética
12.
Plant Sci ; 236: 185-94, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26025532

RESUMO

The fructokinase-like protein2 (FLN2) is a component of the PEP complex. FLN2 knockout mutants displayed a delayed greening phenotype on sucrose-containing medium. Our previous work indicated that partial PEP activity is essential for its greening phenotype. In this study, we further report that sufficient Rubisco accumulation is critical for fln2-4 greening. Sugar serves many important functions, such as an energy source and signaling molecule. Through pharmacological experiments using a sugar analog and sugar signaling inhibitor, we demonstrate that sugar serves as energy to support the fln2-4 greening. Seed-reserve and photosynthetic CO2-fixation are the primary energy sources for early seedling growth. No obvious differences were observed in the seed-reserve of the wild-type and fln2-4 by comparing their seed size and dark-germination, indicating that the defective carbon fixation may account for the energy deficit in fln2-4 during its early seedling growth. The Rubisco content was low in fln2-4, but it rapidly accumulated during the greening of fln2-4. Expression of a nuclear-encoded rbcL gene facilitates Rubisco accumulation and partially complements the mutant defects. These results suggest that the Rubisco accumulation is critical for fln2-4 greening. In summary, the rapid Rubisco accumulation that depends on sufficient PEP activity is important for normal seedling growth.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Ribulose-Bifosfato Carboxilase/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Germinação , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Sementes/genética , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Sacarose/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...