Dataset Information

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

ABSTRACT: 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.).

SUBMITTER: Henry ME

PROVIDER: S-EPMC3811243 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Henry Michael E ME Bolo Nicolas R NR Zuo Chun S CS Villafuerte Rosemond A RA Cayetano Kenroy K Glue Paul P Damle Bharat D BD Andrews Emma E Lauriat Tara L TL Rana Namoode S NS Churchill Jeffrey H JH Renshaw Perry F PF

Antimicrobial agents and chemotherapy 20130812 11

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 fluo ...[more]

PMID: 23939898

Similar Datasets

Project description:Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder. Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T. The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GSH levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites. Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.

Project description:Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adult. Based on transcriptome profile MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate Dehydrogenase-1 (IDH1) mutations have been described in several tumours, including gliomas, while in MB are exceptionally reported and not routinely investigated. By mean of magnetic resonance spectroscopy (MRS) we unequivocally assessed the presence the oncometabolite D-2-Hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutation, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also exceptionally described in MB. To our knowledge this is the first reported case of MB harboring both mutations together. Of note, tumour exhibited a heterogeneous phenotype with a tumour component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting coexistence of two different major tumour clones. These findings draw attention to the need of a deeper genetic characterization of MB in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, reported data underling the importance of performing MRS for the identification of IDH mutations in non-glial tumours. The use of throughput molecular profiling analysis and advanced medical imaging technology will certainly increase the frequency with which rare tumour entities will be identified. Whether they have any particular therapeutic implications or prognostic relevance requires further investigations.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets