Understanding inter-individual variability in pharmacokinetics/pharmacodynamics of aripiprazole in children with tic disorders: Individualized administration based on physiological development and CYP2D6 genotypes.

Objective: This study aims to develop a combined population pharmacokinetic (PPK) model for aripiprazole (ARI) and its main active metabolite dehydroaripiprazole (DARI) in pediatric patients with tic disorders (TD), to investigate the inter-individual variability caused by physiological and genetic factors in pharmacokinetics of ARI and optimize the dosing regimens for pediatric patients. Methods: A prospective PPK research was performed in Chinese children with TD. Totally 84 patients aged 4.83-17.33 years were obtained for the pharmacokinetic analysis. 27 CYP2D6 and ABCB1 gene alleles were detected. Moreover, the clinical efficacy was evaluated according to reduction rate of Yale Global Tic Severity Scale (YGTSS) score at the 12th week comparing with the baseline. Monte Carlo simulations were used to evaluate and optimize dosing regimens. Results: The PPK model was established to predict the concentrations of ARI and DARI. Body weight and CYP2D6 genotype were the significant covariates affecting the clearance of ARI. The DARI/ARI metabolic ratios (MRs) of AUC24h, Cmin and Cmax at the steady state of results were ultra-rapid metabolizers (UMs) > normal metabolizers (NMs) > intermediated metabolizers (IMs). MRs could be used to distinguish UMs or IMs from other patients. The best predictor of clinical efficacy for TD was the trough concentration of ARI and the cut-off point was 101.636 ng/ml. Conclusion: The pharmacokinetics of ARI and DARI in pediatric TD were significantly influenced by body weight and CYP2D6 genotype. Individualized dosing regimens were recommended for pediatric patients with TD to ensure clinical efficacy.

Population Pharmacokinetics and Dosing Regimen Optimization of Latamoxef in Chinese Children.

The present study aimed to establish population pharmacokinetic models of latamoxef, as well as its R- and S-epimers, and generate findings to guide the individualized administration of latamoxef in pediatric patients. A total of 145 in-hospital children aged 0.08-10.58 years old were included in this study. Three population pharmacokinetic models of latamoxef and its R- and S-epimers were established. The stability and predictive ability of the final models were evaluated by utilizing goodness-of-fit plots, nonparametric bootstrapping, and normalized prediction distribution errors. The final model of total latamoxef was considered as a basis for the dosing regimen. A two-compartment model with first-order elimination best described the pharmacokinetics of total latamoxef. The population typical values of total latamoxef were as follows: central compartment distribution volume (V1) of 4.84 L, peripheral compartment distribution volume (V2) of 16.18 L, clearance (CL) of 1.00 L/h, and inter-compartmental clearance (Q) of 0.97 L/h. Moreover, R-epimer has a higher apparent volume of distribution and lower clearance than S-epimer. Body surface area (BSA) was identified as the most significant covariate to V, CL, and Q. Specific recommendations are given for dosage adjustment in pediatric patients based on BSA. This study highlights that a BSA-normalized dose of latamoxef was required when treating different bacteria to reach the therapeutic target more effectively.

Existing drug treatments cannot significantly shorten the clinical cure time of children with COVID-19.

INTRODUCTION: COVID-19 has become a global health security issue, it has caused more than half a million deaths worldwide so far, the treatment strategies are the most concerned issues for clinicians. In this study, the treatments and outcomes in 40 pediatric patients diagnosed with COVID-19 and treated with different drugs were evaluated. METHODOLOGY: All cases were diagnosed with COVID-19 nucleic acid positive by using RT-PCR or clinical manifestations, imaging specific characteristics and epidemiological clinical diagnosis. The biological information and first symptom of all cases were collect. A variety of treatments were employed and the outcomes were evaluated by Cox regression analysis. Multivariable analysis was performed to evaluate cure rate at 14 days with different drug treatment. RESULTS: The average length of hospital stay was 10.4 days. The cure rate was increased with the treatment time extended and 90% of pediatric patients were cured and discharged after 14 days' treatment. And multivariable analysis results proved that none of the covariates were related to the cure rate at 14 days with different drug treatment since p values were over 0.05. CONCLUSIONS: Multivariable analysis suggested that the present drug treatments cannot significantly shorten the clinical cure time and improve the cure rate of children with COVID-19.

Population Pharmacokinetics and Pharmacodynamics of Norvancomycin in Children With Malignant Hematological Disease.

Knowledge of pharmacokinetic (PK) behavior of norvancomycin (NVCM) in pediatric patients is lacking, which leads to empirical therapy in clinical practice. This study developed a population PK model of children aged 0-15 years; 112 opportunistic samples in total from 90 children were analyzed. The stability and prediction of the final model were evaluated by goodness-of-fit plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. The PKs of NVCM in children was described by a 2-compartment model with first-order elimination along with body weight and estimated glomerular filtration rate as significant covariates on clearance. The population typical values of the PK parameters were as follows: clearance 0.12 L/kg/h, central compartment distribution volume 0.17 L/kg, peripheral compartment distribution volume 0.38 L/kg, and intercompartmental clearance 0.35 L/kg/h. Logistic analysis showed that the ratio of area under the concentration-time curve over 24 hours (AUC0-24 ) to minimum inhibitory concentration (MIC) had the strongest correlation with clinical efficacy, and at least 80% clinical efficiency could be achieved when AUC0-24 /MIC ≥ 221.06 was defined as the target. Monte Carlo simulation results suggested that a higher dose was required for this pediatric population in order to reach the target. The dosing regimen was optimized based on the final model. A population PK model of NVCM was first characterized in children with hematologic malignancy, and an evidence-based approach for NVCM dosage individualization was provided.

Population Pharmacokinetics and Dosage Optimization of Teicoplanin in Children With Different Renal Functions.

OBJECTIVE: The purposes of our study were to investigate the population pharmacokinetics of teicoplanin in Chinese children with different renal functions and to propose the appropriate dosing regimen for these pediatric patients. METHODS: We performed a prospective pharmacokinetic research on children aged 0-10 years, with different renal functions. The population pharmacokinetics model of teicoplanin was developed using NLME program. The individualized optimal dosage regimen was proposed on the basis of the obtained population pharmacokinetics parameters. RESULTS: To achieve the target trough level of 10-30 mg/L, optimal dosing regimen for children with different renal functions are predicted as follows based on the population PK simulations: children with moderate renal insufficiency need three loading doses of 6 mg/kg q12h followed by a maintenance dose of 5 mg/kg qd; children with mild renal insufficiency require three loading doses of 12 mg/kg q12h followed by a maintenance dose of 8 mg/kg qd; children with normal or augmented renal function should be given three loading doses of 12 mg/kg q12h followed by a maintenance doses of 10 mg/kg qd. CONCLUSION: The first study on the population pharmacokinetics of teicoplanin in Chinese children with different renal functions was performed. Individualized dosing regimen was recommended for different renal function groups based on population PK model prediction.

Population Pharmacokinetics of Caspofungin and Dosing Optimization in Children With Allogeneic Hematopoietic Stem Cell Transplantation.

Caspofungin is the first echinocandin antifungal agent that licented for pediatric use in invasive candidiasis and aspergillosis. In this study, we evaluated the population pharmacokinetics of caspofungin and investigate appropriate dosing optimization against Candida spp. in children with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in order to improve therapeutic efficacy. All participants received a recommended caspofungin 70 mg/m2 loading dose followed by 50 mg/m2 maintenance dose. A one-compartment model with first-order elimination was best fitted the data from 48 pediatric patients. Body surface area and aspartate aminotransferase had significant influence on caspofungin clearance from covariate analysis. Our results reviewed that dose adjustment is not necessary in patients with mild liver dysfunction. Monte Carlo simulations were performed using pharmacokinetic data from our study to evaluate the probability of target attainment (PTA) of caspofungin regimen in terms of AUC24/MIC targets against Candida spp. The results of simulations predicted that a caspofungin 70 mg/m2 at first dose, 50 mg/m2 of daily dose may have a high probability of successful outcome against C. albicans and C. glabrata whilst 60 mg/m2 maintenance dose was required for fungistatic target against C. parapsilosis but may be not sufficient to achieve optimal fungicidal activity. Caspofungin standard regimen had high probability of successful outcome against C. albicans (MIC ⩽ 0.25 mg/L) and C. glabrata (MIC ⩽ 0.5 mg/L) but insufficient for C. parapsilosis with MIC > 0.25 mg/L. That may provide an evidence based support to caspofungin individualized administration and decrease the risk of therapeutic failure in allo-HSCT pediatric patients.

A novel electrochemical immunosensor based on the rGO-TEPA-PTC-NH2 and AuPt modified C60 bimetallic nanoclusters for the detection of Vangl1, a potential biomarker for dysontogenesis.

The aberrant expression of Vangl1 is highly correlated with dysontogenesis, especially for neural tube defects. Therefore, the ultrasensitive detection of Vangl1 would provide a new approach for the specific early diagnostics in dysembryoplasia. However, no quantitative detection method is currently available. Herein, we describe the development of a new approach to fill this assay gap. We utilized C60-templated AuPt bimetallic nanoclusters for signal amplification because the promising C60 nanomaterial provides a large surface area for the in site reduction of bimetallic nanocomposites as well as excellent conductivity. To further amplify the electrochemical signal, reduced graphene oxide-tetraethylene pentamine (rGO-TEPA) and a derivative of 3,4,9,10-perylenetetracarboxylicdianhydride (PTC-NH2) were selected for modification of the electrode to provide more amino groups for the immobilization of antibodies and to enhance the conductivity. The electrochemical signal was primarily derived from the catalysis of H2O2 by C60-AuPt. Chronoamperometry was applied to record the electrochemical signals. Under optimal conditions, the prepared immunosensor exhibited a wide linear range from 0.1 pg mL(-1) to 450 pg mL(-1) and a low detection limit of 0.03 pg mL(-1). Moreover, the proposed method exhibited good stability and recovery, suggesting its potential for use in clinical research.

A simultaneous electrochemical multianalyte immunoassay of high sensitivity C-reactive protein and soluble CD40 ligand based on reduced graphene oxide-tetraethylene pentamine that directly adsorb metal ions as labels.

A simplified electrochemical multianalyte immunosensor for the simultaneous detection of high sensitivity C-reactive protein (hsCRP) and soluble CD40 ligand (sCD40L) that uses reduced graphene oxide-tetraethylene pentamine (rGO-TEPA) that directly adsorbs metal ions as labels is reported. rGO-TEPA contains a large number of amino groups and has excellent conductivity, making it an ideal template for the loading of Pb(2+) and Cu(2+), which greatly amplifies the detection signals. The signals could be directly detected in a single run through differential pulse voltammetry (DPV), and each biorecognition event produces a distinct voltammetric peak. The position and size of each peak reflects the identity and the level of the corresponding antigen. Primarily designed for an application in a sandwich-type immunoassay based on Pb(2+) and Cu(2+) labels, two main challenges are accomplished with the herein presented nanosheets: fabrication of the template and the amination process for Pb(2+) and Cu(2+) adsorption. To further improve the analytical performance of the immunosensor, Au@bovine serum albumin (BSA) nanospheres synthesized through a "green" synthesis route were used as a sensor platform, which not only provides a biocompatible microenvironment for the immobilization of antibodies but also amplifies the electrochemical signals. Under optimal conditions, hsCRP and sCD40L could be assayed in the range of 0.05 to 100 ng mL(-1) with detection limits of 16.7 and 13.1 pg mL(-1) (S/N=3), respectively. The assay results on clinical serum samples with the proposed immunosensor were in acceptable agreement with those using the standard single-analyte test of the enzyme-linked immunosorbent assay (ELISA). This novel immunosensing system provides a simple, sensitive and low-cost approach for a multianalyte immunoassay.

Ultrasensitive electrochemical immunosensor based on orderly oriented conductive wires for the detection of human monocyte chemotactic protein-1 in serum.

For the first time, a simple, ultrasensitive and label-free electrochemical monocyte chemotactic protein-1 (MCP-1) immunosensor based on orderly oriented conductive wires has been developed. A conductive wire, which is similar to an electron-conducting tunnel, was designed with Au nanoparticles (AuNPs) joined to Au@Pt core-shell microspheres via a cysteamine (CA) crosslinker. To enhance the sensitivity of the immunosensor, Au nanoparticles were electrodeposited onto the gold electrode, and CA was self-assembled via strong Au-S covalent bonds, providing an appropriate surface and promoting electron transfer. Next, Au@Pt core-shell microspheres with large surface area were grafted onto the modified electrode to immobilize more MCP-1 antibodies. MCP-1 is an initiating factor and biomarker of atherosclerotic diseases. Under optimal experimental conditions, differential pulse voltammetry (DPV) current changes were used to detect MCP-1 with a broad linear range of 0.09-360 pg mL(-1) and a low detection limit of 0.03 pg mL(-1) (S/N=3). The proposed immunosensor exhibited good selectivity, reproducibility and reusability. When applied to spiked serum samples, the data for the developed immunosensor were in agreement with an enzyme linked immunosorbent assay, suggesting that the electrochemical immunosensor would be suitable for practical detection.

Ultrasensitive electrochemical detection of secretoneurin based on Pb(2+)-decorated reduced graphene oxide-tetraethylene pentamine as a label.

In this work, a novel electrochemical immunosensor for the detection of secretoneurin (SN), which uses metal ion functionalised reduced graphene oxide-tetraethylene pentamine (rGO-TEPA) as a label, is reported for the first time. rGO-TEPA contains a large number of amino groups, which makes it an ideal templet for the loading of metal ions. rGO-TEPA-Pb(2+) was employed to immobilise secondary secretoneurin (SN) antibody (Ab2), and the resulting nanocomposite (Ab2-rGO-TEPA-Pb(2+)) was used as a trace tag for signal amplification. A modified electrode consisting of functionalised graphene nanosheets (Au@GS) was used as a substrate to immobilise the antibodies. Under the optimal conditions, the immunoassay exhibited high sensitivity, acceptable stability and reproducibility with a wide linear range from 0.001 to 100ngmL(-1) (R=0.996), and an ultra-low detection limit of 0.33pgmL(-1) (S/N=3). Furthermore, the immunosensor could be employed to detect SN in clinical serum samples. The proposed sensing strategy enriches the electrochemical immunoassay and exhibits potential for the point-of-care diagnostic application of the clinical screening of biomarkers.

Ultrasensitive electrochemical biosensor based on graphite oxide, Prussian blue, and PTC-NH2 for the detection of α2,6-sialylated glycans in human serum.

α2,6-Sialylated glycans are crucial molecular targets for cancer diagnosis and clinical research. In this work, a novel ultrasensitive electrochemical biosensor was fabricated based on a graphite oxide (GO), Prussian blue (PB), and PTC-NH2 (an ammonolysis product of 3,4,9,10-perylenetetracarboxylic dianhydride) nanocomposite for the selective detection of α2,6-sialylated glycans. To increase the sensitivity of the electrochemical biosensor, gold nanoparticles (GNPs) were immobilized on a GO-PB-PTC-NH2 modified glassy carbon electrode (GCE). Sambucus nigra agglutinins (SNAs), which specifically bind with α2,6-sialylated glycans, were covalently immobilized on GNPs for the sensitive detection of α2,6-sialylated glycans in serum. This proposed method can be applied to human serum, and it worked well over a broad linear range (0.1 pg mL(-1)-500 ng mL(-1)) with detection limits of 0.03 pg mL(-1). Moreover, recovery of the spiked samples ranged from 100.2% to 105.0%, suggesting that this excellent electrochemical biosensor can be used for the practical detection of α2,6-sialylated glycans.