Evaluation of multiple comparison correction procedures in drug assessment studies using LORETA maps

The identification of the brain regions involved in the neuropharmacological action is a potential procedure for drug development. These regions are commonly determined by the voxels showing significant statistical differences after comparing placebo-induced effects with drug-elicited effects. LORETA is an electroencephalography (EEG) source imaging technique frequently used to identify brain structures affected by the drug. The aim of the present study was to evaluate different methods for the correction of multiple comparisons in the LORETA maps. These methods which have been commonly used in neuroimaging and also simulated studies have been applied on a real case of pharmaco-EEG study where the effects of increasing benzodiazepine doses on the central nervous system measured by LORETA were investigated. Data consisted of EEG recordings obtained from nine volunteers who received single oral doses of alprazolam 0.25, 0.5, and 1 mg, and placebo in a randomized crossover double-blind design. The identification of active regions was highly dependent on the selected multiple test correction procedure. The combined criteria approach known as cluster mass was useful to reveal that increasing drug doses led to higher intensity and spread of the pharmacologically induced changes in intracerebral current density.Peer Reviewe

Evaluation of multiple comparison correction procedures in drug assessment studies using LORETA maps

The identification of the brain regions involved in the neuropharmacological action is a potential procedure for drug development. These regions are commonly determined by the voxels showing significant statistical differences after comparing placebo-induced effects with drug-elicited effects. LORETA is an electroencephalography (EEG) source imaging technique frequently used to identify brain structures affected by the drug. The aim of the present study was to evaluate different methods for the correction of multiple comparisons in the LORETA maps. These methods which have been commonly used in neuroimaging and also simulated studies have been applied on a real case of pharmaco-EEG study where the effects of increasing benzodiazepine doses on the central nervous system measured by LORETA were investigated. Data consisted of EEG recordings obtained from nine volunteers who received single oral doses of alprazolam 0.25, 0.5, and 1 mg, and placebo in a randomized crossover double-blind design. The identification of active regions was highly dependent on the selected multiple test correction procedure. The combined criteria approach known as cluster mass was useful to reveal that increasing drug doses led to higher intensity and spread of the pharmacologically induced changes in intracerebral current density.Peer Reviewe

Plasma and Intracellular (Peripheral Blood Mononuclear Cells) Pharmacokinetics of Once-Daily Raltegravir (800 Milligrams) in HIV-Infected Patients▿

The aim of this study was to evaluate the plasma and intracellular pharmacokinetics of raltegravir in HIV-infected patients receiving once-daily raltegravir. Five HIV-infected patients on stable therapy with lopinavir-ritonavir monotherapy whose HIV-1 RNA load was <50 copies/ml were included in this open-label, pilot study. Raltegravir was added to the antiretroviral regimen at a dose of 800 mg once daily from days 0 to 10. On day 10, a full pharmacokinetic profile was obtained for each participant. Raltegravir concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were determined by high-performance liquid chromatography with a fluorescence detector and by liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively. The values of the raltegravir pharmacokinetic parameters in plasma and PBMCs were calculated by noncompartmental analysis. Raltegravir was well tolerated, and all participants completed the study. No differences in the times to the maximum concentration of raltegravir in plasma or the raltegravir half-lives were observed between plasma and PBMCs. The geometric mean raltegravir maximum concentration, the concentration at the end of the dosing interval, and the area under the concentration-time curve during the dose interval in plasma versus PBMCs were 2,640 ng/ml (range, 887 to 10,605 ng/ml) versus 199 ng/ml (range, 82 to 857 ng/ml) (geometric mean ratio [GMR], 13.30; 95% confidence interval [CI], 3.11 to 56.89; P = 0.003); 89 ng/ml (range, 51 to 200 ng/ml) versus 7 ng/ml (range, 2 to 15 ng/ml) (GMR, 13.21; 95% CI, 3.94 to 44.26; P = 0.001); and 12,200 ng·h/ml (range, 5,152 to 30,130 ng·h/ml) versus 909 ng·h/ml (range, 499 to 2,189 ng·h/ml) (GMR, 13.43; 95% CI, 5.13 to 35.16; P < 0.001), respectively. Raltegravir does not accumulate in PBMCs, with intracellular concentrations being about 1/10 of the concentrations in plasma. Despite once-daily dosing, mean raltegravir concentrations at the end of the dosing interval in plasma and PBMCs exceeded the reported protein-binding-adjusted 95% inhibitory concentration (IC95) and IC50 for wild-type viral strains, respectively