Double-Blind, Placebo-Controlled, Multiple-Ascending-Dose Study on the Pharmacodynamics of ABIO-08/01, a New CNS Drug with Potential Anxiolytic Activity

Abstract

Effects of ABIO-08/01, a new potentially anxiolytic isoxazoline, on regional electrical brain generators were investigated by 3-dimensional EEG tomography. In a double- blind, placebo-controlled, multiple-ascending-dose study, 16 healthy males (30.2 ± 5.7 years) received 3 oral drug doses (10, 20, 40 mg) and placebo for 7 days (8-day wash-out) in a randomized non-balanced design for phase-1 studies. A 3-min vigilance-controlled (V) EEG, a 4-min resting (R) EEG with eyes closed, a 1-min eyes-open (EO) EEG and psychometric tests were performed 0, 1 and 6 h after taking the drug on days 1 and 5. Low-resolution brain electromagnetic tomography (LORETA) was computed from the spectrally analyzed EEG data, and differences between drug and placebo were displayed as statistical parametric maps. Data were registered to the Talairach-Tournoux Human Brain Atlas available as a digitized MRI. An overall omnibus significance test followed by a voxel-by-voxel t test demonstrated significant regional EEG changes after ABIO-08/01 versus placebo, dependent on recording condition, dose and time. While in the EO-EEG specifically the lowest dose of ABIO-08/01 induced pronounced sedative effects (delta/theta and beta increase) 1 h after acute and slightly less so after superimposed administration, in the 6th hour a decrease in alpha and beta activity signaled less sedative and more relaxant action. In the V-EEG these changes were less pronounced, in the R-EEG partly opposite. Hemisphere-specific changes were observed, suggesting increases in LORETA power over the left temporal, parietal, superior frontal regions and decreases over the right prefrontal, temporal pole and occipital regions. These LORETA changes are discussed in the light of neuroimaging findings on anxiety and anxiolytics.

Electroencephalogram-based pharmacodynamic measures: a review

“…While the spatial resolution is considered low, this method is able to take advantage of the high time resolution of EEG recordings. This method has since been applied to characterize the effects of various psychoactive drugs on the spatial distribution of electrical current sources in the brain [50],51,52,53,54,55,56]. Saletu et al [57] describe a “key-lock” principle based on two important observations involving current source density maps.…”

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

“…However, the literature reports several different approaches concerning the thresholding of the obtained statistical tomographic maps. Whereas conservative methods which allow for a fairly accurate localization of the target area have been employed [14,24], other less conservative techniques have been used to show weaker drug effects [3,29]. This duality is accentuated when spontaneous EEG is used because, unlike evoked potentials, the location of the cerebral generators is less clear for spontaneous EEG and the interpretation of results is much more open and less spatially restricted.…”

“…The performance of voxel intensity-based tests has already been examined and validated by Monte Carlo simulations of noisy cluster images with multiple intensities and diameters using the same permutation statistical tests [15]. The binomial test has also been applied in pharmaco-EEG studies, especially when drug effects are weak [3,27,29].…”