Quantification of brain voriconazole levels in healthy adults using fluorine magnetic resonance spectroscopy.

Voriconazole is more effective for aspergillosis infections with central nervous system involvement than other antifungal agents. The clinical efficacy of voriconazole for central nervous system infections has been attributed to its ability to cross the blood-brain barrier. However, pharmacokinetic studies are limited to plasma and cerebrospinal fluid, so it remains unclear how much of the drug enters the brain. Fluorinated compounds such as voriconazole can be quantified in the brain using fluorine-19 magnetic resonance spectroscopy (MRS). Twelve healthy adult males participated in a pharmacokinetic analysis of voriconazole levels in the brain and plasma. Open-label voriconazole was dosed per clinical protocol with a loading dose of 400 mg every 12 h on day 1, followed by 200 mg every 12 h administered orally over a 3-day period. MRS was performed before and after dosing on the third day. Voriconazole levels in the brain exceeded the MIC for Aspergillus. The brain/plasma ratios were 3.0 at steady state on day 3 (predose) and 1.9 postdose. We found that voriconazole is able to penetrate the brain tissue, which can be quantified using a noninvasive MRS technique. (This study has been registered at ClinicalTrials.gov under registration no. NCT00300677.).

Effects of citalopram and escitalopram on fMRI response to affective stimuli in healthy volunteers selected by serotonin transporter genotype.

This study was designed to assess whether functional magnetic resonance imaging (fMRI) following antidepressant administration (pharmaco-fMRI) is sufficiently sensitive to detect differences in patterns of activation between enantiomers of the same compound. Healthy adult males (n=11) participated in a randomized, double-blind, cross-over trial with three medication periods during which they received citalopram (racemic mixture), escitalopram (S-citalopram alone), or placebo for 2 weeks. All participants had high expression serotonin transporter genotypes. An fMRI scan that included passive viewing of overt and covert affective faces and affective words was performed after each medication period. Activation in response to overt faces was greater following escitalopram than following citalopram in the right insula, thalamus, and putamen when the faces were compared with a fixation stimulus. For the rapid covert presentation, a greater response was observed in the left middle temporal gyrus in the happy versus fearful contrast following escitalopram than following citalopram. Thus, the combination of genomics and fMRI was successful in discriminating between two very similar drugs. However, the pattern of activation observed suggests that further studies are indicated to understand how to optimally combine the two techniques.