Randomized, double-blind, placebo-controlled trial to examine the safety, pharmacokinetics and effects of Epimedium prenylflavonoids, on bone specific alkaline phosphatase and the osteoclast adaptor protein TRAF6 in post-menopausal women.

Background: Fragility fractures due to menopausal osteoporosis are a major cause of morbidity and mortality. Osteoporotic medications have substantial side effects that limit long term use.

Hypotheses: Ingestion of a purified extract of Epimedium spp.

Computer modelling of heat strain responses of exercising personnel in tropical climate.

Physiologically based thermoregulatory models are useful for deriving predictions of heat strain for pragmatic applications such as planning of continuous exercise/work-rest protocols. The SCENARIO model is an example of a thermoregulatory model that predicts heat strain including body core temperature (Tc) from individual characteristics, physical activity, clothing properties and environmental conditions. This paper presents work to optimize and enhance the SCENARIO model for prediction of Tc during high intensity load carriage tasks under predominantly tropical climate conditions.

Pharmacokinetics of Prenylflavonoids following Oral Ingestion of Standardized Epimedium Extract in Humans.

Leaves of the plant are traditionally consumed for bone health and other indications. The aim of this study was to establish the safety and pharmacokinetics of the metabolites of prenylflavonoids (icariin, icariside I, icariside II, icaritin, and desmethylicaritin) following single doses of a defined prenylflavonoid extract in humans. A single oral dose of 370, 740, or 1110 mg of a standardized prenylflavonoid extract was administered to 30 healthy male subjects in a randomized, placebo-controlled trial.

Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model.

COX-2 inhibition may be of benefit in the treatment of tuberculosis (TB) through a number of pathways including efflux pump inhibition (increasing intracellular TB drug levels) and diverse effects on inflammation and the immune response. We investigated celecoxib (a COX-2 inhibitor) alone and with standard anti-tuberculosis drugs in the whole-blood bactericidal activity (WBA) model. Healthy volunteers took a single dose of celecoxib (400 mg), followed (after 1 week) by a single dose of either rifampicin (10 mg/kg) or pyrazinamide (25 mg/kg), followed (after 2 or 7 days respectively) by the same anti-tuberculosis drug with celecoxib.

Activity of faropenem with and without rifampicin against Mycobacterium tuberculosis: evaluation in a whole-blood bactericidal activity trial.

Background: Faropenem has in vitro activity against Mycobacterium tuberculosis (Mtb) and shows synergy with rifampicin. We tested this in a whole-blood bactericidal activity (WBA) trial.

Methods: We randomized healthy volunteers to receive a single oral dose of faropenem (600 mg) with amoxicillin/clavulanic acid (500/125 mg) ( n  =   8), rifampicin (10 mg/kg) ( n  =   14) or the combination rifampicin + faropenem + amoxicillin/clavulanic acid ( n  =   14).

Nonlinear mixed effects modelling for the analysis of longitudinal body core temperature data in healthy volunteers.

Many longitudinal studies have collected serial body core temperature (T c) data to understand thermal work strain of workers under various environmental and operational heat stress environments. This provides the opportunity for the development of mathematical models to analyse and forecast temporal T c changes across populations of subjects. Such models can reduce the need for invasive methods that continuously measure T c.

Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI.

Background: Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods.

Methods: Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen.

Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults.

Objectives: Rifampicin is a first-line anti-TB drug. The objectives of this analysis were to evaluate the population pharmacokinetics of rifampicin and its partly active metabolite, 25-deacetyl-rifampicin, with and without isoniazid, and to identify covariates that may explain variability in their disposition under steady-state conditions.

Methods: Thirty-four healthy Asian subjects were randomized to receive rifampicin (600 mg) or rifampicin (600 mg)/isoniazid (300 mg) daily for 14 days.

Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers.

In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function.

Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite-Induced Asthma.

Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform γ-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of γ-tocotrienol in a house dust mite (HDM) experimental asthma model.

CYP3A5*3 and bilirubin predict midazolam population pharmacokinetics in Asian cancer patients.

We aim to evaluate the influence of covariates, including cytochrome P450 3A (CYP3A) genetic polymorphisms, on the pharmacokinetics of midazolam (MDZ) in Asian cancer patients, using a population pharmacokinetic approach. Pharmacokinetic data were obtained from 24 adult cancer patients who received an intravenous bolus dose of 1 mg MDZ as a CYP3A phenotyping probe, 1-day before starting FOLFIRI chemotherapy. Concentrations of MDZ and its major metabolites, 1'-hydroxymidazolam (1OHM) and 1'-hydroxymidazolam glucuronide (HMG) were measured using liquid chromatography/mass spectrometry.

Population pharmacokinetics of modafinil and its acid and sulfone metabolites in Chinese males.

Background: Modafinil is a psychostimulant used to treat excessive sleepiness. The aim of this study was to develop a population pharmacokinetic model of modafinil and its major metabolites in Chinese male adults and to identify covariates that predict variability in disposition.

Methods: Eighty healthy volunteer subjects were randomized to 4 oral dose groups: 3 doses of 50 mg of modafinil, 3 doses of 100 mg of modafinil, 2 doses of 200 mg of modafinil plus 1 dose of placebo, or 3 doses of placebo (each dose given 8 hourly).

Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers.

Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers.

Calibration and validation of a physiologically based model for soman intoxication in the rat, marmoset, guinea pig and pig.

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model has been developed for low, medium and high levels of soman intoxication in the rat, marmoset, guinea pig and pig. The primary objective of this model was to describe the pharmacokinetics of soman after intravenous, intramuscular and subcutaneous administration in the rat, marmoset, guinea pig, and pig as well as its subsequent pharmacodynamic effects on blood acetylcholinesterase (AChE) levels, relating dosimetry to physiological response. The reactions modelled in each physiologically realistic compartment are: (1) partitioning of C(±)P(±) soman from the blood into the tissue; (2) inhibition of AChE and carboxylesterase (CaE) by soman; (3) elimination of soman by enzymatic hydrolysis; (4) de novo synthesis and degradation of AChE and CaE; and (5) aging of AChE-soman and CaE-soman complexes.

Interrelations between plasma caffeine concentrations and neurobehavioural effects in healthy volunteers: model analysis using NONMEM.

The objective was to develop a population pharmacokinetic-pharmacodynamic model of caffeine's psychomotor effects in healthy, non-habitual users of caffeine. Twenty Chinese males each received a single dose of 250 mg of caffeine orally. Plasma concentrations of caffeine were determined at various times within 24 h after dosing.

Viral agents responsible for febrile respiratory illnesses among military recruits training in tropical Singapore.

Background: Military personnel are highly susceptible to febrile respiratory illnesses (FRI), likely due to crowding, stress and other risk factors present in the military environment.

Objective: Our objective was to investigate the viral etiological agents responsible for FRI among military recruits training in a tropical climate in Singapore.

Study Design: From March 2006 through April 2007, a total of 1354 oropharyngeal (throat) swabs were collected from military recruits who reported sick with an oral temperature of > or =38 degrees C and a cough and/or sore throat.

Sensitivity analysis on a physiologically-based pharmacokinetic and pharmacodynamic model for diisopropylfluorophosphate-induced toxicity in mice and rats.

A physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was recently developed to study the effect of diisopropylfluorophosphate (DFP) on acetylcholinesterase (AChE) activity in mouse and rat. That model takes into account relatively complex interactions involving many parameters, some of which may be uncertain and/or highly variable, especially those characterizing AChE activity after DFP intoxication. The primary objective of this study was to identify parameters that contribute most to the variability of AChE dynamics for model optimization against data.

Retrospective population pharmacokinetic/pharmacodynamic analysis of pyridostigmine, a cholinesterase inhibitor, in Chinese males.

Objectives: We have characterised the population pharmacokinetics-pharmacodynamics of pyridostigmine given as pyridostigmine bromide.

Methods: Over three days 50 healthy Chinese male subjects each received seven doses of 30 mg pyridostigmine bromide orally (3 x 10 mg every 8 h). Plasma concentrations of pyridostigmine and red blood cell acetylcholinesterase (AChE) activity were determined at various times within the eight hours after the first and the seventh doses.

Fuzzy least squares for identification of individual pharmacokinetic parameters.

In this paper, we examined the added value of fuzzy nonlinear regression to identify individual pharmacokinetic parameters in the case of noisy fuzzy data and/or small sample sizes. We first described three approaches that use least squares of errors as a fitting criterion for parameter estimation by fuzzy regression. Next, we compared the estimation and prediction capability of fuzzy least squares (FLS) and ordinary least squares (OLS) regressions via a simulation experiment, so as to determine the conditions of data size and variability under which one approach could be deemed superior over the other.

Comparison of statistical data models for identifying differentially expressed genes using a generalized likelihood ratio test.

Currently, statistical techniques for analysis of microarray-generated data sets have deficiencies due to limited understanding of errors inherent in the data. A generalized likelihood ratio (GLR) test based on an error model has been recently proposed to identify differentially expressed genes from microarray experiments. However, the use of different error structures under the GLR test has not been evaluated, nor has this method been compared to commonly used statistical tests such as the parametric t-test.

Physiologically based pharmacokinetic modeling of drug disposition in rat and human: a fuzzy arithmetic approach.

Purpose: Probabilistic methods are insufficient for dealing with the vagueness inherent in human judgment of minimal data available during early drug development. We sought to use fuzzy set theory as a basis for quantifying and propagating vague judgment in a physiologically based pharmacokinetic (PBPK) model for diazepam disposition.

Materials And Methods: First, using diazepam distribution data in rat tissues and fuzzy regression, we estimated fuzzy rat tissue-to-plasma partition coefficients (Kp's).

A fuzzy physiologically based pharmacokinetic modeling framework to predict drug disposition in humans.

To date, the application of physiologically based pharmacokinetic (PBPK) models in support of drug discovery remains limited, in part due to information deficit and uncertainty regarding model parameters. Fuzzy set theory provides a suitable way to objectively account for parameter uncertainty in models. Here, we present a fuzzy set-based PBPK modeling framework and demonstrate its utility in predicting diazepam pharmacokinetics in human plasma, following intravenous dosing, from available animal in vivo and literature data.

A fuzzy physiologically based pharmacokinetic modeling framework to predict drug disposition in humans.

To date, the application of physiologically based pharmacokinetic (PBPK) models in support of drug discovery remains limited, in part due to information deficit and uncertainty regarding model parameters. Fuzzy set theory provides a suitable way to objectively account for parameter uncertainty in models. Here, we present a fuzzy set-based PBPK modeling framework and demonstrate its utility in predicting diazepam pharmacokinetics in human plasma, following intravenous dosing, from available animal in vivo and literature data.

Simulating pharmacokinetic and pharmacodynamic fuzzy-parameterized models: a comparison of numerical methods.

Statistical techniques have been traditionally used to deal with parametric variation in pharmacokinetic and pharmacodynamic models, but these require substantial data for estimates of probability distributions. In the presence of limited, inaccurate or imprecise information, simulation with fuzzy numbers represents an alternative tool to handle parametric uncertainty. Existing methods for implementing fuzzy arithmetic may, however, have significant shortcomings in overestimating (e.

Postoperative ketorolac tromethamine use in infants aged 6-18 months: the effect on morphine usage, safety assessment, and stereo-specific pharmacokinetics.

Background: Nonsteroidal antiinflammatory drugs have been useful for treating postoperative pain in children. The only parenteral nonsteroidal antiinflammatory drug currently available in the United States is ketorolac tromethamine with cyclooxygenase-1 and cyclooxygenase-2 effects. Information on the pharmacokinetics of ketorolac in infants is sparse, making dosing difficult.