Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol

Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations:A Meta-Analysis of Individual Data

Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment

Solidarité et droit de l’Union européenne : un principe à l’épreuve

Les occasions de « tester » la solidarité dans l’Union européenne ont été nombreuses et invitent à s’interroger sur la place et le rôle du droit à cet égard. Le droit de l’Union se présente-t-il comme un vecteur de solidarité ? A-t-il contribué à affermir la constitution d’un espace intégré ? A-t-il laissé au contraire apparaître des failles justifiant un aggiornamento ? C’est précisément l’objet de cet ouvrage que de proposer un bilan du principe de solidarité, de ses formats comme de ses applications dans les principales politiques européennes, depuis le traité de Lisbonne et dans un contexte marqué par de nombreuses crises

L'Ethyl-glucuronide, marqueur de l'éthylisme (mise au point du dosage dans les cheveux et applications)

LIMOGES-BU Médecine pharmacie (870852108) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Étude protéomique des modifications phénotypiques des cellules rénales exposées aux immunosuppresseurs inhibiteurs de la calcineurine

Les médicaments inhibiteurs de la calcineurine, la cyclosporine (CsA) et le tacrolimus (TAC), sont utilisés depuis plus de 30 ans dans les protocoles d immunosuppression afin de prévenir les rejets du greffon et traiter des maladies auto-immunes. Si ces traitements ont considérablement amélioré la survie du greffon à court terme, ils contribuent à long terme à l apparition d une atteinte rénale appelée néphropathie chronique d allogreffe ainsi qu à une dysfonction chronique du greffon, qui conduit au déclin progressif, irréversible de la fonction rénale et à la perte du greffon, en dehors de tout surdosage médicamenteux. Les mécanismes moléculaires impliqués dans la néphrotoxicité des inhibiteurs de la calcineurine sont nombreux et, bien que largement étudiés, restent mal compris. Notre objectif principal a été de développer et de mettre en application une approche protéomique à large échelle, basée sur la spectrométrie de masse, afin d identifier et de quantifier les modifications d expression protéique induites par la CsA et le TAC sur un modèle de cellules rénales en culture. La méthodologie utilisée est l approche SILAC (ou Stable Isotope Labelling by Amino acids in Cell culture), qui consiste en un marquage métabolique des protéines cellulaires avec des acides aminés alourdis par du carbone isotope 13. Nous montrons que l expression intra-cellulaire et la sécrétion de nombreuses protéines sont modulées par la CsA et que le TAC agit différemment sur ces mêmes protéines. Nos résultats confirment ainsi des observations précédemment décrites et nous conduisent également à formuler de nouvelles hypothèses concernant les mécanismes moléculaires potentiellement impliqués dans la néphrotoxicité induite par les inhibiteurs de la calcineurine. Des études ultérieures seront développées pour tester certaines de ces protéines comme biomarqueurs potentiels de cette néphrotoxicité chez des patients transplantés et traités par CsA ou TAC.LIMOGES-BU Médecine pharmacie (870852108) / SudocSudocFranceF

Sirolimus and everolimus intestinal absorption and interaction with calcineurin inhibitors: a differential effect between cyclosporine and tacrolimus.

International audienceThe mTOR inhibitors (ImTORs) sirolimus (SRL) and everolimus (EVR) have been increasingly used in renal transplantation as part of calcineurin inhibitor (CNI) sparing or avoidance regimens. Those drugs have low and variable oral bioavailability that is increased when combined with cyclosporine or tacrolimus (TAC). We investigated the mechanisms involved in ImTORs intestinal absorption in vitro and associated it with their drug-drug interactions with CNIs. The transport of ImTORs across Caco-2 cells was studied in the apical (A) to basolateral (B) and B to A directions, in the absence or presence of cyclosporine, TAC, and GF120918 (P-gp inhibitor). In Caco-2 cells, EVR and SRL displayed a polarized transport with 8.7- and 5.9-fold higher P(app,B→A) than P(app,A→B), respectively. P-gp inhibition by GF120918 resulted in a 70 and 41% decrease in EVR and SRL efflux, respectively. Cyclosporine and TAC led to a comparable and significant decrease in the efflux ratio of ImTORs, suggesting inhibition of a P-gp-mediated efflux transport. Cyclosporine also exhibited a specific increase of P(app,B→A), which may be attributed to the inhibition of other transporters and/or metabolizing enzymes. In conclusion, EVR and SRL are both subject to an apically directed efflux mediated by P-gp. TAC mainly inhibits this efflux mechanism, while the effect of cyclosporine appears to be more complex with mechanisms to be confirmed by further studies

Mapping cyclosporine-induced changes in protein secretion by renal cells using stable isotope labeling with amino acids in cell culture (SILAC).

International audienceNephrotoxicity is an adverse event that strongly limits the use of the immunosuppressant cyclosporine in solid organ transplantation and the precise molecular mechanisms underlying this toxicity remain unclear. MS-based proteomic analysis of the secretome of HEK-293 renal cells exposed to cyclosporine was performed to identify changes in protein secretion, as a first step to discover potential biomarkers of such nephrotoxicity. To detect and quantify the perturbed proteins in the culture medium we used SILAC and nano-scale liquid chromatography followed by MALDI-TOF/TOF mass spectrometry. Among 106 proteins identified, 80 were quantified in both forward/reverse SILAC experiments and quantitative proteomic analysis revealed altered levels of expression for 24 secreted proteins. These included the down-regulation of a number of extracellular matrix/cell adhesion components, and the up-regulation of secreted cyclophilins A and B, macrophage inhibition factor and phosphatidylethanolamine-binding protein 1. These changes in protein secretion were not prevented by co-incubation with the antioxidant N-acetylcysteine, suggesting that they were not triggered by cyclosporine-induced oxidative stress. The results from the present study provide important new knowledge to gain insights into the molecular mechanisms of cyclosporine-related toxicity. Some of the proteins identified here should be tested as potential biomarkers of cyclosporine nephrotoxicity in subsequent clinical studies

Comment on: Pharmacodynamic evaluation of intermittent versus extended and continuous infusions of piperacillin/tazobactam in a hollow-fibre infection model against Klebsiella pneumoniae

International audienc

Opposite effects of the S4-S5 linker and PIP2 on voltage-gated channel function: KCNQ1/KCNE1 and other channels

Voltage-gated potassium (Kv) channels are tetramers, each subunit presenting six transmembrane segments (S1-S6), with each S1-S4 segments forming a voltage-sensing domain (VSD) and the four S5-S6 forming both the conduction pathway and its gate. S4 segments control the opening of the intracellular activation gate in response to changes in membrane potential. Crystal structures of several voltage-gated ion channels in combination with biophysical and mutagenesis studies highlighted the critical role of the S4-S5 linker (S4S5L) and of the S6 C-terminal part (S6T) in the coupling between the VSD and the activation gate. Several mechanisms have been proposed to describe the coupling at a molecular scale. This review summarizes the mechanisms suggested for various voltage-gated ion channels, including a mechanism that we described for KCNQ1, in which S4S5L is acting like a ligand binding to S6T to stabilize the channel in a closed state. As discussed in this review, this mechanism may explain the reverse response to depolarization in HCN-like channels. As opposed to S4S5L, the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2), stabilizes KCNQ1 channel in an open state. Many other ion channels (not only voltage-gated) require PIP2 to function properly, confirming its crucial importance as an ion channel co-factor. This is highlighted in cases in which an altered regulation of ion channels by PIP2 leads to channelopathies, as observed for KCNQ1. This review summarizes the state of the art on the two regulatory mechanisms that are critical for KCNQ1 and other voltage-gated channels function (PIP2 and S4-S5L), and assesses their potential physiological and pathophysiological roles