Peripheral-type benzodiazepine receptors on platelets are correlated with the degrees of anxiety in normal human subjects

RATIONALE: Anxiety is the one of the main symptoms of psychiatric disorders. Psychosocial stressors have been shown to be related to the onset of anxious episodes. Peripheral-type benzodiazepine receptors (PBR) are involved in regulating stress responses. The sensitivity of PBR to acute or chronic stress has been demonstrated in various situations. The State-Trait Anxiety Inventory (STAI) is one of the longest standing and most frequently used measures of anxiety. The development, evaluation, and use of biological markers with anxious conditions in psychiatry are extremely important. OBJECTIVES: The aims of this survey are to see whether PBR can be used in screening the degrees of anxiety which occur when normal persons are placed in the stressful conditions. METHODS: Twenty-four healthy volunteers (14 men, 10 women; mean age 46 years) participated in this study. We administered the STAI to all the volunteers. The binding of the radioactive PBR antagonist [(3)H]PK 11195 to platelet membranes was determined for these volunteers. RESULTS: The mean STAI scores were 40.3+/-8.0 for trait anxiety and 39.0+/-8.9 for state anxiety. B(max) of the platelet PBR binding was 2845+/-2109 fmol/mg protein. Pearson correlational analyses revealed that B(max) values were significantly and positively correlated with scores for trait anxiety but not significantly correlated with scores for state anxiety. CONCLUSIONS: PBR on platelets are correlated with trait anxiety scales of the STAI in healthy normal subjects. It is therefore suggested that the density of platelet PBR is highly associated with these personality traits for anxiety tolerance. PBR density in platelet could also be used as a promising biological marker of stressful conditions.     

Population pharmacokinetics/pharmacodynamics of anesthetics

In this article we review how population pharmacokinetic/pharmacodynamic (PD) modeling has evolved in the specialty of anesthesiology, how anesthesiology benefited from the mixed-effects approach, and which features of modeling need careful attention. Key articles from the anesthesiology literature are selected to discuss the modeling of typical anesthesiological PD end points, such as level of consciousness and analgesia, interactions between hypnotics and analgesics, estimation with poor and sometimes rich data sets from populations of various sizes, covariate detection, covariances between random effects, and Bayesian forecasting.     

Erythropoietin production rate in phlebotomy-induced acute anemia

OBJECTIVE: To estimate the rate of erythropoietin (EPO) production under physiological, conditions and to examine the regulatory mechanism of EPO production in response to acute phlebotomy-induced anemia. METHODS: Six sheep each underwent two phlebotomies in which the hemoglobin (Hb) was reduced to 3-4 g/dl over 4-5 h. The EPO plasma level, reticulocytes, Hb and EPO clearance were followed by frequent blood sampling. The EPO production rate was determined by a semi-parametric method based on a disposition decomposition analysis that accounts for the nonlinear disposition kinetics of EPO and corrects for time-dependent changes in the clearance. RESULTS: The controlled drop in hemoglobin resulted in an abrupt increase in the plasma EPO concentration (peak level 812+/-40 mU/ml, mean+/-CV%) that was followed by a rapid drop 2-4 days after the phlebotomy at a time when the sheep were still anemic (Hb=4.3+/-16 g/dl). The EPO production rate at baseline was 43+/-52 U/day/kg and the amounts of EPO produced over an 8 day period resulting from the first and second phlebotomy were 2927+/-40 U/kg and 3012+/-31 U/kg, respectively. CONCLUSIONS: The rapid reduction in the EPO plasma level observed 2-4 days following the phlebotomy cannot be explained solely by the increase in EPO clearance but also by a reduction in EPO production.     

Application of triple-probe microdialysis for fast pharmacokinetic/pharmacodynamic evaluation of dopamimetic activity of drug candidates in the rat brain

The technique of microdialysis utilizing three simultaneously implanted probes in the anaesthetized rat enables monitoring of pharmacokinetic (PK) profiles of a tested drug both in blood (1st probe) and brain (2nd probe) compartments and the pharmacodynamic (PD) response of neurotransmitters (3rd probe) released into, or accumulating within the brain extracellular fluid (ECF). In the present study, the PK/PD characteristics of cocaine (psychostimulant, strong abuse potential) and methylphenidate (dopamimetic drug without reinforcing properties) and two novel NeuroSearch (NS) drug candidates, NS-A and NS-B, were examined in blood and brain microdialysates from the anaesthetized rats. The extracellular levels of dopamine (DA) were monitored in the striatum or prefrontal cortex. The NS-A compound entered the brain ECF at a slightly slower rate then methylphenidate; however, both compounds showed about the same effect on the speed of accumulation of extracellular DA concentrations, which gradually increased to about 450% of the basal, predrug levels at the end of the sampling period (180 min). The NS-B compound showed more rapid PK profiles than those observed after methylphenidate and NS-A. The concentrations of NS-B reached the maximal values already 40 min after its administration, while at that time, the corresponding DA values were still unchanged. In fact, the increase in DA concentrations was about two times slower when compared to that of methylphenidate or NS-A-drugs. Faster kinetics of NS-B and its delayed effect on extracellular DA suggests that this compound is metabolized to an active intermediate product, which itself exerts stronger dopamimetic activity in the rat prefrontal cortex that the original NS-B substance. The present study illustrates the feasibility of triple-probe microdialysis to monitor the rate of extracellular accumulation of a drug candidate and DA levels in vivo and compare the resulting PK/PD profiles to those obtained for cocaine and methylphenidate. These measures may serve as initial neurochemical indicators of potential psychomimetic or reinforcing properties of the tested substances.     

Use of a pharmacokinetic model to assess chlorpyrifos exposure and dose in children, based on urinary biomarker measurements.

Chlorpyrifos is a common agricultural insecticide and has been used residentially in the United States until the year 2000 when this use was restricted by the U.S. Environmental Protection Agency (U.S. EPA). A chlorpyrifos metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) has been found in urine samples collected during exposure field studies. In this work, we use urinary biomarker data and the inverse solution of a simple pharmacokinetic (PK) model for chlorpyrifos to estimate the magnitude and timing of doses. Three urine samples were collected on separate days from each of 15 children (ages 3-12) who were participants in the Minnesota Children's Pesticide Exposure Study (MNCPES). The total volume of urine was noted and samples analyzed for TCPY: The urinary data was used along with constraints imposed on dose timing, based on responses of the individuals to pesticide-use surveys. We predicted the time and magnitude of multiple "event" exposures characterized by short-term, relatively high doses superimposed over a continuous background exposure. The average dose of chlorpyrifos predicted by the model was 1.61 microg/kg per reported event. Average background dose rate for these children that reported exposure events was 0.0062 microg/kg/h, or 0.15 microg/kg/day. In addition to predicting the total dose of chlorpyrifos received by an individual from urinary biomarker measurements, the model can then be run in a forward manner once the exposure regime is determined. This will allow the prediction of the total amount of TCPy eliminated in the urine over any time period of interest.     

Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat

RATIONALE AND OBJECTIVES: Stimulation of the mitochondrial benzodiazepine receptor (MBR) in the brain activates the synthesis of neurosteroids that can act as positive modulators of the GABA(A) receptor complex. Allopregnanolone is a potent anxiolytic, anticonvulsant, sedative and hypnotic GABAergic neurosteroid. The anxiolytic-like effects of FGIN 1-27, an MBR agonist, were determined after microinjection into the dorsal hippocampus. METHODS: Behavior in the elevated plus-maze was assessed in adult male rats after bilateral injections of 0, 1.25, 2.5, or 5 microg FGIN 1-27. The behavioral effects of FGIN 1-27 were also determined in animals receiving intrahippocampal co-administration of 20 ng picrotoxin, 5 microg flumazenil, or 200 ng PK 11195. The effects of FGIN 1-27 on behavior in the elevated plus-maze and shock-probe burying test were measured in animals pretreated systemically with 10 mg/kg 4-MA, a 5alpha-reductase inhibitor. Hippocampal and blood plasma levels of allopregnanolone were measured in separate groups of animals pretreated with 4-MA and receiving an intrahippocampal injection of FGIN 1-27. RESULTS: Intrahippocampal injections of FGIN 1-27 produced anxiolytic-like effects in the plus-maze and in the shock-probe burying test. Hippocampal and blood levels of allopregnanolone were also increased by FGIN 1-27. The anxiolytic-like effects of FGIN 1-27 were attenuated by PK 11195 and were blocked by picrotoxin and 4-MA pretreatment, but remained unaffected by flumazenil pretreatment. The neurosteroidogenic effect of FGIN 1-27 was also eliminated by 4-MA. CONCLUSION: Activation of the MBR in the hippocampus leads to the synthesis of allopregnanolone, an anxiolytic neurosteroid that potentiates GABA(A) receptor function.     

Growth-compromised HSV-2 vector Delta RR protects from N-methyl-D-aspartate-induced neuronal degeneration through redundant activation of the MEK/ERK and PI3-K/Akt survival pathways, either one of which overrides apoptotic cascades

We have previously shown that intrastriatal injection of Delta RR, the growth-compromised herpes simplex virus type 2 (HSV-2) vector for the antiapoptotic protein ICP10PK, prevents apoptosis caused by the excitotoxin N-methyl-D-aspartate (NMDA) in a mouse model of glutamatergic neuronal cell death (Golembewski et al. [2007] Exp. Neurol. 203:381-393). Because apoptosis regulation is stimulus and cell type specific, our studies were designed to examine the mechanism of Delta RR-mediated neuroprotection in striatal neurons. Organotypic striatal cultures (OSC) that retain much of the synaptic circuitry of the intact striatum were infected with Delta RR or a growth-compromised HSV-2 vector that lacks ICP10PK (Delta PK) and examined for neuroprotection-associated signaling. The mutated ICP10 proteins (p175 and p95) were expressed in 70-80% of neurons from Delta RR- and Delta PK-infected cultures, respectively, as determined by double-immunofluorescent staining with antibodies to ICP10 and NeuN or GAD65. Delta RR- but not Delta PK-treated OSC were protected from NMDA-induced apoptosis, as verified by ethidium homodimer staining, TUNEL, caspase-3 activation, and poly(AD-ribose) polymerase (PARP) cleavage. Neuroprotection was through ICP10PK-mediated activation of the survival pathways MEK/ERK and PI3-K/Akt, up-regulation of the antiapoptotic proteins Bag-1 and Bcl-2, and phosphorylation (inactivation) of the proapoptotic protein Bad. It was blocked by the MEK inhibitor U0126 or the PI3-K inhibitor LY294002, suggesting that either pathway can prevent NMDA-induced apoptosis. The data indicate that Delta RR-delivered ICP10PK stimulates redundant survival pathways that override proapoptotic cascades. Delta RR is a promising gene therapy platform against glutamatergic cell death.     

急性肾损伤并肺部感染患者的抗菌方案阶段性调整探析

目的：对急性肾损伤并肺部感染患者临床抗菌方案进行评价和调整。方法：利用PK/PD理论优化抗菌治疗的综合评价参数的定量范围,以及根据CCr值（内生肌酐清除率）对用药方案进行调整。结果及结论：急性肾损伤初期处于肾衰阶段的患者,CCr大幅下降,全程使用PIP/TAZ（哌拉西林/他唑巴坦）4.5 g q8h的给药方案,其给药剂量或给药频次明显超量。对该类患者,建议初期采用PIP/TAZ 4.5 g q24h～q36h的给药方案,逐步过渡到4.5 g q8h。     

Immune tolerance induction using a factor VIII/von Willebrand factor concentrate (BIOSTATE®), with or without immunosuppression,in Australian paediatric severe haemophilia A patients with high titre inhibitors: A multicentre,retrospective study

Introduction

It has been postulated that factor VIII (FVIII) products containing von Willebrand factor (VWF) may improve immune tolerance induction (ITI) success rate in patients with haemophilia A and poor prognostic factors.

Materials and methods

We conducted a retrospective cohort analysis of a FVIII/VWF concentrate (BIOSTATE®) for ITI in paediatric patients with severe haemophilia A (SHA) and inhibitors, from January 2003 to December 2011 at 3 paediatric-only Haemophilia Treatment Centres in Australia. Response to ITI was assessed at or before 33 months and at completion of ITI. Fifteen male patients with SHA were included in the analysis.

Results

BIOSTATE was used for primary ITI in 8 patients (2 years, range 1.1–11.5 years) and for salvage ITI in 7 patients (9.9 years, range 1.1–15.4). At the end of the observation period there were 11 patients who achieved a complete response with BIOSTATE after a median duration of 21 months (range 5–85 months); a partial response was achieved in 2 patients in whom ITI is ongoing. Therefore, the overall response rate was 86.6%. Two patients were deemed treatment failures: one due to non-compliance after 18 months of ITI and another in whom a partial response had not been achieved after 22 months of ITI.

Conclusion

BIOSTATE was well-tolerated and effective when used for primary or salvage ITI in this cohort of paediatric patients with SHA and a high-level inhibitor.