Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

WHAT IS KNOWN AND OBJECTIVE: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. METHODS: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. RESULTS: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine. WHAT IS NEW AND CONCLUSION: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

Infection, Screening, and Psychological Stress of Health-Care Workers With COVID-19 in a Nonfrontline Clinical Department.

OBJECTIVES: The aim of this study was to investigate risk factors and psychological stress of health-care workers (HCWs) with coronavirus disease 2019 (COVID-19) in a nonfrontline clinical department. METHODS: Data of 2 source patients and all HCWs with infection risk were obtained in a department in Wuhan from January to February 2020. A questionnaire was designed to evaluate psychological stress of COVID-19 on HCWs. RESULTS: The overall infection rate was 4.8% in HCWs. Ten of 25 HCWs who contacted with 2 source patients were diagnosed with confirmed COVID-19 (8/10) and suspected COVID-19 (2/10). Other 2 HCWs were transmitted by other patients or colleagues. Close care behaviors included physical examination (6/12), life nursing (4/12), ward rounds (4/12), endoscopic examination (2/12). Contacts fluctuated from 1 to 24 times and each contact was short (8.1 min ± 5.6 min). HCWs wore surgical masks (11/12), gloves (7/12), and isolation clothing (3/12) when providing medical care. Most HCWs experienced a mild course with 2 asymptomatic infections, taking 9.8 d and 20.9 d to obtain viral shedding and clinical cure, respectively. Psychological stress included worry (58.3%), anxiety (83.3%), depression (58.3%), and insomnia (58.3%). CONCLUSIONS: Close contact with COVID-19 patients and insufficient protection were key risk factors. Precaution measures and psychological support on COVID-19 is urgently required for HCWs.

Effect of venlafaxine dosage, valproic acid concentration, sex, and age on steady state dose-corrected concentrations of venlafaxine and O-desmethylvenlafaxine: A retrospective analysis of therapeutic drug monitoring data in a Chinese population.

PURPOSE: This study aimed to investigate the influence of diagnosis, body weight, sex, age, smoking, formulations, and concomitant drugs on steady-state dose-corrected serum concentrations (C/D) of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV). METHODS: A retrospective analysis of therapeutic drug monitoring (TDM) was carried out. Patients' demographic data, therapeutic regimens, and concentrations were collected. RESULTS: We included 91 verified samples from 80 patients. Females had by average 13% smaller body weight, 50% higher C/D of VEN, and VEN + ODV and 25% smaller ODV/VEN than males. Patients >60 years had by average 33-59% higher C/D levels of ODV and VEN + ODV than younger patients. The concomitant use of valproic acid caused an average 51% higher C/D of ODV and a 2.2-fold larger ODV/VEN, while clozapine was related with 40% smaller ratio of ODV/VEN and 38% lower C/D levels of ODV. Positive correlations were detected between valproic acid concentrations and the C/D of VEN and VEN + ODV. In a multiple linear regression analysis, variance in the C/D of VEN + ODV was partly attributed to the daily dose of VEN, sex, age and valproic acid concentration. CONCLUSION: Our results suggested daily dose of VEN, sex, age, and valproic acid as indicators for the C/D of VEN + ODV in Chinese patients. TDM as a valuable tool was suggested in elderly female patients and patients receiving polypharmacy.

A Retrospective Analysis of Steady-State Olanzapine Concentrations in Chinese Patients Using Therapeutic Drug Monitoring: Effects of Valproate and Other Factors.

BACKGROUND: The objective of this study was to investigate the serum concentrations of olanzapine in relation to age, sex, and other factors in Chinese patients aged between 10 and 90 years. METHODS: Data for 884 olanzapine patients, deposited between 2016 and 2017, were retrieved from the therapeutic drug monitoring database of the Affiliated Brain Hospital of Guangzhou Medical University. The effects of covariates on serum olanzapine concentration, dose-normalized concentration (C/D ratio), and normalized concentration (C/D/weight) were investigated. RESULTS: Generally, male patients had lower olanzapine concentration, C/D ratio, and C/D/weight than female patients (P < 0.001). Smoking and drinking reduced olanzapine concentration, C/D ratio, and C/D/weight (P < 0.001). Coadministration with valproate decreased olanzapine concentration, C/D ratio, and C/D/weight by about 16%, 30%, and 40%, respectively (P < 0.001). Patients younger than 60 years had higher olanzapine concentrations (P < 0.05) but lower C/D ratios and C/D/weight (P < 0.001) than patients older than 60 years. Age was correlated with olanzapine concentration (r = -0.082, P < 0.05), C/D ratio (r = 0.196, P < 0.001), and C/D/weight (r = 0.169, P < 0.001). Sample timing after dose and diagnostic factors also contributed to the olanzapine concentrations. Multiple linear regression analysis revealed significant influences of dosage, age, sex, valproate comedication, smoking, postdose interval, and schizophrenia (vs bipolar affective disorders) on serum olanzapine concentrations. CONCLUSIONS: The metabolism of olanzapine may be altered by several factors. Patients characterized with a combination of factors may benefit from therapeutic drug monitoring for the adjustment of olanzapine dose to minimize adverse reactions.

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy.

Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1-1222AA carriers. Patients with the ABCG2-34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1-2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13-65 years of age.

[Determination of morroniside concentration in rat plasma by high performance liquid chromatography-tandem mass spectrometry].

Morroniside, an iridoid glycoside extracted from Cornus officinalis, has multiple pharmacological effects such as neuroprotection. This study took the lead in establishing a method for determining morroniside concentration in rat plasma by high performance liquid chromatography-tandem mass spectrometry. Plasma samples were processed with protein precipitation method, with hyperoside as the internal standard. An Inertsil C8-3 column (2. 1 mm x 50 mm, 5 microm) was adopted, with a mobile phase composed of water (containing 1 mmol L-1 Sodium formate)-acetonitrile (gradient elution) at a flow rate of 0.4 mL . min -1. Electrospray ionization (ESI) was adopted in the positive ion mode for multi-reaction monitoring (MRM). Morroniside showed a good linear relationship ranging between 2-5 000 microg L-1 (r = 0. 995 7), with the minimum limit of quantification of 2 microg L-1. Its precise, accuracy, recovery and matrix effect were all in line with the biological sample measurement requirements. Therefore, the method described above was proved to be suitable for the determination of morroniside concentration in rat plasma. To use the method in the pharmacokinetic study on morroniside in rats, oral administration dose shall be set at 20 mg . kg - to map the plasma concentration-time curve. Main pharmacokinetic parameters were calculated by DAS 2. 0. Specifically, AUC0-inifinity was (587.6 +/- 290. 7) microg min L-1, Cmax was (334.2+/-148.0) microg L-1, Tmax was (0.6 +/-0.3) h, t1/2 was (0.7+/-0.3) h.

[Preparation and characterization of curcumin polybutylcyanoacrylate nanoparticles].

OBJECTIVE: To prepare curcumin polybutylcyanoacrylate nanoparticles (Cur-PBCNs) and evaluate its characteristics. METHODS: Cur-PBCNs were prepared by emulsion polymerization, and the formulation was optimized by L16 (4(3)) orthogonal design test with entrapment efficiency and drug loading as indices. In addition, its characteristics were investigated. RESULTS: The nanoparticles were spherical in appearance under transmission electron microscope (TEM). The mean diameter of the nanoparticles was 93.8 nm, the mean entrapment efficiency was (50.4 +/- 2.2)%, the mean drug-loading was (33.5 +/- 0.9)% and the Zeta potential was -6.81 mV. The total drug release was 34.74% in 2 hours followed by a sustained release in vitro for Cur-PBCNs, and the in vitro release profile of the nanoparticles was fit for two phases kinetics equation: 100 - Q = 4.5235e(-0.1724t) + 4.1641e(-0.0114t). CONCLUSION: The optimal Cur-PBCNs show good characteristics and sustained release character in vitro.

Effects of Fuzhenghuayu decoction on collagen synthesis of cultured hepatic stellate cells, hepatocytes and fibroblasts in rats.

AIM:To study the mechanism of Fuzhenghuayu (FZHY) decoction on anti-liver fibrosis.METHODS:FZHY 10% decoction sera was incubated with rat normal subcultured hepatic stellate cells (HSC) and fibrotic primarily cultured HSC, normal and fibrotic hepatocytes and subcultured skin fibroblasts seperately. Cell intracellular and extracellular collagen synthesis rates were measured by the method of (3)H Proline impulse and collagenase digestion.RESULTS:For primarily cultured HSC and hepatocytes, both of intracellular and extracellular collagen synthesis rates decreased in the drug sera group. For the normal subcultured HSC and primarily cultured hepatocytes, the extracellular collagen secretion was decreased obviously by the drug sera, and intracellular collagen synthesis rates were inhibited to some extents.For fibroblasts, both intracellular and extracellular collagen synthesis rates were inhibited somewhat, but no significant differences were found.CONCLUSION:The mechanism of FZHY decoction on anti-liver fibrosis may be associated with inhibition of liver collagen production.