Lability of IgE Levels Early in Life

We report a case of a very fast and intriguing decrease in IgE concentrations after exclusion from the diet of any CM lysate in an unusual clinical presentation of cow's milk allergy in an infant. Analysis of IgE kinetics after allergen elimination suggests rapid cessation of IgE biosynthesis and a short IgE half-life

Infliximab in ankylosing spondylitis: alone or in combination with methotrexate? A pharmacokinetic comparative study.

International audienceINTRODUCTION: Methotrexate (MTX) has been shown to modify infliximab pharmacokinetics in rheumatoid arthritis. However, its combination with infliximab in the treatment of ankylosing spondylitis (AS) is not recommended. The objective of this study was to examine the influence of MTX on infliximab exposure in patients with AS. METHODS: Patients with AS patients who had predominantly axial symptoms were randomised to receive infliximab alone (infusions of 5 mg/kg at weeks 0, 2, 6, 12 and 18) or infliximab combined with MTX (10 mg/week). Infliximab concentrations were measured before and 2 hours after each infusion and at 1, 3, 4, 5, 8, 10, 14 and 18 weeks. We estimated individual cumulative area under the concentration versus time curves (AUC) for infliximab concentration between baseline and week 18 (AUC(0-18)). Clinical and laboratory evaluations were performed at each visit. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was the primary end point for clinical response. RESULTS: Twenty-six patients were included (infliximab group: n = 12, infliximab + MTX group: n = 14), and 507 serum samples were available for measurement of infliximab concentration. The two groups did not differ with regard to AUC(0-18) or evolution of BASDAI scores and biomarkers of inflammation. CONCLUSIONS: The combination of MTX and infliximab does not increase the exposure to infliximab over infliximab alone in patients with AS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00507403

Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases

International audienceINTRODUCTION: A proportion of patients receiving infliximab have antibodies toward infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of infliximab. METHODS: All patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving infliximab beginning in December 2005 were retrospectively followed until January 2009 or until infliximab discontinuation. Trough serum infliximab and ATI concentrations were measured at each visit. The patients were separated into two groups: ATI(pos) if ATI were detected at least once during the follow-up period and ATI(neg) otherwise. Repeated measures analysis of variance was used to study the association of infliximab concentration at treatment initiation and the development of ATI. Maintenance of infliximab in the two groups was studied by using Kaplan-Meier curves. RESULTS: We included 108 patients: 17 with RA and 91 with SpA. ATI were detected in 21 patients (19%). The median time to ATI detection after initiation of infliximab was 3.7 months (1.7 to 26.0 months). For both RA and SpA patients, trough infliximab concentration during the initiation period was significantly lower for ATI(pos) than ATI(neg) patients. RA patients showed maintenance of infliximab at a median of 19.5 months (5.0 to 31.0 months) and 12.0 months (2.0 to 24.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.08). SpA patients showed infliximab maintenance at a median of 16.0 months (3.0 to 34.0 months) and 9.5 months (3.0 to 39.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.20). Among SpA patients, those who were being treated concomitantly with methotrexate had a lower risk of developing ATI than patients not taking methotrexate (0 of 14 patients (0%) vs. 25 of 77 patients (32%); P = 0.03). CONCLUSIONS: High concentrations of infliximab during treatment initiation reduce the development of ATI, and the absence of ATI may be associated with prolonged maintenance of infliximab. Thus, trough serum infliximab concentration should be monitored early in patients with rheumatic diseases

P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment

The P2X7 receptor is an ATP-gated cation channel with a still ambiguous role in cancer progression, proposed to be either pro- or anti-cancerous, depending on the cancer or cell type in the tumour. Its role in mammary cancer progression is not yet defined. Here, we show that P2X7 receptor is functional in highly aggressive mammary cancer cells, and induces a change in cell morphology with fast F-actin reorganization and formation of filopodia, and promotes cancer cell invasiveness through both 2- and 3-dimensional extracellular matrices in vitro. Furthermore, P2X7 receptor sustains Cdc42 activity and the acquisition of a mesenchymal phenotype. In an immunocompetent mouse mammary cancer model, we reveal that the expression of P2X7 receptor in cancer cells, but not in the host mice, promotes tumour growth and metastasis development, which were reduced by treatment with specific P2X7 antagonists. Our results demonstrate that P2X7 receptor drives mammary tumour progression and represents a pertinent target for mammary cancer treatment

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Infections à virus respiratoire syncytial (VRS) et bronchiolite du nourrisson

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Etude de l'influence du polymorphisme de fcgrt sur la pharmacocinétique des anticorps monoclonaux thérapeutiques à l'aide d'un modèle murin

TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Etude des relations dose-concentration-effet des anticorps thérapeutiques par modélisation pharmacocinétique et pharmacocinétique-pharmacodynamique

Les anticorps thérapeutiques (AcT) ont révolutionné la thérapeutique. Cependant, la variabilité de leur relation dose-concentration-effet reste mal connue. L objectif de ce travail était de décrire cette variabilité pour le bevacizumab, l infliximab, le rituximab et les globulines antilymphocytaires polyclonales (ALG). La pharmacocinétique des anticorps a été décrite par un modèle bicompartimental. La variabilité pharmacocinétique semble être influencée par le poids des sujets, la présence d anticorps induits contre les anticorps du bevacizumab et des ALG a été décrite par un modèle physiologique indirect. Nous avons observé une influence du polymorphisme du FCGR3A, sur la RCE des ALG, ce qui suggère que les ALG agissent en partie par cytotoxicité cellulaire dépendante des anticorps. La prise en compte des facteurs de variabilité identifiés permettra l optimisation des posologies et de l efficacité des AcT.Therapeutic antibodies (TAbs) have largely improved therapeutic management. However, the variability of their dose-concentration-effect relationship remains poorly known. The objective were to describe this variability for bevacizumab, infliximab, rituximab and antilymphocyte globulins (ALG). The pharmacokinetics of antibodies was described using a 2 compartment model. The pharmacokinetic variability seems to be influenced by body weight and immune response against Tabs, and antigenic burden. The concentration-effect relationship (CER) of bevacizumab and ALG was described by a indirect response model. We found an influence of FCGR3A polymorphism on CER of ALG, which suggests that ALG act, at least in part, by antibody-dependent cellular cytotoxicity. Account for identified variability factors should enable the optimisation of dosing regimen and efficacy of Tabs.TOURS-BU Médecine (372612103) / SudocSudocFranceF

Variabilité pharmacocinétique des anticorps thérapeutiques

Les anticorps thérapeutiques sont de plus en plus utilisés dans le traitement de différentes pathologies, dont les cancers et les maladies inflammatoires chroniques. La variabilité pharmacocinétique interindividuelle des anticorps est grande et influence la réponse clinique. Certaines caractéristiques de l’individu jouent un rôle majeur car elles modifient fortement cette pharmacocinétique, telles les dimensions corporelles, l’immunisation contre les anticorps thérapeutiques utilisés ou la masse antigénique. D’autres jouent un rôle mineur, comme l’âge, le sexe ou des polymorphismes génétiques. Cette variabilité doit être décrite avec soin pour déterminer le schéma posologique optimal

Suivi thérapeutique pharmacologique de l'infliximab (Remicade®)

TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF