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1.
Sensors (Basel) ; 21(22)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34833832

RESUMO

Paving thickness and evenness are two key factors that affect the paving operation quality of earth-rock dams. However, in the recent study, both of the key factors characterising the paving quality were measured using finite point random sampling, which resulted in subjectivity in the detection and a lag in the feedback control. At the same time, the on-site control of the paving operation quality based on experience results in a poor and unreliable paving quality. To address the above issues, in this study, a novel assessment and feedback control framework for the paving operation quality based on the observe-orient-decide-act (OODA) loop is presented. First, in the observation module, a cellular automaton is used to convert the location of the bulldozer obtained by monitoring devices into the paving thickness of the levelling layer. Second, in the orient module, the learning automaton is used to update the state of the corresponding and surrounding cells. Third, in the decision module, an overall path planning method is developed to realise feedback control of the paving thickness and evenness. Finally, in the act module, the paving thickness and evenness of the entire work unit are calculated and compared to their control thresholds to determine whether to proceed with the next OODA loop. The experiments show that the proposed method can maintain the paving thickness less than the designed standard value and effectively prevent the occurrence of ultra-thick or ultra-thin phenomena. Furthermore, the paving evenness is improved by 21.5% as compared to that obtained with the conventional paving quality control method. The framework of the paving quality assessment and feedback control proposed in this paper has extensive popularisation and application value for the same paving construction scene.


Assuntos
Aprendizagem , Retroalimentação
2.
Front Pharmacol ; 12: 732503, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34675806

RESUMO

Evidence supports linezolid therapeutic drug monitoring as the exposure-response relationship has been identified for toxicity among patients receiving linezolid, but the data to establish the upper limit are limited and the published toxicity thresholds range widely. The purpose of this study was to determine the linezolid exposure-toxicity thresholds to improve the safety of linezolid. This is a multicenter retrospective study of adult patients treated with linezolid from 2018 to 2019. The population pharmacokinetic model of linezolid was established based on 270 plasma concentrations in 152 patients, which showed creatinine clearance and white cell count are covariates affecting the clearance of linezolid, and serum albumin is the covariate affecting the volume of distribution. Classification and regression tree analysis was used to determine the linezolid exposure thresholds associated with an increased probability of toxicity. Among 141 patients included for toxicity analysis, the rate of occurring toxicity was significantly higher among patients with an AUC0-24, d1 ≥163 mg h/L, AUC0-24, d2 ≥207 mg h/L, AUC0-24, ss ≥210 mg h/L, and Cmin,d2 ≥6.9 mg/L, Cmin,ss ≥6.9 mg/L, while no threshold was discovered for Cmin, d1. Those exposure thresholds and duration of linezolid treatment were independently associated with linezolid-related toxicity in the logistic regression analyses. In addition, the predictive performance of the AUC0-24 and Cmin thresholds at day 2 and steady state were close. Considering that the AUC estimation is cumbersome, Cmin threshold at 48 h and steady state with a value of ≥6.9 mg/L is recommended to improve safety, especially for patients with renal insufficiency and patients with low serum albumin.

3.
Environ Pollut ; 291: 118253, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34597734

RESUMO

The synthetic resin industry plays an important role in Volatile organic compounds (VOCs) emissions from industrial sources. However, owing to various products and their different emission characteristics, it is extremely difficult to study the source profiles of synthetic resins. In this study, the product-based pollution characteristics of VOCs from eight synthetic resin enterprises were investigated in Shanghai, China. Up to 133 VOCs were identified, including 106 based on the Photochemical Assessment Monitoring Stations (PAMS) and the Toxic Organics (TO-15) methods, and the remaining 27 were identified based on the new mass spectrometry analysis method. Aromatics (39.7%) and oxygenated VOCs (29.9%) accounted for a relatively high proportion in the synthetic resin industry. The product-based source profiles of each process unit are compiled. Generally, 1,4-dioxane, methyl isobutyl ketone, toluene, benzene, styrene, propane, and dichloromethane are the most abundant species in synthetic resin. Furthermore, the product-based ozone formation potentials (OFPs) and sources reactivity (SR) were calculated, the synthetic resin industry SR range from 0.3 g g-1 to 4.6 g g-1. Results suggest that toluene, benzene, styrene, propylene, ethylene, and oxygenated VOCs (including 1,4-dioxane, methyl isobutyl ketone, and aldehyde) should be preferentially controlled to reduce the OFPs. A three-level classification was established to evaluate the degree of photochemical pollution in different industries. Emission factors were calculated and ranked for eight synthetic resins. A VOC emission inventory of Chinese synthetic resin from 2005 to 2018 was compiled. It is estimated that the Chinese synthetic resin emitted 23.96 Gg of VOCs in 2018. In this study, a product-based VOC source profile and emission inventory of the synthetic resin industry were established for the first time. Finally, combined with product types, processes, and processing equipment, feasible recommendations for reducing VOC emissions in the synthetic resin industry are proposed.


Assuntos
Poluentes Atmosféricos , Ozônio , Compostos Orgânicos Voláteis , Poluentes Atmosféricos/análise , China , Monitoramento Ambiental , Ozônio/análise , Resinas Sintéticas , Compostos Orgânicos Voláteis/análise
4.
Pharmgenomics Pers Med ; 14: 1093-1106, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34511980

RESUMO

Purpose: In this study, we aimed to establish a tacrolimus population pharmacokinetic model and better understand the drug-drug interaction between Wuzhi capsule and tacrolimus in Chinese renal transplant recipients. Patients and Methods: We performed a population pharmacokinetic analysis using a non-linear mixed-effects model to determine the suitable Wuzhi capsule dose in combination with tacrolimus. Data on 1378 tacrolimus steady-state concentrations were obtained from 142 patients who received kidney transplant in Changhai Hospital and Huashan Hospital. Demographic characteristics, laboratory tests, genetic polymorphisms, and co-medications were evaluated. Results: The one-compartment model best described data. Our final model identified creatinine clearance rate, hematocrit, Wuzhi capsule dose, CYP3A5*3 genetic polymorphisms, and tacrolimus daily dose as significant covariates for tacrolimus clearance, with the value of 14.4 L h-1, and the between-subject variability (BSV) was 25.4%. The Wuzhi capsule showed a dose-dependent effect on tacrolimus pharmacokinetics, demonstrating a stronger inhibitory effect than inductive effect. Conclusion: Our model can accurately describe population pharmacokinetics of tacrolimus when combined with different doses of Wuzhi capsule. Additionally, this model can be used for individualizing tacrolimus dose following kidney transplantation.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34453256

RESUMO

The sustainable development of the economy is a key issue of global concern. Green total factor productivity (GTFP) combining economic growth with resources and the environment can evaluate the quality of economic development comprehensively and accurately. In this paper, super slack-based measure (Super-SBM) model and Malmquist-Luenberger (ML) index were used to calculate GTFP. The trend of industrial GTFP in China's 30 provinces from 2006-2015 was analyzed. Furtherly, a dynamic panel model was used to discuss the impact of trade openness on GTFP. The results showed that (1) the growth rate of GTFP rose from 2007 to 2011 and declined significantly from 2011 to 2015, and GTFP only achieved positive growth in 2011; (2) the growth rate of GTFP in the eastern region was higher than that in the central and western regions; (3) the trend of technical progress change (MLTECH) index was highly consistent with that of ML index. That was, technical progress played a major role in the variation of GTFP; (4) trade openness could significantly improve China's GTFP. Every 1% increase in trade openness could increase GTFP by 0.097% on average. It is advisable to implement differentiated economic development and environmental policies in different regions. Meanwhile, relevant measures can be taken to promote import and export trade, such as encouraging companies to increase investment in green technology research and development, optimizing the trade environment.

6.
Int Immunopharmacol ; 98: 107827, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34284341

RESUMO

The population pharmacokinetics (PPK) of tacrolimus (TAC) in children with refractory nephrotic syndrome (RNS) have not been well-characterized. This study aimed to investigate the significant factors affecting the TAC PPK characteristics of children with RNS and to optimize the dosing regimen. A total of 494 concentrations from 108 children were obtained from routine therapeutic drug monitoring between 2016 and 2018. Information regarding the demographic features, laboratory test results, genetic polymorphisms of CYP3A5 (rs776746) and co-therapy medications were collected. PPK analysis was performed using the nonlinear mixed-effects modelling (NONMEM) software and two modelling strategies (the linear one-compartment model and nonlinear Michaelis-Menten model) were evaluated and compared. CYP3A5 genotype, weight, daily dose of TAC and daily dose of diltiazem were retained in the final linear model. The absorption rate constant (Ka) was set at 4.48 h-1 in the linear model, and the apparent clearance (CL/F) and volume of distribution (V/F) in the final linear model were 14.2 L/h and 172 L, respectively. CYP3A5 genotype, weight and daily dose of diltiazem were the significant factors retained in the final nonlinear model. The maximal dose rate (Vmax) and the average steady-state concentration at half-Vmax (Km) in the final nonlinear model were 2.15 mg/day and 0.845 ng/ml, respectively. The nonlinear model described the pharmacokinetic data of TAC better than the linear model in children with RNS. A dosing regimen was proposed based on weight, CYP3A5 genotype and daily dose of diltiazem according to the final nonlinear PK model, which may facilitate individualized drug therapy with TAC.

7.
J Clin Pharm Ther ; 46(6): 1564-1575, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34312870

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Mycophenolate mofetil, an ester prodrug of mycophenolic acid (MPA), is widely used to prevent graft rejection after kidney transplantation. The pharmacokinetic (PK) of MPA has been extensively studied, which revealed a high degree of variability. An integrated population PK (PopPK) model of MPA and its main metabolite mycophenolic acid glucuronide (MPAG) was developed using the adult patients who underwent kidney transplant and were administered oral mycophenolate mofetil combined with tacrolimus. METHODS: In total, 917 MPA and 740 MPAG concentrations in191 adult patients were analysed via nonlinear mixed-effects modelling. The concentration-time data were adequately described using a chain compartment model, including central and peripheral compartments for MPA and a central compartment for MPAG. Stepwise forward inclusion and backward elimination procedures were used to investigate the effects of genetic polymorphisms, including in UGT1A8, UGT1A9, UGT2B7, ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, and HNF1α. RESULTS AND DISCUSSION: These genetic polymorphisms in metabolic enzymes and transporters have no obvious impact on the PK of MPA in adult patients who underwent kidney transplant and were co-treated with tacrolimus. The post-transplant time, serum albumin, and creatinine clearance were identified as significant covariates affecting the PK of MPA and MPAG, which should be considered in the clinical use of mycophenolate mofetil. WHAT IS NEW AND CONCLUSION: We established a PopPK model of MPA and MPAG in Chinese adult patients who underwent kidney transplant and were co-treated with tacrolimus. Genetic polymorphisms in metabolic enzymes and transporters showed no obvious impact on MMF PK. A model-informed dosing strategy was proposed by the established model, and MMF dose adjustment should be based on ALB levels and the post-transplantation time.

8.
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.

9.
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
10.
BMC Pharmacol Toxicol ; 22(1): 26, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947475

RESUMO

BACKGROUND: We aim to develop a population pharmacokinetics (PopPK) model of vancomycin for the treatment of septicemia in infants younger than one year. Factors influence of the PK was investigated to optimize vancomycin dosing regimen. METHODS: The nonlinear mixed effects modelling software (NONMEM) was used to develop the PopPK model of vancomycin. The stability and predictive ability of the final model were assessed by using normalized prediction distribution errors (NPDE) and bootstrap methods. The final model was subjected to Monte Carlo simulation in order to determine the optimal dose. RESULTS: A total of 205 trough and peak concentrations in 94 infants (0-1 year of age) with septicemia were analyzed. The interindividual variability of the PK parameter was described by the exponential model. Residual error was better described by the proportional model than the mixed proportional and addition models. Serum creatinine concentration and body weight are the major factors that affect the PK parameters of vancomycin. The clearance was shown to be higher when ceftriaxone was co-treated. More than two model evaluation methods showed better stability than the base model, with superior predictive performance, which can develop individualized dosing regimens for clinical reference. Through prediction of final model, the trough concentration was more likely < 5 mg/L when a routine dose of 10 mg/kg is administered every 6 h to 3-9-month-old infants. Therefore, the dose should be increased in the treatment of infant septicemia. CONCLUSIONS: The stable and effective PopPK model of vancomycin in Chinese infants with septicemia was established. This model has satisfactory predictive ability for clinically individualized dosing regimens in this vulnerable population.

11.
J Glob Antimicrob Resist ; 25: 238-263, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33845162

RESUMO

OBJECTIVES: Effective antifungal therapy is important to reduce mortality in patients with invasive fungal infections (IFIs). Numerous factors affect pharmacokinetic/pharmacodynamic (PK/PD) parameters in critically-ill patients. To guide individualised administration in critically-ill patients, it is of great significance to determine the population pharmacokinetics of caspofungin. METHODS: A prospective study in 42 ICU patients with IFIs was conducted in China. A population pharmacokinetic model of caspofungin was established using a non-linear mixed-effects model, which was utilised to investigate the effects of demographic indices, liver function and kidney function on pharmacokinetics. Additionally, appropriate dosages of caspofungin under various scenarios were determined based on MICs and probability of target attainment (PTA) at specific dosages. RESULTS: In critically-ill Chinese patients, clearance (CL), volume of distribution (V) and area under the curve at steady-state (AUCss) of caspofungin were 0.32 L/h, 6.77 L and 135.47 mg•h/L, respectively. Blood albumin and total bilirubin levels were factors affecting CL, while body weight was the only factor affecting V among Chinese people with relatively low weight compared with other populations. A maintenance dose of 50 mg caspofungin achieved a high PTA for treating IFIs caused by Candida albicans (MIC ≤ 0.06 mg/L) and Candida glabrata (MIC ≤ 0.125 mg/L). The maintenance dose of caspofungin should be adjusted to 70-200 mg for IFIs caused by C. albicans (MIC, 0.06-0.125 mg/L). For IFIs caused by Candida parapsilosis, an MIC > 0.03 mg/L is associated with a very low PTA, but higher doses of caspofungin or alternative antifungals need to be further studied. CONCLUSION: The population pharmacokinetic model established here described well the PK/PD characteristics of caspofungin in critically-ill Chinese patients. These results could guide the formulation of individualised caspofungin dosing regimens for critically-ill patients.


Assuntos
Unidades de Terapia Intensiva , Caspofungina , China , Humanos , Probabilidade , Estudos Prospectivos
12.
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
13.
Front Pharmacol ; 12: 623907, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897418

RESUMO

Background: Numerous vancomycin population pharmacokinetic models in neonates have been published; however, their predictive performances remain unknown. This study aims to evaluate their external predictability and explore the factors that might affect model performance. Methods: Published population pharmacokinetic models in neonates were identified from the literature and evaluated using datasets from two clinical centers, including 171 neonates with a total of 319 measurements of vancomycin levels. Predictive performance was assessed by prediction- and simulation-based diagnostics and Bayesian forecasting. Furthermore, the effect of model structure and a number of identified covariates was also investigated. Results: Eighteen published pharmacokinetic models of vancomycin were identified after a systematic literature search. Using prediction-based diagnostics, no model had a median prediction error of ≤ ± 15%, a median absolute prediction error of ≤30%, and a percentage of prediction error that fell within ±30% of >50%. A simulation-based visual predictive check of most models showed there were large deviations between observations and simulations. After Bayesian forecasting with one or two prior observations, the predicted performance improved significantly. Weight, age, and serum creatinine were identified as the most important covariates. Moreover, employing a maturation model based on weight and age as well as nonlinear model to incorporate serum creatinine level significantly improved predictive performance. Conclusion: The predictability of the pharmacokinetic models for vancomycin is closely related to the approach used for modeling covariates. Bayesian forecasting can significantly improve the predictive performance of models.

14.
J Clin Pharm Ther ; 46(4): 1117-1128, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33768546

RESUMO

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729  × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

15.
Eur J Pharm Sci ; 162: 105814, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33753216

RESUMO

Biapenem is a carbapenem antibiotic. It is excreted predominantly through the kidney as unchanged forms. However, the molecular mechanism of renal excretion of biapenem and potential drug-drug interactions (DDIs) were still unknown. In the present study, the role of organic anion transporters (OAT) 1/3 and organic cation transporters (OCT) 2 in the renal excretion of biapenem, and the potential DDIs between biapenem and six clinical commonly prescribed antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3 were evaluated in vitro. Further, the effect of probenecid on the pharmacokinetics of biapenem was explored in the rats. We observed that biapenem could not inhibit the transport activities of OAT1 or OCT2, while mildly inhibited OAT3 (IC50 >500 µM). Among the tested antibiotics and antiviral drugs, the relatively high DDI index values (maximal unbound plasma concentration over IC50, Imax,u/IC50) were found for piperacillin, linezolid and benzylpenicillin, which were 2.84, 1.7 and 0.62, respectively. Although probenecid had the highest DDI index (27.1) in vitro, no significant impact of it on the pharmacokinetics of biapenem was observed in the rats. Our results indicated that biapenem was primarily eliminated by the glomerular filtration, while OAT3-mediated renal tubular secretion was a minor route. Biapenem is not a clinically relevant substrate or inhibitor because of its low affinity to OAT3. According to current results, it would be safe to use biapenem with other antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3.


Assuntos
Proteína 1 Transportadora de Ânions Orgânicos , Preparações Farmacêuticas , Animais , Interações Medicamentosas , Células HEK293 , Humanos , Rim/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Preparações Farmacêuticas/metabolismo , Ratos , Eliminação Renal , Tienamicinas
16.
Genet Test Mol Biomarkers ; 25(3): 236-246, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33734892

RESUMO

Aims: To assess the expression and epigenetic regulation of Syncoilin, intermediate filament protein (SYNC) in gastric cancer tissues, and to determine its associations with clinicopathological features; immune infiltration of macrophages in tumors; and patient survival. Materials and Methods: Clinicopathological features, expression profiles, and methylation data of the SYNC gene were obtained from multi-institutional real-world public datasets. A total of 1601 samples from patients with gastric cancer were examined. The associations between clinicopathological features and SYNC expression levels were assessed by the chi-square test; survival was assessed using the Kaplan-Meier analysis. The infiltration levels of M1, 2-polarized tumor-associated macrophages (TAMs) in a gastric tumor immune microenvironment were quantified using deconvolution, and the correlation between SYNC expression level and M1, 2-polarized macrophages' infiltration was examined using the Pearson correlation test. SYNC gene methylation data were analyzed to investigate epigenetic control of its expression. Results: SYNC expression was elevated in gastric cancer tissues (p < 0.01), and was associated with a poorer overall survival (p < 0.01) and poorer postprogression survival (p = 0.01). Higher SYNC levels were significantly associated with more aggressive clinicopathological features in gastric cancer patients (p < 0.05). SYNC was also associated with the infiltration of M2-polarized TAMs in the gastric tumor immune microenvironment (p < 0.001). Hypomethylation was shown to be associated with SYNC's upregulation (p < 0.05). Conclusion: SYNC is highly expressed in gastric cancer tissues and has the potential to be a therapeutic target and to serve as a prognostic marker.


Assuntos
Proteínas de Filamentos Intermediários/genética , Linfócitos do Interstício Tumoral/imunologia , Proteínas Musculares/genética , Neoplasias Gástricas/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinogênese/genética , Carcinogênese/imunologia , China , Metilação de DNA , Bases de Dados Genéticas , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Estimativa de Kaplan-Meier , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Prognóstico , Estômago/patologia , Neoplasias Gástricas/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
17.
Int J Antimicrob Agents ; 57(3): 106300, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33567334

RESUMO

INTRODUCTION: Few studies incorporating population pharmacokinetic/pharmacodynamic (Pop-PK/PD) modelling have been conducted to quantify the exposure target of vancomycin in neonates. A retrospective observational cohort study was undertaken in neonates to determine this target and dosing recommendations (chictr.org.cn, ChiCTR1900027919). METHODS: A Pop-PK model was developed to estimate PK parameters. Causalities between acute kidney injury (AKI) occurrence and vancomycin use were verified using Naranjo criteria. Thresholds of vancomycin exposure in predicting AKI or efficacy were identified via classification and regression tree analysis. Associations between exposure thresholds and clinical outcomes, including AKI and efficacy, were analysed by logistic regression. Dosing recommendations were designed using Monte Carlo simulations based on the optimised exposure target. RESULTS: Pop-PK modelling included 182 neonates with 411 observations. On covariate analysis, neonatal physiological maturation, renal function and concomitant use of vasoactive agents (VAS) significantly affected vancomycin PK. Seven cases of vancomycin-induced AKI were detected. Area under the concentration-time curve from 0-24 hours (AUC0-24) ≥ 485 mg•h/L was an independent risk factor for AKI after adjusting for VAS co-administration. The clinical efficacy of vancomycin was analysed in 42 patients with blood culture-proven staphylococcal sepsis. AUC0-24 to minimum inhibitory concentration (AUC0-24/MIC) ≥ 234 was the only significant predictor of clinical effectiveness. Monte Carlo simulations indicated that regimens in Neonatal Formulary 7 and Red Book (2018) were unsuitable for all neonates. CONCLUSION: An AUC0-24 of 240-480 (assuming MIC = 1 mg/L) is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Antibacterianos/administração & dosagem , Vancomicina/administração & dosagem , Vancomicina/farmacocinética , Antibacterianos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Feminino , Humanos , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Estudos Retrospectivos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus/efeitos dos fármacos , Staphylococcus/isolamento & purificação , Resultado do Tratamento
18.
Biomed Environ Sci ; 34(1): 40-49, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33531106

RESUMO

Objective: Epidemiological studies reveal that exposure to fine particulate matter (aerodynamic diameter ≤ 2.5 µm, PM 2.5) increases the morbidity and mortality of respiratory diseases. Emerging evidence suggests that human circulating extracellular vesicles (EVs) may offer protective effects against injury caused by particulate matter. Currently, however, whether EVs attenuate PM 2.5-induced A549 cell apoptosis is unknown. Methods: EVs were isolated from the serum of healthy subjects, quantified via nanoparticle tracking analysis, and qualified by the marker protein CD63. PM 2.5-exposed (50 µg/mL) A549 cells were pre-treated with 10 µg/mL EVs for 24 h. Cell viability, cell apoptosis, and AKT activation were assessed via Cell Counting Kit-8, flow cytometry, and Western blot, respectively. A rescue experiment was also performed using MK2206, an AKT inhibitor. Results: PM 2.5 exposure caused a 100% increase in cell apoptosis. EVs treatment reduced cell apoptosis by 10%, promoted cell survival, and inhibited the PM 2.5-induced upregulation of Bax/Bcl2 and cleaved caspase 3/caspase 3 in PM 2.5-exposed A549 cells. Moreover, EVs treatment reversed PM 2.5-induced reductions in p-AKT Thr308 and p-AKT Ser473. AKT inhibition attenuated the anti-apoptotic effect of EVs treatment on PM 2.5-exposed A549 cells. Conclusions: EVs treatment promotes cell survival and attenuates PM 2.5-induced cell apoptosis via AKT phosphorylation. Human serum-derived EVs may be an efficacious novel therapeutic strategy in PM 2.5-induced lung injury.


Assuntos
Poluentes Atmosféricos/toxicidade , Vesículas Extracelulares , Material Particulado/toxicidade , Substâncias Protetoras/farmacologia , Soro , Células A549 , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt/metabolismo
19.
Br J Clin Pharmacol ; 87(10): 3878-3889, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33638184

RESUMO

AIM: Several studies have reported population pharmacokinetic models for phenobarbital (PB), but the predictive performance of these models has not been well documented. This study aims to do external evaluation of the predictive performance in published pharmacokinetic models. METHODS: Therapeutic drug monitoring data collected in neonates and young infants treated with PB for seizure control was used for external evaluation. A literature review was conducted through PubMed to identify population pharmacokinetic models. Prediction- and simulation-based diagnostics, and Bayesian forecasting were performed for external evaluation. The incorporation of allometric scaling for body size and maturation factors into the published models was also tested for prediction improvement. RESULTS: A total of 79 serum concentrations from 28 subjects were included in the external dataset. Seven population pharmacokinetic studies of PB were identified as relevant in the literature search and included for our evaluation. The model by Voller et al showed the best performance concerning prediction-based evaluation. In simulation-based analyses, the normalized prediction distribution error of two models (those of Shellhaas et al and Marsot et al) obeyed a normal distribution. Bayesian forecasting with more than one observation improved predictive capability. Incorporation of both allometric size scaling and maturation function generally enhanced the predictive performance, with improvement as observed in the model of Vucicevic et al. CONCLUSIONS: The predictive performance of published pharmacokinetic models of PB was diverse. Bayesian forecasting and incorporation of both size and maturation factors could improve the predictability of the models for neonates.


Assuntos
Modelos Biológicos , Fenobarbital , Teorema de Bayes , Simulação por Computador , Monitoramento de Medicamentos , Humanos , Lactente , Recém-Nascido
20.
Eur J Pharm Sci ; 159: 105729, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33484815

RESUMO

OBJECTIVE: Pyrotinib, a new oral irreversible pan-ErbB tyrosine kinase inhibitor (TKI), has been approved in China for the treatment of HER2-positive advanced or metastatic breast cancer. This study aimed to conduct a population pharmacokinetics (PK) analysis of pyrotinib and to evaluate the impact of patient characteristics on pyrotinib's PK. METHOD: A total of 1152 samples, provided by 59 adult female patients from two phase I clinical trials, were analyzed by nonlinear mixed-effects modeling. Monte Carlo simulation was conducted to assess impact of covariates on the exposure to pyrotinib. RESULTS: The PK of pyrotinib was adequately described by a one-compartment model with first-order absorption and elimination. Patient's age and total protein levels could affect pyrotinib's apparent volume of distribution, and concomitant use of montmorillonite could decrease the bioavailability of pyrotinib by 50.3%. No PK interactions were observed between capecitabine and pyrotinib. CONCLUSION: In this study, a population PK model of pyrotinib was developed to determine the influence of patient characteristics on the PK of pyrotinib. While patient age and total protein levels can significantly affect the apparent distribution volume of pyrotinib, the magnitude of the impact was limited, thus no dosage adjustment was recommended. Furthermore, concomitant use of montmorillonite for diarrhea needs to be taken with precaution.


Assuntos
Neoplasias da Mama , Acrilamidas , Adulto , Aminoquinolinas , Neoplasias da Mama/tratamento farmacológico , China , Feminino , Humanos , Receptor ErbB-2
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