Synthesis of azafluorenones and related compounds using deprotocupration-aroylation followed by intramolecular direct arylation

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.International audienceThe efficiency of the deprotocupration-aroylation of 2-chloropyridine using lithiocuprates prepared from CuX (X=Cl, Br) and LiTMP (TMP=2,2,6,6-tetramethylpiperidido, 2 equiv) was investigated. CuCl was identified as a more suitable copper source than CuBr for this purpose. Different diaryl ketones bearing a halogen at the 2 position of one of the aryl groups were synthesized in this way from azines and thiophenes. These were then involved in palladium-catalyzed ring closure: substrates underwent expected CH-activation-type arylation to afford fluorenone-type compounds, and were also subjected to cyclization reactions leading to xanthones, notably in the presence of oxygen-containing substituents or reagents

New anti-CD20 monoclonal antibodies: which is the best?

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Simultaneous evaluation of six human glucuronidation activities in liver microsomes using liquid chromatography-tandem mass spectrometry.: Simultaneous evaluation of glucuronidation activities

International audienceThis article describes the development of a procedure for the simultaneous evaluation of the activity of six different uridine diphosphate (UDP)-glucuronyltransferases (UGTs) in human liver microsomes (HLMs). The method consists of incubations of probe substrates for UGT1A1 (etoposide), UGT1A3 (chenodeoxycholic acid), UGT1A4 (trifluoperazine), UGT1A6 (serotonin), UGT1A9 (mefenamic acid), and UGT2B7 (azidothymidine) with HLMs. The six substrates were divided into three different incubations (etoposide + mefenamic acid; chenodeoxycholic acid + serotonin + azidothymidine; and trifluoperazine alone), the media of which were pooled before analysis. Glucuronide formation rates were determined in a single run of 20 min using a validated liquid chromatography-tandem mass spectrometry method. No significant difference was observed between glucuronidation activities measured using the current procedure and individual incubations of the probes. The method was used successfully for the determination of UGT activities in 44 individual HLM preparations and for the phenotyping of preparations predicted to have altered UGT1A1 and UGT2B7 activities because of known genetic polymorphisms

Résultats préliminaires de l’étude de la prévalence de la cachexie en hématologie au sein de la cohorte HEMODIAG : perspectives de prévention par l’activité physique adaptée

Les lymphomes et le myélome sont des hémopathies malignes traitées par chimiothérapies. Ces traitements favorisent la survenue d’une cachexie, caractérisée par une perte de poids involontaire, entraînant une augmentation du risque de mortalité et une diminution de la qualité de vie. L’objectif principal de cette étude était d’investiguer la prévalence de la cachexie chez les patients atteints d’un lymphome ou d’un myélome au sein de la cohorte HEMODIAG, selon les critères diagnostiques de Fearon et al. et Martin et al. Respectivement, parmi les 146 patients inclus dans notre étude, 16 % des patients sont cachectiques via le critère de Fearon contre 38 % via celui de Martin. Basé sur une matrice de corrélation corrélée à la survie, le score de Martin semble plus pertinent pour évaluer la cachexie. L’activité physique adaptée constituerait un moyen de prévenir la cachexie en agissant sur l’ensemble des mécanismes physiopathologiques, mais aucune étude ne le prouve chez l’humain atteint de cancer. Nos prochains travaux s’attacheront donc à évaluer l’effet préventif d’un programme d’APA supervisé au domicile du patient atteint de lymphome ou de myélome sur la cachexie

Calcineurin Activity Assay Measurement by Liquid Chromatography-Tandem Mass Spectrometry in the Multiple Reaction Monitoring Mode.

International audienceBACKGROUND: Blood concentrations of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus are currently measured to monitor immunosuppression in transplant patients. The measurement of calcineurin (CN) phosphatase activity has been proposed as a complementary pharmacodynamic approach. However, determining CN activity with current methods is not practical. We developed a new method amenable to routine use.METHODS: Using liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM-MS), we quantified CN activity by measuring the dephosphorylation of a synthetic phosphopeptide substrate. A stable isotope analog of the product peptide served as internal standard, and a novel inhibitor cocktail minimized dephosphorylation by other major serine/threonine phosphatases. The assay was used to determine CN activity in peripheral blood mononuclear cells (PBMCs) isolated from 20 CNI-treated kidney transplant patients and 9 healthy volunteers.RESULTS: Linearity was observed from 0.16 to 2.5 μ mol/L of product peptide, with accuracy in the 15% tolerance range. Intraassay and interassay recoveries were 100.6 (9.6) and 100 (7.5), respectively. Michaelis-Menten kinetics for purified CN were Km = 10.7 (1.6) μ mol/L, Vmax = 2.8 (0.3) μ mol/min/mg, and for Jurkat lysate, Km = 182.2 (118.0) μ mol/L, Vmax = 0.013 (0.006) μ mol/min/mg. PBMC CN activity was successfully measured in a single tube with an inhibitor cocktail.CONCLUSIONS: Because LC-MRM-MS is commonly used in routine clinical dosage of drugs, this CN activity assay could be applied, with parallel blood drug concentration monitoring, to a large panel of patients to reevaluate the validity of PBMC CN activity monitoring

Troubles du comportement et hallucinations après consommation d’infusions de feuilles de boldo

Nous rapportons un cas de troubles du comportement avec hallucinations chez une enfant de 12 ans après consommation d’infusions de feuilles de boldo. La boldine, pourrait être responsable des troubles neuropsychiatriques transitoires présentés par la patiente. L’apparition de troubles du comportement et d’hallucinations sans cause évidente doit faire rechercher la consommation de produits de phytothérapie, notamment d’infusions (« tisanes »). La consommation d’infusions à base de feuilles de boldo doit être évitée chez l’enfant