Lipidomics study of Liujunzi decoction in hyperlipidemia rats with spleen deficiency based on UPLC-Q-TOF/MS.

Hyperlipidemia refers to the abnormal levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) in peripheral blood circulation. It is a predominant risk factor underlying cardiovascular and cerebrovascular diseases, including coronary heart disease and atherosclerosis. Furthermore, it is also one of the most prevalent chronic diseases globally. Liujunzi Decoction is the basic prescription for the treatment of spleen and stomach diseases. It can tonify the spleen and qi, remove dampness, and reduce turbidity. Moreover, it is also clinically used for the treatment of spleen deficiency hyperlipidemia. However, its metabolites and therapeutic effect on spleen deficiency hyperlipidemia have not been comprehensively determined in vitro and in vivo. This study established a rat model of spleen deficiency hyperlipidemia by inducing starvation and satiety disorders, exhaustion swimming, and intragastric administration of the fat emulsion. To identify related metabolite changes and serum lipid composition, UPLC-Q-TOF-MS, PCA, and OPLS-DA lipidological methods were performed. The results demonstrated significant changes in rat's signs during the modeling process, which were consistent with the criteria for the syndrome differentiation of spleen deficiency in traditional Chinese medicine. Furthermore, this study identified 100 potential biomarkers in rat serum, of which 52 were associated with lipid synthesis, such as LPC, PC, PI, PE, PA, Cer, SM, etc. The pathways involved were glycerol phospholipid, sphingomyelin, and glycerol ester metabolisms. After the Liujunzi decoction intervention, 56 potential biomarkers were observed in the high-dose group, alleviating the metabolic spectrum imbalance by reducing metabolite levels. In addition, metabolic pathway disturbances were markedly improved. This study provides references for future studies on Liujunzi decoction and furnishes essential data for assessing the relationships between chemical constituents and pharmacological activities of Liujunzi decoction.

Population pharmacokinetics of valproic acid in children with epilepsy: Implications for dose tailoring when switching from oral syrup to sustained-release tablets.

Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady-state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20-50 kg. As a result, the PK characteristics of VPA were described using a one-compartment model with first-order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h-1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.

LC-MS/MS and EMIT measure the whole blood concentration of cyclosporine A: The two methods yield concordant results within the dynamic range of the latter, but the former shows broader application scenarios.

Cyclosporine A (CsA) is a widely used immunosuppressive drug with a narrow therapeutic index and large individual differences. Its therapeutic and toxic effects are closely related to blood drug concentrations, requiring routine therapeutic drug monitoring (TDM). The current main methods for TDM of CsA are enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, few study on the method comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children has been reported. In this study, we developed a simple and sensitive LC-MS/MS assay for the determination of CsA, and 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by the validated in-house LC-MS/MS method on the same batch of samples, aimed to address the aforementioned concern. Consistency between the two assays was evaluated using linear regression and Bland-Altman analysis. The linear range of LC-MS/MS was 0.500-2000 ng/mL and that of the EMIT was 40-500 ng/mL, respectively. Overall, the correlation between the two methods was significant (r-value ranging from 0.8842 to 0.9441). Unsatisfactory consistency was observed in the concentrations < 40 ng/mL (r = 0.7325) and 200-500 ng/mL (r = 0.6851). Bland-Altman plot showed a mean bias of -18.0 % (±1.96 SD, -73.8 to 37.8 %) between EMIT and LC-MS/MS. For Passing-Bablok regression between EMIT and LC-MS/MS did not differ significantly (p > 0.05). In conclusion, the two methods were closely correlated, but the CsA concentration by LC-MS/MS assay was slightly higher than that by EMIT method. Switching from the EMIT assay to the LC-MS/MS method was acceptable, and the LC-MS/MS method will receive broader application in clinical settings due to its better analytical capabilities, but the results need to be further verified in different laboratories.

Cordycepin alleviates hepatic fibrosis in association with the inhibition of glutaminolysis to promote hepatic stellate cell senescence.

Cordycepin (CRD) is an active component derived from Cordyceps militaris, which possesses multiple biological activities and uses in liver disease. However, whether CRD improves liver fibrosis by regulating hepatic stellate cell (HSC) activation has remained unknown. The study aims further to clarify the activities of CRD on liver fibrosis and elucidate the possible mechanism. Our results demonstrated that CRD significantly relieved hepatocyte injury and inhibited HSC activation, alleviating hepatic fibrogenesis in the Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC)-induced mice model. In vitro, CRD exhibited dose-dependent repress effects on HSC proliferation, migration, and pro-fibrotic function in TGF-ß1-activated LX-2 and JS-1 cells. The functional enrichment analysis of RNA-seq data indicated that the pathway through which CRD alleviates HSC activation involves cellular senescence and cell cycle-related pathways. Furthermore, it was observed that CRD accumulated the number of senescence-associated a-galactosidase positive cells and the levels of senescencemarker p21, and provoked S phasearrestof activated HSC. Remarkably, CRD treatment abolished TGF-ß-induced yes-associated protein (YAP) nuclear translocation that acts upstream of glutaminolysis in activated HSC. On the whole, CRD significantly inhibited glutaminolysis of activated-HSC and induced cell senescence through the YAP signaling pathway, consequently alleviating liver fibrosis, which may be a valuable supplement for treating liver fibrosis.

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together.

Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children's Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.

Effectiveness and safety of mono- and add-on perampanel in pediatric patients with epilepsy: Experience from a single-center retrospective study.

OBJECTIVE: To evaluate the effectiveness and safety of perampanel (PER) monotherapy (MT) or add-on therapy (AT) in Chinese children with epilepsy, as well as to evaluate the data from routine therapeutic drug monitoring (TDM) of PER for these pediatric patients. METHODS: This retrospective and observational study was carried out on children with epilepsy (n = 340) from 2020 to 2022 at the Children's Hospital of Nanjing Medical University. Outcome measures were the responder rate (50% or greater seizure reduction), long-term efficacy, and tolerability (number and types of adverse events) in MT and AT groups. Concentrations of plasma PER obtained from these patients, if available, were analyzed too. RESULTS: A total of 279 patients achieved at least 3 months of therapy, and 58.1% responded to PER therapy. 53 of the responders were seizure-free (32.7%). The retention rate dropped from 88.0% at 3 months to 40.6% at 12 months after treatment. Patients with MT achieved better seizure control than those with AT (P < 0.001). Intriguingly, PER exerted a very weak effect on patients who took more than 2 ASMs or were diagnosed with drug-resistant epilepsy. There were no significant differences in tolerability between the two groups. In addition, 179 patients were routinely monitored for PER, and the trough concentrations (C0 ) for these patients ranged from 30.0 to 992.0 ng/mL. However, no significant difference in C0 was observed between responders and nonresponders (333 ng/mL vs 325.5 ng/mL, P = 0.264). SIGNIFICANCE: This study provides effectiveness and safety data on Chinese children with epilepsy treated with PER either as MT or as AT. The efficacy of patients receiving MT was much better than cases administered with more than 2 ASMs or diagnosed with drug-resistant epilepsy. In addition, no association was found between the plasma PER concentration and efficacy or safety. PLAIN LANGUAGE SUMMARY: The study reports the effects of perampanel on seizures and adverse effects in Chinese patients with epilepsy younger than 18 years. Seizures decreased in 58.1% of patients (responders); in a third of these responders, seizures stopped. After treatment was started, 88% of patients were still on perampanel at 3 months and 40.6% at 12 months. People who were treated with perampanel only were more likely to respond than those who received perampanel and other antiseizure treatments, although perampanel was tolerated equally well in these groups. Plasma perampanel concentration did not predict seizure response or adverse effects.

From "wet" matrices to "dry" blood spot sampling strategy: a versatile LC-MS/MS assay for simultaneous monitoring caffeine and its three primary metabolites in preterm infants.

OBJECTIVES: To update traditional "wet" matrices to dried blood spot (DBS) sampling, based on the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technique, and develop a method for simultaneous analyzing caffeine and its three primary metabolites (theobromine, paraxanthine, and theophylline), supporting routine therapeutic drug monitoring (TDM) for preterm infants. METHODS: DBS samples were prepared by a two-step quantitative sampling method, i.e., volumetric sampling of a quantitative 10 µL volume of peripheral blood and an 8 mm diameter whole punch extraction by a methanol/water (80/20, v/v) mixture containing 125 mM formic acid. Four paired stable isotope labeled internal standards and a collision energy defect strategy were applied for the method optimization. The method was fully validated following international guidelines and industrial recommendations on DBS analysis. Cross validation with previously developed plasma method was also proceeded. The validated method was then implemented on the TDM for preterm infants. RESULTS: The two-step quantitative sampling strategy and a high recovery extraction method were developed and optimized. The method validation results were all within the acceptable criteria. Satisfactory parallelism, concordance, and correlation were observed between DBS and plasma concentrations of the four analytes. The method was applied to provide routine TDM services to 20 preterm infants. CONCLUSIONS: A versatile LC-MS/MS platform for simultaneous monitoring caffeine and its three primary metabolites was developed, fully validated, and successfully applied into the routine clinical TDM practices. Sampling method switching from "wet" matrices to "dry" DBS will facilitate and support the precision dosing of caffeine for preterm infants.

Dynamics of an SEIR model with media coverage mediated nonlinear infectious force.

Media coverage can greatly impact the spread of infectious diseases. Taking into consideration the impacts of media coverage, we propose an SEIR model with a media coverage mediated nonlinear infection force. For this novel disease model, we identify the basic reproduction number using the next generation matrix method and establish the global threshold results: If the basic reproduction number $ \mathcal{R}_{0} < 1 $, then the disease-free equilibrium $ P_{0} $ is stable, and the disease dies out. If $ \mathcal{R}_{0} > 1 $, then the endemic equilibrium $ P^{*} $ is stable, and the disease persists. Sensitivity analysis indicates that the basic reproduction number $ \mathcal{R}_{0} $ is most sensitive to the population recruitment rate $ \Lambda $ and the disease transmission rate $ \beta _{1} $.

Pseudo-heterostructure and condensation of 1D moiré excitons in twisted phosphorene bilayers.

Heterostructures are not expected to form in a single homogeneous material. Here, we show that planar pseudo-heterostructures could emerge in a twisted bilayer of phosphorene (tbP), driving in-plane energy and charge transfer. The formation of moiré superlattices combined with electronic anisotropy in tbPs yields one-dimensional (1D) moiré excitons with long radiative and nonradiative lifetimes, large binding energies, and deep moiré potentials. Low-frequency moiré phonons and dynamic moiré potentials are revealed to be responsible for the in-plane energy/charge transfer and exciton dynamics. The 1D moiré excitons are predicted to exhibit Bose-Einstein condensation at high temperatures and may lead to exotic Tonks-Girardeau Bose gases.

Successful LC-MS/MS assay development and validation for determination of valproic acid and its metabolites supporting proactive pharmacovigilance.

Valproic acid (VPA) is a well-documented contributor to liver injury, which is likely caused by the formation of its toxic metabolites. Monitoring VPA and its metabolites is very meaningful for the pharmacovigilance, but the availability of a powerful assay is a prerequisite. In this study, for the first time, a sensitive and specific LC-MS/MS method was developed and validated to simultaneously quantify the concentrations of VPA and its six pestering isomer metabolites (3-OH-VPA, 4-OH-VPA, 5-OH-VPA, 2-PGA, VPA-G, and 2-ene-VPA) in human plasma, using 5-OH-VPA-d7 and VPA-d6 as the internal standards (ISs). We also figured out another tricky problem that the concentrations of the parent drug and the metabolites vary widely. Of note, after protein precipitation and dilution with acetonitrile (ACN) and 50% ACN successively, the analytes and the ISs were successfully separated on a Kinetex C18 column. Intriguingly, sacrificing its signal intensity by elevated collision energy of VPA finally achieved the simultaneous determination. As expected, the method showed great linearity (r > 0.998) over the concentration ranges for all analytes. The inter-day and intra-day accuracy and precision were both acceptable. The method was successfully applied in 127 children with epilepsy. This novel assay will support the VPA-associated pharmacovigilance in the future.

Effects of Sodium Tripolyphosphate Addition on the Dispersion and Hydration of Pure Calcium Aluminate Cement.

In this paper, the effect of a sodium tripolyphosphate (STPP) addition on the dispersion and hydration of pure calcium aluminate cement (PCAC) was investigated, and the corresponding mechanism of effect was studied. The effects of STPP on the dispersion, rheology, and hydration processes of PCAC and its adsorption capacity on the surface of cement particles were analysed by measuring the 𝜁-potential on the surface of cement particles, the changes in the concentrations of elemental P and Ca2+ ions in a solution at different STPP additions. The experimental results show that STPP easily complexes with Ca2+ ions to produce the complex [CaP3O10]3- adsorbed on the surface of cement particles, which changes the potential on the surface of cement particles and increases the electrostatic repulsive force between cement particles, thus improving the dispersion and rheology of cement. At the same time, the contact area between cement particles and water is reduced, which hinders the hydration process and makes the time of hydration process longer. A comprehensive analysis shows that the best effect of STPP on pure calcium aluminate cements is achieved when the addition of STPP is 0.2%. This study can provide a reference for the addition of water-reducing agents in refractory castables as well as improving the quality of refractory materials.

Rapid determination of plasma vigabatrin by LC-ESI-MS/MS supporting therapeutic drug monitoring in children with infantile spasms.

Vigabatrin is one of the second-generation anti-seizure medications (ASMs) designated orphan drugs by the FDA for monotherapy for pediatric patients with infantile spasms from 1 month to 2 years of age. Vigabatrin is also indicated as the adjunctive therapy for adults and pediatric patients 10 years of age and older with refractory complex partial seizures. Ideally, the vigabatrin treatment entails achieving complete seizure freedom without significant adverse effects, and the therapeutic drug monitoring (TDM) will make a significant contribution to this aim, which provides a pragmatic approach to such epilepsy care in that the dose tailoring can be undertaken for uncontrollable seizures and in cases of clinical toxicity guided by the drug concentrations. Thus, reliable assays are mandatory for TDM to be valuable, and blood, plasma, or serum are the matrixes of choice. In this study, a simple, rapid, and sensitive LC-ESI-MS/MS method for the measurement of plasma vigabatrin was developed and validated. The sample clean-up was performed by an easy-to-use method, i.e., protein precipitation using acetonitrile (ACN). Chromatographic separation of vigabatrin and vigabatrin-13C,d2 (internal standard) was achieved on the Waters symmetry C18 column (4.6 mm × 50 mm, 3.5 µm) with isocratic elution at a flow rate of 0.35 mL min-1. The target analyte was completely separated by elution with a highly aqueous mobile phase for 5 min, without any endogenous interference. The method showed good linearity over the 0.010-50.0 µg mL-1 concentration range with a correlation coefficient r2 = 0.9982. The intra-batch and inter-batch precision and accuracy, recovery, and stability of the method were all within the acceptable parameters. Moreover, the method was successfully used in pediatric patients treated with vigabatrin and also provided valuable information for clinicians by monitoring plasma vigabatrin levels in our hospital.

Study on persulfate activated by Ce-modified tea waste biochar to degrade tetracycline.

In this study, the Ce-modified tea residue biochar (Ce-TBC) was successfully generated and applied to the biochar/persulfate system (Ce-TBC/PDS), the mechanism of the removal of tetracycline (TC) using Ce-TBC/PDS was elaborated. Under the optimal experimental conditions (Ce-TBC = 0.8 g L-1, PDS = 4 mM, TC = 10 mg L-1), the removal efficiency of TC was 91.28%, and after 5 cycles, the elimination rate of Ce-TBC/PDS still reached up to 80%. The mechanism of TC removal by Ce-TBC/PDS was analyzed by scanning electron microscopy (SEM), X-ray diffractometer (XRD), Fourier infrared transform spectrometer (FT-IR), and X-ray photoelectron spectrometer (XPS) characterization, and influence factor experiments. The results showed that the introduction of CeOx increased the oxygen vacancies on the TBC surface and promoted the interconversion between Ce3+ and Ce4+ for better activation of PDS and generation of active species. Free radical quenching experiments and paramagnetic resonance spectrometry (EPR) analysis showed that the non-radical pathway 1O2 played a dominant role in the Ce-TBC/PDS system. The present work provided an efficient means of PDS activator and recycling of tea waste.

A rapid and sensitive LC-ESI-MS/MS method for determining vincristine in micro-volumes of plasma for pediatric cancer patients.

Vincristine is a natural vinca alkaloid drug, which is widely used in pediatric cancer treatment with dose-dependent neurotoxicity. Thus far, little is known about the association between neurotoxicity and plasma vincristine concentration, which markedly varies among individuals. Routine therapeutic drug monitoring (TDM) can be seen as a reliable strategy to improve efficacy and reduce side effects. Therefore, a rapid, sensitive, and reproducible method is critical for the clinical implementation of TDM. In this study, micro-volume (50 µL) human plasma samples were prepared by a simple one-step protein precipitation method with acetonitrile. Chromatographic separation of vincristine and its internal standard vincristine-d3 from background noise was achieved on a Kinetex C18 column (2.1 mm × 50 mm, 1.7 µm) with a gradient elution program at a flow rate of 0.3 mL min-1 in 4 min. The mass spectrometric detection was performed in electrospray ionization multiple reaction monitoring mode using the ion transitions of 825.4 → 765.1 for vincristine, and 828.2 → 768.2 for vincristine-d3, respectively. As a result, no matrix effect was observed. The lower limit of quantification was 0.5 ng mL-1 with a precision of 14.6% and an accuracy of 97.4%. The calibration curve was linear from 0.5 to 100 ng mL-1 (r2 > 0.99, n = 8). The intra- and inter-batch precision and accuracy, recovery, and stability of the new method were all within the acceptable criteria. The method was successfully applied to monitor the vincristine concentration for six pediatric cancer patients. Arguably, such proactive TDM of vincristine may be helpful to manage the treatment for these cancer patients.

Integrating metabolomics and lipidomics revealed a decrease in plasma fatty acids but an increase in triglycerides in children with drug-refractory epilepsy.

OBJECTIVE: The drug-refractory epilepsy (DRE) in children is commonly observed but the underlying mechanisms remain elusive. We examined whether fatty acids (FAs) and lipids are potentially associated with the pharmacoresistance to valproic acid (VPA) therapy. METHODS: This single-center, retrospective cohort study was conducted using data from pediatric patients collected between May 2019 and December 2019 at the Children's Hospital of Nanjing Medical University. Ninety plasma samples from 53 responders with VPA monotherapy (RE group) and 37 non-responders with VPA polytherapy (NR group) were collected. Non-targeted metabolomics and lipidomics analysis for those plasma samples were performed to compare the potential differences of small metabolites and lipids between the two groups. Plasma metabolites and lipids passing the threshold of variable importance in projection value >1, fold change >1.2 or <0.8, and p-value <0.05 were regarded as statistically different substances. RESULTS: A total of 204 small metabolites and 433 lipids comprising 16 different lipid subclasses were identified. The well-established partial least squares-discriminant analysis (PLS-DA) revealed a good separation of the RE from the NR group. The FAs and glycerophospholipids status were significantly decreased in the NR group, but their triglycerides (TG) levels were significantly increased. The trend of TG levels in routine laboratory tests was in line with the lipidomics analysis. Meanwhile, cases from the NR group were characterized by a decreased level of citric acid and L-thyroxine, but with an increased level of glucose and 2-oxoglutarate. The top two enriched metabolic pathways involved in the DRE condition were biosynthesis of unsaturated FAs and linoleic acid metabolism. SIGNIFICANCE: The results of this study suggested an association between metabolism of FAs and the medically intractable epilepsy. Such novel findings might propose a potential mechanism linked to the energy metabolism. Ketogenic acid and FAs supplementation might therefore be high-priority strategies for DRE management.

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Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence.

PURPOSE: There is marked heterogeneity in treatment response of atomoxetine in patients with attention deficit/hyperactivity disorder (ADHD), especially for the pediatric population. This review aims to evaluate current evidence to characterize the dose-exposure relationship, establish clinically relevant metrics for systemic exposure to atomoxetine, define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. METHODS: A comprehensive search was performed across electronic databases (PubMed and Embase) covering the period of January 1, 1985 to July 10, 2022, to summarize recent advances in the pharmacokinetics, pharmacogenomics/pharmacogenetics (PGx), therapeutic drug monitoring (TDM), physiologically based pharmacokinetics (PBPK), and population pharmacokinetics (PPK) of atomoxetine in children with ADHD. RESULTS: Some factors affecting the pharmacokinetics of atomoxetine were summarized, including food, CYP2D6 and CYP2C19 phenotypes, and drug‒drug interactions (DDIs). The association between treatment response and genetic polymorphisms of genes encoding pharmacological targets, such as norepinephrine transporter (NET/SLC6A2) and dopamine ß hydroxylase (DBH), was also discussed. Based on well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response was far from sufficient. CONCLUSION: Personalizing atomoxetine dosage may be even more complex than anticipated thus far, but elucidating the best way to tailor the non-stimulant to a patient's individual need will be achieved by combining two strategies: detailed research in linking the pharmacokinetics and pharmacodynamics in pediatric patients, and better understanding in nature and causes of ADHD, as well as environmental stressors.

Coherent Phonon-Induced Gigahertz Optical Birefringence and Its Manipulation in SrTiO3.

Birefringence, which modulates the polarization of electromagnetic wave, has been commercially developed and widely used in modern photonics. Fostered by high-frequency signal processing and communications, feasible birefringence technologies operating in gigahertz (GHz) range are highly desired. Here, a coherent phonon-induced GHz optical birefringence and its manipulation in SrTiO3 (STO) crystals are demonsrated. With ultrafast laser pumping, the coherent acoustic phonons with low damping are created in the transducer/STO structures. A series of transducer layers are examined and the optimized one with relatively high photon-phonon conversion efficiency, i.e., semiconducting LaRhO3 film, is obtained. The most intriguing finding here is that, by virtue of high sensitivity to strain perturbation of STO, GHz optical birefringence can be induced by the coherent acoustic phonons and the birefringent amplitudes possess crystal orientation dependence. Optical manipulation of both coherent phonons and its induced GHz birefringence by double pump technique are also realized. These findings reveal an alternative mechanism of ultrafast optical birefringence control, and offer prospects for applications in high-frequency acoustic-optics devices.

Strong Interlayer Coupling in Twisted Transition Metal Dichalcogenide Moiré Superlattices.

Moiré superlattices in twisted van der Waals materials offer a powerful platform for exploring light-matter interactions. The periodic moiré potentials in moiré superlattices can induce strongly correlated quantum phenomena that depend on the moiré potential associated with interlayer coupling at the interface. However, moiré superlattices are primarily prepared by mechanical exfoliation and manual stacking, where the transfer methods easily cause interfacial contamination, and the preparation of high-quality bilayer 2D materials with small twist angles by growth methods remains a significant challenge. In this work, WSe2 /WSe2 homobilayers with different twist angles by chemical vapor deposition (CVD), using a heteroatom-assisted growth technique, are synthesized. Using low-frequency Raman scattering, the uniformity of the moiré superlattices is mapped to demonstrate the strong interfacial coupling of the CVD-fabricated twist-angle homobilayers. The moiré potential depths of the CVD-grown and artificially stacked homostructures with twist angles of 1.5° are 115 and 45 meV (an increase of 155%), indicating that the depth of moiré potential can be modulated by the interfacial coupling. These results open a new avenue to study the modulation of moiré potential by strong interlayer coupling and provide a foundation for the development of twistronics.

A Systematic Review of Linezolid Pharmacokinetics/Pharmacodynamics in Patients Undergoing Continuous Renal Replacement Therapy: Does One Size Fit All?

BACKGROUND: Selection of the optimal antimicrobial posology in critically ill patients remains a challenge, especially in patients with sepsis who undergo continuous renal replacement therapy (CRRT). This systematic review aimed to analyze factors that influence the extracorporeal removal of linezolid. METHODS: A comprehensive search was performed to identify studies published up to March 2022 in PubMed, MEDLINE and EMBASE databases. Studies involving adults receiving CRRT and treatment with linezolid were considered eligible if the CRRT setting and linezolid's pharmacokinetic parameters were clearly mentioned. RESULTS: Six out of 110 potentially relevant studies were included. A total of 101 treatments were identified among 97 enrolled patients. Our analysis showed that continuous veno-venous hemodiafiltration (CVVHDF) was the most frequential used modality (52 cases). Despite distribution volume, the clearance (CL) of linezolid in these studies had large variability. Extracorporeal linezolid removal may be markedly impacted by CRRT dose. There is significant between-subject variability in the probability of pharmacokinetics-pharmacodynamics (PK-PD) target attainment of patients treated with CRRT. CONCLUSION: Dose adjustment, shortening the dosing interval, and continuous infusion were proposed as regimen optimization. Therapeutic drug monitoring is recommended due to the high variability of linezolid exposure among patients with CRRT, specifically for those whose bodyweight is high, renal function is preserved, and the MIC of infection bacteria is above 2 µg/mL.