Population pharmacokinetics and dosing optimization of mezlocillin in neonates and young infants.

OBJECTIVES: Mezlocillin is used in the treatment of neonatal infectious diseases. However, due to the absence of population pharmacokinetic studies in neonates and young infants, dosing regimens differ considerably in clinical practice. Hence, this study aimed to describe the pharmacokinetic characteristics of mezlocillin in neonates and young infants, and propose the optimal dosing regimen based on the population pharmacokinetic model of mezlocillin. METHODS: A prospective, open-label pharmacokinetic study of mezlocillin was carried out in newborns. Blood samples were collected using an opportunistic sampling method. HPLC was used to measure the plasma drug concentrations. A population pharmacokinetic model was developed using NONMEM software. RESULTS: Ninety-five blood samples from 48 neonates and young infants were included. The ranges of postmenstrual age and birth weight were 29-40 weeks and 1200-4000 g, respectively, including term and preterm infants. A two-compartment model with first-order elimination was developed to describe the population pharmacokinetics of mezlocillin. Postmenstrual age, current weight and serum creatinine concentration were the most important covariates. Monte Carlo simulation results indicated that the current dose of 50 mg/kg q12h resulted in 89.2% of patients achieving the therapeutic target, when the MIC of 4 mg/L was used as the breakpoint. When increasing the dosing frequency to q8h, a dose of 20 mg/kg resulted in 74.3% of patients achieving the therapeutic target. CONCLUSIONS: A population pharmacokinetic model of mezlocillin in neonates and young infants was established. Optimal dosing regimens based on this model were provided for use in neonatal infections.

Thioredoxin interacting protein drives astrocytic glucose hypometabolism in corticosterone-induced depressive state.

Brain energetics disturbance is a hypothesized cause of depression. Glucose is the predominant fuel of brain energy metabolism; however, the cell-specific change of glucose metabolism and underlying molecular mechanism in depression remains unclear. In this study, we firstly applied 18 F-FDG PET and observed brain glucose hypometabolism in the prefrontal cortex (PFC) of corticosterone-induced depression of rats. Next, astrocytic glucose hypometabolism was identified in PFC slices in both corticosterone-induced depression of rats and cultured primary astrocytes from newborn rat PFC after stress-level corticosterone (100 nM) stimulation. Furthermore, we found the blockage of glucose uptake and the decrease of plasma membrane (PM) translocation of glucose transporter 1 (GLUT1) in astrocytic glucose hypometabolism under depressive condition. Interestingly, thioredoxin interacting protein (TXNIP), a glucose metabolism sensor and controller, was found to be over-expressed in corticosterone-stimulated astrocytes in vivo and in vitro. High TXNIP level could restrict GLUT1-mediated glucose uptake in primary astrocytes in vitro. Adeno-associated virus vector-mediated astrocytic TXNIP over-expression in rat medial PFC suppressed GLUT1 PM translocation, consequently developed depressive-like behavior. Conversely, TXNIP siRNA facilitated GLUT1 PM translocation to recover glucose hypometabolism in corticosterone-exposed cultured astrocytes. Notably, astrocyte-specific knockdown of TXNIP in medial PFC of rats facilitated astrocytic GLUT1 PM translocation, showing obvious antidepressant activity. These findings provide a new astrocytic energetic perspective in the pathogenesis of depression and, more importantly, provide TXNIP as a promising molecular target for novel depression therapy.

Banxia-houpu decoction restores glucose intolerance in CUMS rats through improvement of insulin signaling and suppression of NLRP3 inflammasome activation in liver and brain.

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia-houpu decoction is a famous formula in traditional Chinese medicine (TCM) with the powerful anti-depressant activity. AIM OF THE STUDY: This study aimed to investigate the effect of Banxia-houpu decoction on glucose intolerance associated with anhedonia in chronic unpredictable mild stress (CUMS) rats, then to explore its underlying pharmacological mechanisms. MATERIALS AND METHODS: After 6-week CUMS procedure, male Wistar rats were given Banxia-houpu decoction (3.29 and 6.58g/kg, intragastrically) for 6 weeks. Sucrose solution consumption test was employed to evaluate the anhedonia behavior. Oral glucose tolerance test (OGTT) was used to determine glucose tolerance. Serum levels of corticosterone, corticotropin-releasing factor (CRF), insulin and interleukin-1 beta (IL-1ß) were measured by commercial enzyme-linked immunosorbent assay kits, respectively. Furthermore, the key proteins for insulin signaling, as well as nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, were analyzed by Western blot in periphery liver and brain regions hypothalamus, hippocampus and prefrontal cortex, respectively. RESULTS: Banxia-houpu decoction significantly increased sucrose solution consumption and decreased serum corticosterone and CRF levels in CUMS rats, further demonstrating its antidepressant activity. More importantly, Banxia-houpu decoction improved glucose tolerance in OGTT in this animal model. Furthermore, it protected against CUMS-induced insulin signaling impairment in the liver, as well as hypothalamus and prefrontal cortex in rats. Although without significant effect on serum IL-1ß levels, Banxia-houpu decoction inhibited NLRP3 inflammasome activation in the liver, hypothalamus, hippocampus and prefrontal cortex of CUMS rats, respectively. CONCLUSIONS: The present study demonstrates that Banxia-houpu decoction suppresses NLRP3 inflammasome activation and improves insulin signaling impairment in both periphery liver and brain regions in CUMS rats, possibly contributing to its anti-depressive effect with glucose tolerance improvement. These results may provide the evidence that Banxia-houpu decoction is a potential antidepressant with the advantage to reduce the risk of comorbid depression with type 2 diabetes mellitus.

Up-regulated fractalkine (FKN) and its receptor CX3CR1 are involved in fructose-induced neuroinflammation: Suppression by curcumin.

Recent studies suggest that diet-induced fractalkine (FKN) stimulates neuroinflammation in animal models of obesity, yet how it occurs is unclear. This study investigated the role of FKN and it receptor, CX3CR1, in fructose-induced neuroinflammation, and examined curcumin's beneficial effect. Fructose feeding was found to induce hippocampal microglia activation with neuroinflammation through the activation of the Toll-like receptor 4 (TLR4)/nuclear transcription factor κB (NF-κB) signaling, resulting in the reduction of neurogenesis in the dentate gyrus (DG) of mice. Serum FKN levels, as well as hypothalamic FKN and CX3CR1 gene expression, were significantly increased in fructose-fed mice with hypothalamic microglia activation. Hippocampal gene expression of FKN and CX3CR1 was also up-regulated at 14d and normalized at 56d in mice fed with fructose, which were consistent with the change of GFAP. Furthermore, immunostaining showed that GFAP and FKN expression was increased in cornu amonis 1, but decreased in DG in fructose-fed mice. In vitro studies showed that GFAP and FKN expression was stimulated in astrocytes, and suppressed in mixed glial cells exposed to 48h-fructose, with the continual increase of pro-inflammatory cytokines. Thus, increased FKN and CX3CR1 may cause a cross-talk between activated glial cells and neurons, playing an important role in the development of neuroinflammation in fructose-fed mice. Curcumin protected against neuronal damage in hippocampal DG of fructose-fed mice by inhibiting microglia activation and suppressed FKN/CX3CR1 up-regulation in the neuronal network. These results suggest a new therapeutic approach to protect against neuronal damage associated with dietary obesity-associated neuroinflammation.