Pharmacogenetic and pharmacokinetic factors for dexmedetomidine-associated hemodynamic instability in pediatric patients.

Purpose: The incidence of hemodynamic instability associated with dexmedetomidine (DEX) sedation has been reported to exceed 50%, with substantial inter-individual variability in response. Genetic factors have been suggested to contribute significantly to such variation. The aim of this study was to identify the clinical, pharmacokinetic, and genetic factors associated with DEX-induced hemodynamic instability in pediatric anesthesia patients.

Physiologically Based Pharmacokinetic Modeling of Vancomycin and its Comparison with Population Pharmacokinetic Model in Neonates.

Vancomycin has a narrow therapeutic window and a high inter-individual pharmacokinetic variability, especially in neonates with fast maturational and pathophysiological changes, that needs individualized dosing. Physiologically based pharmacokinetic (PBPK) model and population pharmacokinetic (PopPK) model are both useful tools in model-informed precision dosing, while the former is under research in application of vancomycin in neonates. This study aimed to develop a PBPK model of vancomycin in adult and pediatric population, and compared it with published PopPK model (priori or Bayesian method) in predicting vancomycin concentration in 230 neonatal patients (postmenstrual age, PMA, 25-45 weeks).

Physiologically-based pharmacokinetic modelling to investigate the effect of CYP3A4/3A5 maturation on tacrolimus pharmacokinetics in paediatric HSCT patients.

Tacrolimus (FK506) is a cornerstone of GVHD-prophylaxis treatment in paediatrics undergoing haematopoietic stem cell transplantation (HSCT). However, due to concerns about highly inter/intra-individual variability, precision dosing of FK506 is crucial. Cytochrome P450 (CYP) 3A4 and 3A5 are considered important sources of FK506 pharmacokinetic variability.

Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy.

Background And Objectives: A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy.

Methods: The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence.

Early proactive monitoring of DNA-thioguanine in patients with Crohn's disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers.

Background: Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines. Dose optimization guided by nudix hydrolase 15 () has significantly reduced the early leucopenia rate, but there are no definitive biomarkers for late risk leucopenia prediction.

Aim: To determine the predictive value of early monitoring of DNA-thioguanine (DNATG) or 6-thioguanine nucleotides (6TGN) for late leucopenia under a -guided thiopurine dosing strategy in patients with Crohn's disease (CD).

Physiologically-Based Pharmacokinetic Modeling and Dosing Optimization of Cefotaxime in Preterm and Term Neonates.

Background: Cefotaxime is commonly used in treating bacterial infections in neonates. To characterize the pharmacokinetic process in neonates and evaluate different recommended dosing schedules of cefotaxime, a physiologically-based pharmacokinetic (PBPK) model of cefotaxime was established in adults and scaled to neonates.

Methods: A whole-body PBPK model was built in PK-SIM® software.

Development and validation of a sensitive LC-MS/MS method for the assay of four PARP inhibitors in human plasma and its application in ovarian cancer patients.

PARP inhibitors have demonstrated marked efficacy in ovarian cancer patients with BRCA1/2 loss-of-function mutations. In this study, we established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) based method to simultaneously quantify the four frequently prescripted PARP inhibitors, namely niraparib, olaparib，fluzoparib, and pamiparib, in ovarian cancer. The mobile phase was 50 % methanol with 0.

A high-throughput UHPLC-MS/MS method for the determination of eight anti-tumor drugs in plasma.

Rapidly developing UHPLC-MS/MS bioassays with high throughput and quality are challenging yet desired in routine clinics. METHODS & RESULTS: A high-throughput UHPLC-MS/MS bioassay has been built for simultaneously quantifying gefitinib, ruxolitinib, dasatinib, imatinib, ibrutinib, methotrexate, cyclophosphamide and paclitaxel. After the protein precipitation with methanol, samples were separated on an Acquity BEH C column following a gradient elution system with methanol and 2 mM ammonium acetate in water at 40 °C with a run time of 3 min (flow rate 0.

Simultaneous Quantitation of Anlotinib and Osimertinib by Isotope-Labeled UHPLC-MS/MS in Human Plasma: Application in NSCLC Patients.

Anlotinib and osimertinib are a class of tyrosine kinase inhibitors for the treatment of malignant tumor. The combination of anlotinib and osimertinib is currently used for treating non-small cell lung cancer (NSCLC) patients. This study aimed to develop a simple and rapid isotope-labeled UHPLC-MS/MS method for the simultaneous determination of anlotinib and osimertinib in human plasma.

Genotype and phenotype analysis of epilepsy caused by ADGRV1 mutations in Chinese children.

Objective: To investigate the genotype and phenotype of epilepsy caused by ADGRV1 variants in Chinese children.

Methods: A total of 625 patients with epilepsy who had undergone whole-exon gene sequencing or epilepsy and related paroxysmal disease gene panel sequencing were recruited. Variants were evaluated for susceptibility pathogenicity based on their frequency in the Genome Aggregation Database (≤ 0.

Machine learning approach identified clusters for patients with low cardiac output syndrome and outcomes after cardiac surgery.

Background: Low cardiac output syndrome (LCOS) is the most serious physiological abnormality with high mortality for patients after cardiac surgery. This study aimed to explore the multidimensional data of clinical features and outcomes to provide individualized care for patients with LCOS.

Methods: The electronic medical information of the intensive care units (ICUs) was extracted from a tertiary hospital in South China.

Nongenetic and genetic predictors of haemodynamic instability induced by propofol and opioids: A retrospective clinical study.

Aim: Propofol and opioids are commonly used in anaesthesia, but are highly susceptible to haemodynamic instability, thereby threatening the patient's surgical safety and prognosis. The purpose of this study was to investigate the predictors of haemodynamic instability and establish its predictive model.

Methods: A total of 150 Chinese patients undergoing thyroid or breast surgery participated in the study, with target-controlled infusion concentrations of propofol, opioids dosage, heart rate (HR), mean arterial pressure (MAP) and Narcotrend Index recorded at key points throughout the procedure.

Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients.

There is a substantial lack of tacrolimus pharmacokinetic information in pediatric hematopoietic stem cell transplant (HSCT) patients. This study aimed to develop population pharmacokinetics (PopPK) of tacrolimus in pediatric HSCT patients and to devise model-guided dosage regimens. A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally.

Nicotine Delivery and Pharmacokinetics of an Electronic Cigarette Compared With Conventional Cigarettes in Chinese Adult Smokers: A Randomized Open-Label Crossover Clinical Study.

Introduction: To evaluate the nicotine pharmacokinetics of a commercial electronic cigarette (e-cigarette) relative to conventional cigarettes in Chinese adult smokers.

Aims And Methods: A randomized, open-label, crossover clinical study was conducted on 23 healthy adult Chinese smokers. In two sessions, subjects used either the e-cigarettes with 30 mg/g nicotine in e-liquid or conventional cigarettes of a given brand, at one puff every 30 seconds for a total of 10 puffs.

LC-MS/MS quantification of levetiracetam, lamotrigine and 10-hydroxycarbazepine in TDM of epileptic patients.

Background: To minimize drug-related toxicity and monitor dosing regimens, an ultra-sensitive, simple and high-throughput analytical method for therapeutic drug monitoring is required. A novel LC-MS/MS bioassay of levetiracetam, lamotrigine and 10-hydroxycarbazepine in human plasma was established. The analytes were separated on a Hypersil GOLD™ C column under a 2.

Development, validation and application of a UHPLC-MS/MS method for quantification of the adiponectin-derived active peptide ADP355 in rat plasma.

A UHPLC-MS/MS method for the quantification of ADP355, an adiponectin-derived active peptide, was developed and validated. The extraction method employed simple protein precipitation using methanol and chromatographic separation was achieved on anAccucore™ RP-MS C column (100 × 2.1 mm, 2.

A single nucleotide polymorphism-based formula to predict the risk of propofol TCI concentration being over 4 µg mL at the time of loss of consciousness.

We aim to develop a formula based on single nucleotide polymorphisms (SNPs) to predict whether the propofol target-controlled infusion (TCI) concentration would be over 4 μg mL at the time of loss of consciousness (LOC). We recruited 184 patients undergoing thyroid or breast surgeries with propofol anaesthesia. A total of 48 SNPs of CYP2B6, CYP2C9, UGT1A9, HNF4A, ABCB1, ABCC4, ABCG2, GABRA2, GABRA4, GABRB1, GABRB3, GABRG2, GABBR2, GAD1, SLC1A3, BDNF, and NRXN1, previously associated with propofol metabolic and pharmacology pathway, were genotyped.

Novel Clinical Biomarkers for Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) remains a critical clinical issue and has been a treatment challenge today as it was in the past. However, the traditional biomarkers or indicators are insufficient to predict the risks and outcome of patients with DILI due to its poor specificity and sensitivity. Recently, the development of high-throughput technologies, especially omics and multiomics has sparked growing interests in identification of novel clinical DILI biomarkers, many of which also provide a mechanistic insight.

Rituximab exposure-response in triweekly R-CHOP treatment in DLBCL: A loading dose is recommended to improve clinical outcomes.

Previous exposure-response analyses for rituximab suggest that higher rituximab concentrations were associated with an improvement in efficacy, however, clinical studies investigating a higher rituximab dose had mixed results. To further explore the exposure-response relationship of rituximab, a prospective observational analysis was performed involving 121 newly diagnosed patients with diffuse large B-cell lymphoma treated with triweekly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The trough concentration in the first cycle (C ) was significantly higher in patients achieving complete response (CR) compared with patients that did not achieve CR (22.

Global research trends of drug-induced liver injury (DILI) in the past two decades: a bibliometric and visualized study.

Background: Drug-induced liver injury (DILI) has become one of the most common and serious adverse drug reactions owing to its high morbidity and leading cause of hepatic failures, which had attracted great attentions worldwide in the past two decades. A need therefore exists to conduct a bibliometric and visualized analysis of the global research trends on DILI with the aim of identifying the status of current research and prioritize the future research areas.

Methods: Publications related to DILI from 1999 to 2019 were extracted through an electronic search of the Web of Science (WoS) and PubMed databases.

Circulating microRNA-30a-5p, microRNA-101-3p, microRNA-140-3p and microRNA-141-3p as potential biomarkers for dexmedetomidine response in pediatric patients.

Purpose: The aim of this study was to investigate the expression levels of plasma miR-30a-5p, miR-101-3p, miR-140-3p and miR-141-3p and their relationship to dexmedetomidine efficacy and adverse effects in pediatric patients.

Methods: The expression levels of miR-30a-5p, miR-101-3p, miR-140-3p and miR-141-3p were measured by qRT-PCR in plasma of 133 pediatric patients receiving dexmedetomidine for preoperative sedation. We analyzed the relationship between miRNA abundance and dexmedetomidine response, including sedative effect and adverse effects, and assessed the predictive power of miRNAs for drug response.

Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2.

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals.

Developing an isotope dilution UHPLC-MS/MS method to quantify linezolid in human plasma: application to therapeutic drug monitoring.

To optimize clinical efficacy and reduce the drug-exposure-related toxicity of linezolid, whose concentrations show wide inter-variabilities, a simple and reliable quantitative assay for therapeutic drug monitoring is necessary. A UHPLC-MS/MS assay has been established for determination of linezolid in human plasma and fully validated according to the US FDA guidelines. After a simple, isotope-dilluted precipitation with methanol, the analytes were separated by a straightforward isocratic mode and the MS/MS was conducted under the ESI mode fitted with SRM.

Simultaneous determination of canrenone, digoxin and tolvaptan by UHPLC-MS/MS: application in heart failure patients.

Heart failure patients are frequently given comedication of digoxin and diuretics like spironolactone and tolvaptan. A UHPLC-MS/MS assay for determining canrenone (main active metabolite of spironolactone), digoxin and tolvaptan simultaneously should be developed so as to support related drug-drug interaction studies. A UHPLC-MS/MS method for simultaneous determination of these three drugs in human plasma was established and fully verified as per CFDA guidelines.