Memory function in childhood epilepsy syndromes.

Objective: Children with epilepsy are at risk of specific cognitive deficits. We aimed to compare and characterize the memory function of children with childhood absence epilepsy (CAE), frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE).

Methods: Epilepsy syndrome was identified by clinical data, seizure semiology, interictal and ictal electroencephalogram (EEG).

Validation of the quality of life in childhood epilepsy questionnaire in American epilepsy patients.

The aim of this study was to adapt the Australian Quality of Life in Childhood Epilepsy Questionnaire (QOLCE) and determine its psychometric properties in a North American population. Participants were North American families with children diagnosed with epilepsy. Parents were asked to complete the American QOLCE (USQOLCE) and the Child Health Questionnaire (CHQ).

Application of statistical parametric mapping to SPET in the assessment of intractable childhood epilepsy.

Statistical parametric mapping (SPM) quantification and analysis has been successfully applied to functional imaging studies of partial epilepsy syndromes in adults. The present study evaluated whether localisation of the epileptogenic zone (determined by SPM) improves upon visually examined single-photon emission tomography (SPET) imaging in presurgical assessment of children with temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE). The patient sample consisted of 24 children (15 males) aged 2.

The health-related quality of life of childhood epilepsy syndromes.

Objective: There is increasing awareness of the importance of assessing physical, psychological, social and behavioural well-being in chronic disease. The aim of this study was to examine the health-related quality of life (HRQoL) of children with common epilepsy syndromes and to explore if there are HRQoL differences between those syndromes.

Methods: Each child had their epilepsy syndrome defined according to the International League Against Epilepsy classification.

Evaluation of the effects of penicillin G potassium and potassium chloride on the motility of the large intestine in horses.

Objective: To evaluate effects of IV administration of penicillin G potassium (KPEN) or potassium chloride (KCl) on defecation and myoelectric activity of the cecum and pelvic flexure of horses.

Animals: 5 healthy horses.

Procedure: Horses with 12 bipolar electrodes on the cecum and pelvic flexure received KPEN or KCl solution by IV bolus 4 hours apart.

Survival after pulmonary edema due to enterovirus 71 encephalitis.

Background: A distinctive pattern of enterovirus 71 (EV71) infection, characterized by fever, exanthem, acute pulmonary edema (PE), brainstem encephalitis, and flaccid paresis, affects infants and young children. Most die rapidly owing to respiratory failure and fulminant PE.

Method: The authors report short- and long-term outcome of six survivors of the acute illness.

Intelligence in childhood epilepsy syndromes.

Unlabelled: Intellectual deficits play a significant role in the psychosocial comorbidity of children with epilepsy. Early educational intervention is critical.

Objective: This study aims to determine the intellectual ability of children with common childhood epilepsy syndromes-generalised idiopathic epilepsy (GIE), generalised symptomatic epilepsy (GSE), temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), central epilepsy (CE) and non-localised partial epilepsy (PE).

Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving and withdrawal.

Rationale: Research on the effects of nicotine abstinence and nicotine replacement has not provided consistent information about the impact of replacement therapies on tobacco withdrawal and craving.

Objective: . This study investigated craving and withdrawal symptoms over a 72-h period of abstinence from cigarettes.

Correlation and predictive performances of saliva and plasma nicotine concentration on tobacco withdrawal-induced craving.

Aims: To investigate whether saliva is a useful alternative to plasma for routine monitoring of nicotine and evaluate the predictive performances of saliva and plasma concentration on craving estimated by a Tiffany Questionnaire on Smoking Urge-Brief Form.

Methods: Thirteen healthy smokers were enrolled in a randomized, two period, crossover trial. Linear and power models were evaluated to predict the plasma nicotine concentrations from the saliva measurements, whereas a population PK/PD indirect response model was used to predict craving using either saliva or plasma nicotine concentration as the independent variable.

Absolute quantification of cerebral blood flow with magnetic resonance, reproducibility of the method, and comparison with H2(15)O positron emission tomography.

While H2(15)O positron emission tomography (PET) is still the gold standard in the quantitative assessment of cerebral perfusion (rCBF), its technical challenge, limited availability, and radiation exposure are disadvantages of the method. Recent work demonstrated the feasibility of magnetic resonance (MR) for quantitative cerebral perfusion imaging. There remain open questions, however, especially regarding reproducibility.

Clinical, EEG, and quantitative MRI differences in pediatric frontal and temporal lobe epilepsy.

Objective: To examine the clinical, electrographic, and quantitative MRI differences between frontal lobe (FLE) and mesial temporal lobe epilepsy (MTLE) in children.

Methods: The population included children who underwent video-EEG monitoring between 1995 and 2000 who were classified as either FLE (n = 39) or MTLE (n = 17) according to the criteria of the International League Against Epilepsy. Clinical, EEG, and quantitative MRI data (including frontal cortical volumes) were compared between the two syndromes and a control group (n = 42).

Rational dose selection for a nonnucleoside reverse transcriptase inhibitor through use of population pharmacokinetic modeling and Monte Carlo simulation.

In order to choose a rational dose for GW 420867X, we first set a goal of therapy. We hypothesized that, for optimal antiretroviral activity, the trough free drug concentration should remain above the 90% effective concentration (EC90) of human immunodeficiency virus type 1. We performed population pharmacokinetic analysis on three different doses of GW 420867X (50, 100, and 200 mg).

In silico prediction of optimal in vivo delivery properties using convolution-based model and clinical trial simulation.

Purpose: To develop a new strategy for the in silico evaluation of the optimal in vivo delivery properties of a drug, minimizing a cost function defined by the brain receptor occupancy obtained in positron-emission tomography experiments.

Methods: A convolution-based model was formulated to link in vivo delivery rate to plasma concentrations whereas a second-stage model was used to link plasma concentrations to the pharmacodynamic effect. A feedback control approach was applied to identify the optimal in vivo delivery rate given an appropriate optimality criterion.

Pharmacodynamics of abacavir in an in vitro hollow-fiber model system.

Abacavir is a potent new carbocyclic nucleoside analogue. We employed our hollow-fiber pharmacodynamic modeling system to examine the antiretroviral effects of different abacavir exposures, as well as the impact of the schedule of drug administration on efficacy. Dose ranging of abacavir revealed that a concentration of four times the 50% effective concentration (EC(50)) (approximately the EC(95)) was required to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) (strain MN) either in a continuous-infusion hollow-fiber experiment or in a classical tissue culture flask experiment.

Estimate the time varying brain receptor occupancy in PET imaging experiments using non-linear fixed and mixed effect modeling approach.

Positron-Emission Tomography (PET) is an imaging technology currently used in drug development as a non-invasive measure of drug distribution and interaction with biochemical target system. The level of receptor occupancy achieved by a compound can be estimated by comparing time-activity measurements in an experiment done using tracer alone with the activity measured when the tracer is given following administration of unlabelled compound. The effective use of this surrogate marker as an enabling tool for drug development requires the definition of a model linking the brain receptor occupancy with the fluctuation of plasma concentrations.

Transport characteristics of the anti-human immunodeficiency virus nucleoside analog, abacavir, into brain and cerebrospinal fluid.

The role of the blood-brain and blood-cerebrospinal fluid (CSF) barriers in the distribution of anti-human immunodeficiency virus (HIV) drugs is integral to the design of effective treatment regimens for HIV infection within the brain. Abacavir (formerly 1592U89) is a nucleoside analog reverse transcriptase inhibitor, which has activity against HIV. The ability of this drug to reach the brain at therapeutic concentrations has been explored by means of an established bilateral in situ brain perfusion model in combination with high-performance liquid chromatography analysis in the anesthetized guinea pig.

Population pharmacokinetic-pharmacodynamic model of craving in an enforced smoking cessation population: indirect response and probabilistic modeling.

Purpose: A population pharmacokinetic-pharmacodynamic model accounting for placebo effect was used to relate nicotine concentration and enforced smoking cessation craving score measured by the Tiffany rating scale short form.

Methods: Twenty-four smokers were enrolled in a placebo-controlled, randomized, double-blind, three periods, crossover trial. The study objective was to describe the nicotine-induced changes on craving scores.

Computer-assisted drug development (CADD): an emerging technology for designing first-time-in-man and proof-of-concept studies from preclinical experiments.

Computer-assisted drug development (CADD) is an emerging technology for accelerating drug development based on the integration of mathematical modelling and simulation. This methodology provides a knowledge-based decisional tool on alternative development strategies based on the evaluation of potential risks on drug safety, and the definition of experimental design of new trials with expected power and probability of success. An example of CADD implementation is presented to design the first-time-in-man (FTIM) and the proof-of-concept (PoC) study of a new CNS compound.

The health-related quality of life of children with refractory epilepsy: a comparison of those with and without intellectual disability.

Purpose: To determine whether refractory epilepsy affects the health-related quality of life (HRQOL) of children with or without intellectual disability (ID), and if the presence of ID independently compromises HRQOL in children with refractory epilepsy.

Methods: Subjects were parents of children with refractory epilepsy, whose syndrome had been defined using ILAE (International League Against Epilepsy) criteria and video-EEG monitoring. Children had the presence or absence of ID determined by formal neuropsychological or educational assessment.

Severe infantile axonal neuropathy with respiratory failure.

We describe 5 infants (4 male, 1 female) with a severe intractable form of motor-sensory axonal neuropathy. All became ventilator-dependent, 4 have since died and 1 remains static. Diaphragmatic paralysis was an early feature with generalized neuropathy evolving rapidly.

Bioavailability of orally administered micronised fluticasone propionate.

Objective: The aim of this study was to determine the absolute oral bioavailability of fluticasone propionate (FP) in healthy volunteers.

Methods: A 3-period incomplete block crossover design was used. On separate occasions, 21 male volunteers received a single 250 microg intravenous dose of FP (n = 21) and twice daily oral doses of either micronised FP 0.

The relationship between systemic exposure to fluticasone propionate and cortisol reduction in healthy male volunteers.

Objective: The aim of this analysis was to assess the pharmacokinetic/pharmacodynamic relationship between systemic exposure to fluticasone propionate (FP) and reductions in the plasma cortisol level and urinary cortisol excretion.

Methods: A total of 122 healthy male volunteers participating in 7 different studies received either oral (5 to 40 mg), inhaled (500 to 2000 microg) or intravenous (250 to 1000 g) single morning doses of FP or placebo. Data on systemic exposure to FP, expressed in terms of the area under the FP concentration-time curve up to 24 hours (AUC(24h,FP)) for the 3 different routes of administration were pooled, together with corresponding data on the 24-hour plasma cortisol level or urinary cortisol excretion.

Pharmacokinetics of fluticasone propionate inhaled via the Diskhaler and Diskus powder devices in healthy volunteers.

Objective: The aim of these studies was to determine the absolute bioavailability in healthy volunteers of inhaled fluticasone propionate (FP) administered as a single dose via the Diskhaler and Diskus powder devices, and the pharmacokinetics of inhaled FP after repeated administration via the Diskhaler device.

Methods: In 2 of the studies, single inhaled doses of FP were administered via the Diskhaler and the Diskus powder devices, and, in the third study, repeated doses of FP were administered via the Diskhaler. In the single dose studies, 12 healthy volunteers were randomised to receive FP 1000 microg by inhalation and FP 250 microg intravenously, using a double-blind crossover design.

Systemic exposure to fluticasone propionate administered via metered-dose inhaler containing chlorofluorocarbon or hydrofluoroalkane propellant.

Objective: The pharmacokinetic profile of a single dose of inhaled fluticasone propionate (FP) administered via a metered-dose inhaler (MDI), containing either a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellant was investigated in healthy volunteers.

Methods: Two randomised, double-blind, crossover studies were conducted, each in 12 male volunteers. Both studies compared pharmacokinetic data after a single inhaled dose of FP 1000 microg from a MDI containing either CFC (CFC MDI) or HFA (HFA MDI) with a single intravenous dose of FP 250 microg.

Absorption kinetics after inhalation of fluticasone propionate via the Diskhaler, Diskus and metered-dose inhaler in healthy volunteers.

Objective: The aim of this analysis was to assess the rate and extent of systemic availability of inhaled fluticasone propionate (FP) from 2 dry powder systems (Diskhaler and Diskus) and a metered-dose inhaler (MDI) by deconvolution analysis.

Methods: The inhalation devices were evaluated in 3 separate studies with identical protocols. 12 healthy male volunteers were randomised to receive FP given as a 1000 microg inhaled dose and 250 microg by intravenous infusion according to a double-blind double-dummy crossover design.