Exploring various measures of the area under the curve for the assessment of dose-proportionality and estimation of bioavailability.

Objective: In pharmacokinetics, the area under the concentration versus time curve (AUC) extrapolated to infinity (AUC0-∞) is the preferred metric but it is not always possible to have a reliable estimate of the terminal phase half-life. Here we sought to explore the accuracy of three different area measures to accurately identify dose proportionality and bioavailability.

Methods: One to three compartment model simulations with different doses for dose-proportionality or different rates and/or extents of bioavailability.

Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-β1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants.

Aim: To evaluate the pharmacokinetics and safety of single intravenous doses of JNJ-54452840 infused over 1 minute in healthy male Japanese and Caucasian participants. JNJ-54452840 is a novel peptide for the treatment of chronic heart failure, with a proposed mechanism of action of binding interference and decreased production of anti-β1-adrenergic receptor (anti-β1-AR) antibodies, which stimulate the cardiac β1-AR.

Methods: In this randomized, single-centre, double-blind, placebo-controlled, four-way crossover study, 32 male Japanese and Caucasian participants (16 in each group) received single intravenous doses of JNJ-54452840 20, 80 and 240 mg, and placebo, each separated by a ≥7-day washout period.

A PBPK model describing a xenobiotic with a short PK event scale.

Physiologically-based pharmacokinetic (PBPK) modeling has been widely used in human risk assessment and in early drug development to predict human PK from in vitro and/or in vivo animal data. Recently, the application of PBPK modeling has been extended to the evaluation of drug-drug interactions. For most xenobiotic agents, the PK event scale such as elimination is in hours or days.

Pharmacokinetics and safety of coadministered oseltamivir and rimantadine in healthy volunteers: an open-label, multiple-dose, randomized, crossover study.

Preclinical data suggest increased antiviral activity and less viral resistance when neuraminidase inhibitors and adamantanes are used in combination to harness the complementary effects of their different mechanisms of action. Healthy volunteers were randomized to 5-day oral treatment with oseltamivir 75 mg or rimantadine 100 mg twice daily as monotherapy or to combination treatment. Each participant received all 3 regimens in 1 of 6 treatment sequences, with a minimum of 7 days' washout between periods.

Absence of adverse effects of oseltamivir on sleep: a double-blind, randomized study in healthy volunteers in Japan.

Influenza-associated neuropsychiatric symptoms include parasomnias such as sleepwalking which is a common sleep disturbance in childhood. Oseltamivir is a widely used antiviral drug for influenza. Recently, sleepwalking-like events have been reported in patients with influenza receiving oseltamivir.

Surge in expression of carboxylesterase 1 during the post-neonatal stage enables a rapid gain of the capacity to activate the anti-influenza prodrug oseltamivir.

Background: Oseltamivir, a widely used anti-influenza drug, is hydrolytically activated by carboxylesterase 1 (CES1). The expression of this carboxylesterase is developmentally regulated. This study was performed to determine when after birth infants acquire competence of activating this prodrug.

Effect of oseltamivir treatment on anticoagulation: a cross-over study in warfarinized patients.

Aim: To investigate whether oseltamivir enhances the anticoagulant effect of warfarin and to evaluate any pharmacokinetic (PK) interaction between the agents.

Methods: Twenty volunteers (mean age 62 years) receiving daily warfarin and with INR values of 2.0-3.

Exploring cell tropism as a possible contributor to influenza infection severity.

Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity. Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types. The two cell types differ only in their susceptibility to infection and rate of virus production.

Neuraminidase inhibitors for treatment of human and avian strain influenza: A comparative modeling study.

Treatment of seasonal influenza viral infections using antivirals such as neuraminidase inhibitors (NAIs) has been proven effective if administered within 48h post-infection. However, there is growing evidence that antiviral treatment of infections with avian-derived strains even as late as 6 days post-infection (dpi) can significantly reduce infection severity and duration. Using a mathematical model of in-host influenza viral infections which can capture the kinetics of both a short-lived, typical, seasonal infection and a severe infection exhibiting sustained viral titer, we explore differences in the effects of NAI treatment on both types of influenza viral infections.

Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations.

Influenza is a transmissible viral pathogen that continues to cause substantial morbidity and mortality. Oseltamivir is an orally administered antiviral medication that selectively inhibits the influenza neuraminidase enzymes that are essential for viral replication. Treatment of infected children > or =1 year and adults of all ages may decrease the severity and duration of the symptoms of infection, while prophylactic dosing can prevent their onset.

Lack of age and gender effects on single-dose pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem.

Aims: To investigate the effect of age and gender on the tolerability, safety and pharmacokinetics (PK) of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite.

Methods: Forty-two subjects were assigned to one of the following three groups: young men, elderly men and elderly women. The PK, safety and tolerability of an intravenous infusion of 1500 mg tomopenem and its resultant major metabolite (open beta-lactam ring) were assessed.

Protective values for soil lead with respect to child health: a critique of UK guidelines.

In 2002, The (UK) Department for Environment, Food and Rural Affairs (DEFRA) together with the Environment Agency published document SGV10 "Contaminants in soil: collation of toxicological data and intake values for humans. Lead". This publication sets out the derivation of Soil Guideline Values for lead contamination.

Effect of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem.

The objective of this study was to assess the impact of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite in humans. Thirty-two subjects were enrolled in an open-label, two-center study. Subjects were evenly assigned to one of four groups, based on creatinine clearance ranges of > or =80, 50 to 79, 30 to 49, and <30 ml/min.

Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response.

This study characterized the relationship between clinical response, serum rituximab concentrations, and peripheral B-cell levels in patients with rheumatoid arthritis treated with rituximab. Data were analyzed from a double-blind, phase IIa trial in which 161 patients with active rheumatoid arthritis despite continuing methotrexate were randomized to methotrexate alone (10-25 mg/wk), rituximab alone (single course: 1000 mg administered intravenously on days 1 and 15), rituximab plus cyclophosphamide (750 mg administered intravenously on days 3 and 17), or rituximab plus methotrexate. Serum samples for pharmacokinetic analysis were collected through 24 weeks, and peripheral circulating CD19+ B-cell levels were measured through 48 weeks.

Variation of metals in bed sediments of Qaraaoun Reservoir, Lebanon.

The Qaraaoun Reservoir (impoundment of the River Litani) is the only artificial surface water body in the country, Lebanon. Earlier study on the water quality of the Qaraaoun Reservoir identified three water quality zoning with a central distinct zone suitable for multipurpose water usage. The objective of this study was to extend the earlier work by considering the total metal content of reservoir bed sediments and hence to evaluate factors that control metal deposition or capture.

Effect of R667, a novel emphysema agent, on the pharmacokinetics of midazolam in healthy men.

The purpose of this study was to investigate the potential for a CYP3A4-mediated drug interaction between R667 and midazolam (MDZ) in healthy subjects. R667 is metabolized by CYP3A4 and therefore may interact with CYP3A4 substrates. In the present study, 18 healthy male subjects received a single 15-mg oral dose of MDZ with and without R667 coadministration.

A comparison of metals in sediments and water in the River Nahr-Ibrahim, Lebanon: 1996 and 1999.

Rivers whose basins are underlain by carbonate rocks exhibit high pH, lower desorption of metals and possess high buffering capacity against acidic inputs to the river. The catchment of River Nahr-Ibrahim, Lebanon, is largely underlain by limestone. Compared to neighbouring countries, Lebanon is relatively fortunate since precipitation is high.

Evaluation of water quality of the Qaraaoun Reservoir, Lebanon: suitability for multipurpose usage.

The increased demand on water resources in Lebanon as a result of: progressive urbanization, socio-economic growth, agricultural activities and development of industries is, according to the national authorities, a major critical factor by the year 2010. Political difficulties in earlier years imply a dearth of pertinent data. The objective of this study was to evaluate water quality of the Qaraaoun Reservoir of the Litani River and assess its feasibility for multi-purpose usage as one of the solutions to the aggravated water problems in Lebanon.

Pharmacokinetics and safety of gadobenate dimeglumine (multihance) in subjects with impaired liver function.

Rationale And Objectives: To characterize the pharmacokinetics of gadolinium and to evaluate the safety of gadobenate dimeglumine (Gd-BOPTA) compared with placebo, in subjects with impaired liver function.

Methods: Volunteer adult subjects with hepatic impairment (Child-Pugh classification B or C) received, randomly and in double-blind fashion, either 0.1 mmol/kg gadobenate dimeglumine (n = 11) or placebo (n = 5) by intravenous injection.