1H-13C NMR-based urine metabolic profiling in autism spectrum disorders.

International audienceAutism Spectrum Disorders (ASD) are a group of developmental disorders caused by environmental and genetic factors. Diagnosis is based on behavioral and developmental signs detected before 3 years of age with no reliable biological marker. The purpose of this study was to evaluate the potential use of a 2D NMR-based approach to express the global biochemical signature of autistic individuals compared to normal controls. This technique has greater spectral resolution than to 1D (1)H NMR spectroscopy, which is limited by overlapping signals. The urinary metabolic profiles of 30 autistic and 28 matched healthy children were obtained using a (1)H-(13)C NMR-based approach. The data acquired were processed by multivariate orthogonal partial least-squares discriminant analysis (OPLS-DA). Some discriminating metabolites were identified: β-alanine, glycine, taurine and succinate concentrations were significatively higher, and creatine and 3-methylhistidine concentrations were lower in autistic children than in controls. We also noted differences in several other metabolites that were unidentified but characterized by a cross peak correlation in (1)H-(13)C HSQC. Statistical models of (1)H and (1)H-(13)C analyses were compared and only 2D spectra allowed the characterization of statistically relevant changes [R(2)Y(cum)=0.78 and Q(2)(cum)=0.60] in the low abundance metabolites. This method has the potential to contribute to the diagnosis of neurodevelopment disorders but needs to be validated on larger cohorts and on other developmental disorders to define its specificity

GC-MS-based urine metabolic profiling of autism spectrum disorders.: GC-MS-based Urine Metabolic Profiling in ASD

International audienceAutism spectrum disorders (ASD) are a group of neurodevelopmental disorders resulting from multiple factors. Diagnosis is based on behavioural and developmental signs detected before 3 years of age, and there is no reliable biological marker. The purpose of this study was to evaluate the value of gas chromatography combined with mass spectroscopy (GC-MS) associated with multivariate statistical modeling to capture the global biochemical signature of autistic individuals. GC-MS urinary metabolic profiles of 26 autistic and 24 healthy children were obtained by liq/liq extraction, and were or were not subjected to an oximation step, and then were subjected to a persilylation step. These metabolic profiles were then processed by multivariate analysis, in particular orthogonal partial least-squares discriminant analysis (OPLS-DA, R(2)Y(cum) = 0.97, Q(2)(cum) = 0.88). Discriminating metabolites were identified. The relative concentrations of the succinate and glycolate were higher for autistic than healthy children, whereas those of hippurate, 3-hydroxyphenylacetate, vanillylhydracrylate, 3-hydroxyhippurate, 4-hydroxyphenyl-2-hydroxyacetate, 1H-indole-3-acetate, phosphate, palmitate, stearate, and 3-methyladipate were lower. Eight other metabolites, which were not identified but characterized by a retention time plus a quantifier and its qualifier ion masses, were found to differ between the two groups. Comparison of statistical models leads to the conclusion that the combination of data obtained from both derivatization techniques leads to the model best discriminating between autistic and healthy groups of children

Metabolomics Study of Urine in Autism Spectrum Disorders Using a Multiplatform Analytical Methodology

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with no clinical biomarker. Aims of this study were to characterize a metabolic signature of ASD, and to evaluate multi-platform analytical methodologies in order to develop predictive tools for diagnosis and disease follow up. Urines were analyzed using: 1H- and 1 H-13C-NMR-based approaches and LC-HRMS-based approaches (ESI+ and ESI- on a HILIC and C18 chromatography column). Data tables obtained from the six analytical modalities on a training set of 46 urines (22 autistic children and 24 controls) were processed by multivariate analysis (OPLS-DA). Prediction of each of these OPLS-DA models were then evaluated using a prediction set of 16 samples (8 autistic children and 8 controls) and ROC curves. Thereafter, a data fusion block-scaling OPLS-DA model was generated from the 6 best models obtained for each modality. This fused OPLSDA model showed an enhanced performance (R 2Y(cum)=0.88, Q 2 (cum)=0.75) compared to each analytical modality model, as well as a better predictive capacity (AUC=0.91, p-value 0.006). Metabolites that are most significantly different between autistic and control children (p<0.05) are indoxyl sulfate, N-\u2329-Acetyl-L-arginine, methyl guanidine and phenylacetylglutamine. This multi-modality approach has the potential to contribute to find robust biomarkers and characterize a metabolic phenotype of the ASD population

Synthèse de médicaments radiopharmaceutiques pour visualiser le transporteur de la sérotonine par imagerie TEP

TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Dianostic précoce de la maladie d'Alzheimer (l'apport des médicaments radiopharmaceutiques)

TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Intérêt de la crénothérapie et de l'éducation thérapeutique dans la prise en charge de la dermatite atopique

TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

18 F-Labeled Aryl-Tracers through Direct Introduction of [ 18 F]Fluoride into Electron-Rich Arenes

International audienceRapid and efficient methods using no-carried-added [18F]fluoride as the source of fluorine-18 for nucleophilic aromatic fluorination play an important role in the development of new radiopharmaceuticals for positron emission tomography (PET). Molecules that bear electron-rich aromatic moieties are especially difficult to label by direct single-step nucleophilic no-carrier-added radiofluorination. Classical Balz-Schiemann reaction with its modifications, Wallach reaction and diaryliodonium salts methodology are a few methods to enable this. The present review provides a critical overview of these chemical methods with the emphasis on diaryliodonium salt as precursors for the direct introduction of [18F]fluoride into electron-rich arenes in synthesis of 18F-labeled molecules for PET scanning

Quels accès à l'innovation thérapeutique pour des patients en impasse thérapeutique ? (Etat des lieux et perspectives au travers d'un exemple pratique)

Pour être commercialisé, un médicament doit obtenir une autorisation de mise sur le marché (AMM) délivrée par une autorité compétente (européenne ou nationale). Toutefois, dans le cas de maladies graves ou rares dont les besoins médicaux ne sont pas satisfaits, malgré les incertitudes quant à l efficacité et la sécurité du médicament, les autorités de santé compétentes sont parfois prêtes à accepter une prise de risque pour le patient en mettant à leur disposition des produits en cours de développement, c'est-à-dire sans AMM. Les médicaments destinés à traiter ces pathologies peuvent ainsi disposer d un accès précoce au marché via des procédures spécifiques européennes ou nationales.Cette thèse détaille dans une première partie, les différents dispositifs mis en œuvre en Europe, et plus particulièrement en France, pour accéder à l innovation : au stade de développement clinique avec l AMM donnée à un stade précoce et l usage compassionnel, et après la commercialisation du médicament avec les Recommandations Temporaires d Utilisation. La deuxième partie illustre ces propos en présentant la mise en place et la gestion d une Autorisation Temporaire d Utilisation de cohorte au sein d un laboratoire pharmaceutique, avec l exemple pratique du pomalidomide Celgene.TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development.

International audienceAmyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder that is believed to have complex genetic and environmental influences in the pathogenesis, but etiologies are unidentified for most patients. Until the major causes are better defined, drug development is directed at downstream pathophysiological mechanisms, themselves incompletely understood. For nearly 30 years, glutamate-induced excitotoxicity has lain at the core of theories behind the spiraling events, including mitochondrial dysfunction, oxidative stress, and protein aggregation, that lead to neurodegenerative cell death. One drug, riluzole, which possesses anti-glutamatergic properties, is approved as neuroprotective for ALS. Following the achievement of the riluzole trials, numerous other agents with similar mechanisms have been tested without success. This article provides an overview of excitotoxicity in ALS, focusing on the events that contribute to excess glutamate, how the excess might damage nerve cells, and how this information is being harnessed in the development of potential new neuroprotective agents. The work highlights clinical trials of drugs that have targeted the glutamate system, comments on the potential role of glutamate as a biomarker and concludes with a section on future directions for the field. As research uncovers elusive etiologies and brings clarity to pathophysiological mechanisms, the success of new interventions will increasingly depend on the design of agents that target particular mechanisms for specific individuals. The heady future of personalized drug regimens for ALS rests with medicinal chemists, the scientists whose ideas and work produce these designer drugs