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Levamisole (an increasingly frequent contaminant of cocaine) can cause antineutrophil cytoplasmic antibody-associated vasculitis. Dermatologists should consider a diagnosis of cocaine/levamisole-associated cutaneous vasculopathy syndrome in cases of purpura of the ears and/or extensive retiform purpura in drug users. We report a case of particularly severe levamisole-induced necrotic purpura and immunological abnormalities in a 40-year-old woman. [ABSTRACT FROM AUTHOR]

Abstract: Ozone treatment (10g/kg) of common wheat grains with a new patented process, Oxygreen®, used before milling was found to significantly reduce (by 10–20%) the required energy at breaking stage whatever the grain hardness and without changes in the flour yield. Detailed study of each of the milling steps undertaken on a hard type cultivar showed that both the breaking and the reduction energy were decreased. Reduction of the coarse bran yield was also observed concomitantly with an increase in the yield of white shorts. Biochemical characterization of the milling fractions pointed out changes in technological flour properties as starch damage reduction, aleurone content enrichment and increase of insoluble glutenin polymers. Measurement of wheat grain tissue mechanical properties showed that ozone treatment leads to reduction of the aleurone layer extensibility and affects the local endosperm resistance to rupture. These data as well as the direct effect of ozone oxidation on biochemical compounds could explain the observed changes in milling energy, bran and shorts yield and flour composition. [Copyright &y& Elsevier]

Abstract: 2-Chloro-N-S-phenyl 2S-piperidin-2-yl methyl]-3-trifluoromethyl benzamide, monohydrochloride (SSR504734) is a potent and selective inhibitor of the glycine transporter type 1, which increases central N-methyl-d aspartate glutamatergic tone. Since glutamate has been shown to play a role in the regulation of the dopaminergic system in dopamine-related disorders, such as schizophrenia, we investigated the possibility that SSR504734 may modify the basolateral amygdala-elicited stimulation of dopamine release in the nucleus accumbens via an augmentation of glutamate receptor-mediated neurotransmission. First, our data confirmed that SSR504734 is an inhibitor of GlytT1. In the nucleus accumbens of anesthetized rat, SSR504734 (10mg/kg, i.p.) induced an increase of extracellular levels of glycine as measured by microdialysis coupled with capillary electrophoresis with laser-induced fluorescence detection. Second, the data demonstrated that SSR504734 (10mg/kg, i.p.) enhanced the facilitatory influence of glutamatergic afferents on dopamine neurotransmission in the nucleus accumbens. Using an electrochemical technique, we measured dopamine release in the nucleus accumbens evoked by an electrical stimulation of the basolateral amygdala. SSR504734 facilitated dopamine release evoked by a 20 or a 40Hz frequency basolateral amygdala stimulation. This facilitatory effect was dependent on glutamatergic tone, as intra-nucleus accumbens application of 6-7-dinitroquinoxaline-2,3-dione (10−3 M) or dl-2-amino-5-phosphonopentanoic acid (10−3 M), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-d aspartate receptors antagonists, respectively, inhibited dopamine release evoked by basolateral amygdala stimulation. Furthermore dl-2-amino-5-phosphonopentanoic acid co-administrated with SSR504734 hampered the dopamine-evoked release facilitation. These data underline the in vivo implication of the glycine uptake mechanism in the control of subcortical glutamate/dopamine interactions. [Copyright &y& Elsevier]

La guidance interactive est une technique de psychothérapie parent–enfant. Initialement développée par Susan Mc Donough aux États-Unis, pour soutenir l'alliance auprès des parents en grandes difficultés. Elle a ensuite montré sont efficacité auprès de dyades dont les bébés présentaient des troubles fonctionnels du nourrisson, dans l'étude Princeps du Geneva Group. Cette technique choisit comme porte d'entrée dans l'interaction parent–enfant, la dimension interpersonnelle, et la lecture des comportements interactifs, pour ensuite aborder les pensées et cognitions et les émotions en lien avec le symptôme de l'enfant ou de la dyade. Le visionnement de séquences de jeu libre est au cœur du dispositif thérapeutique, permettant une co-construction de la lecture de l'interaction, entre le thérapeute et le parent concerné. Nous proposons une description des grands principes de cette technique et son illustration par deux cas cliniques. Le premier décrit une interaction dont la lecture fut un moment clé dans une thérapie mère–bébé auprès d'une patiente présentant une dépression périnatale. Le second illustre la création d'une alliance thérapeutique forte, dans une situation de parentalité à haut risque, par la description et soutien des compétences parentales à travers le visionnement de moments positifs de l'interaction. Ces situations illustrent le processus thérapeutique et les liens qui se font entre la symptomatologie maternelle et la synchronie de l'interaction. Nous discuterons cette technique au regard d'autres interventions utilisant le vidéo feed-back. Interactive guidance is a parent-child psychotherapy technique, which was initially developed by Susan Mc Donough in the United States to support parental alliance in high-risk families. Later the Geneva Group Study showed its effectiveness in dyads whose babies had functional disorders. This technique chooses as a gateway in the parent–child interaction the interpersonal dimension, and the reading of the Interactive behaviors, to then approach thoughts, cognitions, and emotions related to the symptom of the child or of the dyad. The viewing of free play sequences is at the heart of the therapeutic device allowing a co-construction of the interaction reading between the therapist and the concerned parent. We propose a main principles description of this technique and its illustration by two clinical cases. The first one describes an interaction whose reading was a key moment in a mother–baby therapy with a mother suffering from perinatal depression. The second illustrates the creation of a strong therapeutic alliance in a situation of high-risk parenting through the description and support of parenting skills by means of viewing positive moments of interaction. These situations illustrate the therapeutic process and the links that arise between the maternal symptomatology and the synchrony of the interaction. We will discuss this technique in conceptual contrast to some other interventions using video feedback. [ABSTRACT FROM AUTHOR]

Abstract: Arginine vasopressin and corticotropin-releasing factor are two neuroactive peptides that regulate hypothalamic–pituitary-axis and associated stress response. While the potential antidepressant and anxiolytic profiles of corticotropin-releasing factor 1 antagonists have been well studied, the concept of blockade of vasopressin system as another approach for the treatment of emotional processes has only been made available recently by the synthesis of the first non-peptide antagonist at the V1b receptor, SSR149415. In the present study SSR149415 has been compared with the corticotropin-releasing factor 1 antagonist SSR125543 and with anxiolytic and antidepressant drugs on the response of hippocampal cholinergic and cortical noradrenergic systems to the anxiogenic benzodiazepine receptor inverse agonist FG 7142. Acute (0.3–10 mg/kg, i.p.) and long-term administration (10 mg/kg, i.p., 21 days) of SSR149415 and SSR125543 reduced the FG 7142-induced increase in extracellular concentrations of acetylcholine in the hippocampus of anesthetized rats measured by microdialysis. By contrast acute and long-term administration of SSR149415 failed to reduce the FG 7142-induced increase in the release of norepinephrine in the cortex of freely moving rats. The present results demonstrate that the two compounds have similar profiles in a model of activation by an anxiogenic drug of the hippocampal cholinergic system and they suggest that SSR149415 and SSR125543 may have anti-stress anxiolytic and antidepressant effects via a mechanism of action different from classical benzodiazepine ligands and noradrenergic antidepressants. [Copyright &y& Elsevier]

Abstract: SR58611A is a selective β3-adrenoceptor (Adrb3) agonist which has demonstrated antidepressant and anxiolytic properties in rodents. The present study confirmed the detection of Adrb3 mRNA transcript in rodent brain sub-regions and evaluated the effect of SR58611A on serotonergic and noradrenergic transmission in rats and mice in an attempt to elucidate the mechanism(s) underlying these properties. SR58611A (3 and 10 mg/kg, p.o.) increased the synthesis of 5-HT and tryptophan (Trp) levels in several rodent brain areas (cortex, hippocampus, hypothalamus, striatum). Moreover, SR58611A (10 mg/kg, p.o.) increased the release of 5-HT assessed by in vivo microdialysis in rat prefrontal cortex. Systemic (3 mg/kg, i.v.) or chronic administration of SR58611A (10 mg/kg, p.o.), in contrast to fluoxetine (15 mg/kg, p.o.), did not modify the activity of serotonergic neurons in the rat dorsal raphe nucleus. The increase in 5-HT synthesis induced by SR58611A was not observed in Adrb3s knockout mice, suggesting a selective involvement of Adrb3s in this effect. SR58611A (3 and 10 mg/kg, p.o.) did not modify norepinephrine synthesis and metabolism but increased its release in rat brain. Repeated administration of SR58611A (10 mg/kg, p.o.) did not modify basal norepinephrine release in rat prefrontal cortex whereas it prevented its tail-pinch stress-induced enhancement similarly to reboxetine (15 mg/kg, p.o.). Finally SR58611A increased the firing rate of noradrenergic neurons in the rat locus coeruleus following systemic (3 mg/kg, i.v.) or local (0.01 and 1 μM) but not chronic (10 mg/kg, p.o.) administration. These results suggest that the anxiolytic- and antidepressant-like activities of SR58611A involve an increase of brain serotonergic and noradrenergic neurotransmissions, triggered by activation of Adrb3s. [Copyright &y& Elsevier]

Aims: Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model., Methods: We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L)., Results: Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (V max  = 26.07 mg/day, K m  = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (V max /CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively., Conclusions: Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases., Methods: Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival., Results: Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R 0  = 8.4 nM), steady-state dissociation constant (K SS  = 10 nM) and antibody-target complexes elimination constant (k int  = 0.52 day -1 ). The distribution of R 0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival., Conclusion: This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship., (© 2023 British Pharmacological Society.)

Background: Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted., Methods: This study is a double-blind multicenter randomized phase 2 trial with a 1:1 active-treatment-to-placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3-month period before and after treatment., Results: A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention-to-treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (p = 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group (p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions (p = 0.03). Fifty-nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm., Conclusion: Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background and Objective: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal immunoglobulin (Ig)G1 antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The influence of target-antigen on cetuximab pharmacokinetics has never been investigated using target-mediated drug disposition (TMDD) modelling. This study aimed to investigate the relationship between cetuximab concentrations, target kinetics and progression-free survival (PFS)., Methods: In this ancillary study (NCT00559741), 91 patients with mCRC treated with cetuximab were assessed. Influence of target levels on cetuximab pharmacokinetics was described using TMDD modelling. The relationship between cetuximab concentrations, target kinetics and time-to-progression (TTP) was described using a joint pharmacokinetic-TTP model, where unbound target levels were assumed to influence hazard of progression by an E max model. Mitigation strategies of concentration-response relationship, i.e., time-varying endogenous clearance and mutual influences of clearance and time-to-progression were investigated., Results: Cetuximab concentration-time data were satisfactorily described using the TMDD model with quasi-steady-state approximation and time-varying endogenous clearance. Estimated target parameters were baseline target levels (R 0 = 43 nM), and complex elimination rate constant (k int = 0.95 day -1 ). Estimated time-varying clearance parameters were time-invariant component of CL (CL 0 = 0.38 L/day -1 ), time-variant component of CL (CL 1 = 0.058 L/day -1 ) and first-order rate of CL 1 decreasing over time (k des = 0.049 day -1 ). Part of concentration-TTP was TTP-driven, where clearance and TTP were inversely correlated. In addition, increased target occupancy was associated with increased TTP., Conclusion: This is the first study describing the complex relationship between cetuximab target-mediated pharmacokinetics and PFS in mCRC patients using a joint PK-time-to-progression model. Further studies are needed to provide a more in-depth description of this relationship., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Protein separation can be achieved with different modes of capillary electrophoresis, such as with capillary gel electroporesis (CGE) or with capillary zone electrophoresis (CZE). CZE protein mapping of peanut extract was approached in four different ways, combining neutral-coated or multilayer-coated capillaries with pHs well over or under the isoelectric point range of the proteins of interest. At acidic pHs, the mobility ranges of the major peanut allergens Ara h1, Ara h2, Ara h3, and Ara h6 were identified. Although the pH is a major factor in CZE separation, buffers with different compositions but with the same pH and ionic strength showed significantly different resolutions. Different components of the electrolyte were studied in a multifactorial design of experiment. CE-SDS and CZE proved to be suitable for protein mapping and we were able to distinguish different batches of peanut extract and burned peanut extract., (© 2021 The Authors. Electrophoresis published by Wiley-VCH GmbH.)

In France, the current recommendation is to perform a routine abdominopelvic ultrasound in any child under 2 years of age who is suspected to have been abused. We retrospectively studied the relevance of this practice in our center over the past fifteen years. This was a descriptive, retrospective study of all children under 2 years of age who had been subject to suspected abuse. Abdominal images and reports were reviewed and cross-referenced with possible clinical and biological signs. Four hundred and five children were included between 2006 and 2020, of whom 296 underwent abdominal imaging (2 initial abdominopelvic CT scans, 4 ultrasounds followed by CT scans, and 290 ultrasounds alone). Four examinations revealed traumatic abnormalities related to abuse. These four children all had clinical or biological anomalies. In the absence of clinical or biological signs, no imagery showed any abnormality related to abuse.

Background and Objectives: Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on rituximab pharmacokinetics has never been investigated for several cancer and non-cancer diseases simultaneously. This study aimed at assessing this influence using an integrated semi-mechanistic model accounting for target-mediated elimination of rituximab., Methods: Rituximab concentration-time data from five studies previously published in patients with CLL, DLBCL, FL, RA, and AAV were described using a two-compartment model with irreversible binding of rituximab to its target antigen. Both underlying disease and target antigen measurements were assessed as covariates., Results: Central volume of distribution was [95% confidence interval] 1.7-fold [1.6-1.9] higher in DLBCL than in RA, FL, and CLL, and it was 1.8-fold [1.6-2.1] higher in RA, FL, and CLL than in AAV. First-order elimination rate constants were 1.8-fold [1.7-2.0] and 1.3-fold [1.2-1.5] higher in RA, DLBCL, and FL than in CLL and AAV, respectively. Baseline latent antigen level (L 0 ) was 54-fold [30-94], 20-fold [11-36], and 29-fold [14-64] higher in CLL, DLBCL, and FL, respectively, than in RA and AAV. In lymphoma, L 0 increased with baseline total metabolic tumor volume (p = 6.10 -7 ). In CLL, the second-order target-mediated elimination rate constant (k deg ) increased with baseline CD20 count on circulating B cells (CD20 cir , p = 0.0081)., Conclusions: Our results show for the first time that rituximab pharmacokinetics is strongly influenced by underlying disease and disease activity. Notably, neoplasms are associated with higher antigen amounts that result in decreased exposure to rituximab compared to inflammatory diseases. Our model might be used to estimate unbound target amounts in upcoming studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (R C 0 = 3.3 nM and R P 0 = 0.46 nM), steady-stated dissociation rates (K C SS = 15.4 nM and K P SS = 0.49 nM), and first-order elimination rates of complexes (k C int = 0.17 day -1 and k P int = 0.0079 day -1 ). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.

Background: Ultrasound elastography has been suggested for assessing organ fibrosis., Objective: To study the feasibility of shear-wave elastography in children with kidney disease and the correlation between elasticity and kidney fibrosis in order to reduce the indications for kidney biopsy and its complications., Materials and Methods: Four operators measured kidney elasticity in children with kidney diseases or transplants, all of whom also had a renal biopsy. We assessed the feasibility and the intraobserver variability of the elasticity measurements for each probe used and each kidney explored. Then we tested the correlation between elasticity measurements and the presence of fibrosis., Results: Overall, we analyzed 95 children and adolescents, 31 of whom had renal transplant. Measurements with the convex probe were possible in 100% of cases. Linear probe analysis was only possible for 20% of native kidneys and 50% of transplants. Intraobserver variabilities ranged from moderate to high, depending on the probe and kidney studied. Elasticity was higher with the linear probe than with the convex probe (P<0.001 for left kidney and P=0.03 for right kidney). Measurements did not differ from one kidney to another in the same child. Elasticity and fibrosis were both higher in transplant patients (P=0.02 with convex probe; P=0.01 with linear probe; P=0.04 overall). There was no correlation between elasticity and fibrosis., Conclusion: Of the devices used in this work, kidney elastography was more accurately analyzed with a convex probe. Our study did not identify any correlation between elasticity and kidney fibrosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Diffusion-weighted imaging (DWI) has been described to correlate with tumoural necrosis in response to preoperative chemotherapy for osteosarcoma., Objective: To assess the accuracy of DWI in evaluating the response to neoadjuvant chemotherapy at the mid-course treatment of long-bone osteosarcoma and in predicting survival., Materials and Methods: We conducted a prospective single-centre study over a continuous period of 11 years. Consecutive patients younger than 20 years treated with a neoadjuvant regimen for peripheral conventional osteosarcoma were eligible for inclusion. Magnetic resonance imaging (MRI) with DWI was performed at diagnosis, and mid- and end-course chemotherapy with mean apparent diffusion coefficients (ADC) calculated at each time point. A percentage less than or equal to 10% of the viable residual tissue at the histological analysis of the surgical specimen was defined as a good responder to chemotherapy. Survival comparisons were calculated using the Kaplan-Meier method. Uni- and multivariate analyses with ADC change were performed by Cox modelling. This is an expansion and update of our previous work., Results: Twenty-six patients between the ages of 4.8 and 19.6 years were included, of whom 14 were good responders. At mid-course chemotherapy, good responders had significantly higher mean ADC values (P=0.046) and a higher increase in ADC (P=0.015) than poor responders. The ADC change from diagnosis to mid-course MRI did not appear to be a prognosticator of survival and did not impact survival rates of both groups., Conclusion: DWI at mid-course preoperative chemotherapy for osteosarcoma should be considered to evaluate the degree of histological necrosis and to predict survival. The anticipation of a response to neoadjuvant treatment by DWI may have potential implications on preoperative management., (© 2021. The Author(s).)

Intravenous administration of monoclonal antibodies leads to low concentrations in the central nervous system, which is a serious concern in neuro-oncology, especially in leptomeningeal carcinomatosis of HER2-overexpressing breast cancer. Case reports of i.t. administrations of trastuzumab have shown promising results in these patients but dosing regimens are empirical in absence of pharmacokinetic (PK) study. With a population PK approach, we described the fate of trastuzumab after i.t. administration in 21 women included in a phase I-II clinical trial. Trastuzumab was administered by i.t. route every week for 8 weeks and both cerebrospinal fluid (CSF) and serum were sampled to measure trough concentrations. Some patients showed noticeable CSF concentration fluctuations predicted using a target-mediated drug disposition. This target was latent and produced with a delayed feedback. Apparent volumes of distribution were close to physiological volumes (V 1  = 3.25 L, V 2  = 0.644 L, for serum and CSF, respectively). Estimated (constant) transfer from serum to CSF was very slow (k 12  = 0.264 mg/day) whereas estimated half-life of transfer from CSF to serum was rapid (2.2 days). From the individual parameters of patients, a single i.t. administration of 150 mg of trastuzumab corresponded to median mean residence times of 3.8 days and 15.6 days in CSF and serum, respectively. Survival without neurological relapse was not related to trastuzumab exposure. This study confirms that transfer of trastuzumab from serum to CSF is very limited and that this monoclonal antibody, when administered by i.t. route, is rapidly transferred to the serum., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

The FcγRIIA/CD32A is mainly expressed on platelets, myeloid and several endothelial cells. Its affinity is considered insufficient for allowing significant binding of monomeric IgG, while its H131R polymorphism (histidine > arginine at position 131) influences affinity for multimeric IgG2. Platelet FcγRIIA has been reported to contribute to IgG-containing immune-complexe clearance. Given our finding that platelet FcγRIIA actually binds monomeric IgG, we investigated the role of platelets and FcγRIIA in IgG antibody elimination. We used pharmacokinetics analysis of infliximab (IgG1) in individuals with controlled Crohn's disease. The influence of platelet count and FcγRIIA polymorphism was quantified by multivariate linear modelling. The infliximab half-life increased with R allele number (13.2, 14.4 and 15.6 days for HH, HR and RR patients, respectively). It decreased with increasing platelet count in R carriers: from ≈20 days (RR) and ≈17 days (HR) at 150 × 10 9 /L, respectively, to ≈13 days (both HR and RR) at 350 × 10 9 /L. Moreover, a flow cytometry assay showed that infliximab and monomeric IgG1 bound efficiently to platelet FcγRIIA H and R allotypes, whereas panitumumab and IgG2 bound poorly to the latter. We propose that infliximab (and presumably any IgG1 antibody) elimination is partly due to an unappreciated mechanism dependent on binding to platelet FcγRIIA, which is probably tuned by its affinity for IgG2.

Background & aim: Resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (CRC) is frequent and prognostic biomarkers are lacking. MicroRNAs (miR) are good candidates in this context. We aimed to characterize cetuximab and panitumumab exposure influence on miR expression in colorectal cancer cells to identify those regulating the EGFR pathway and implicated in resistance to treatment. Finally, we aimed to identify miR expression in serum of patients with advanced CRC treated with cetuximab or panitumumab. Results: Cetuximab and panitumumab exposure induced significant expression variations of 17 miR out of a miRnome panel of 752. Six of those miR interacted with at least one downstream element of the EGFR pathway. Conclusion: After the bioinformatics two-phase process, five miR rarely described before could be potential actors of anti-EGFR monoclonal antibody resistance: miR-95-3p, miR-139-5p, miR-145-5p, miR-429 and miR-1247-5p. In vivo , we detected the expression of miR-139-5p and miR-145-5p in serum of patients with metastatic CRC.

Aim: Ramucirumab, an anti-VEGFR2 monoclonal antibody, has been approved for the treatment of metastatic gastric and colorectal cancer. An assay measuring ramucirumab serum concentrations was needed to investigate its pharmacokinetics and concentration-response relationship. Results: An ELISA was developed and validated according to the international guidelines for ligand-binding assays. Ramucirumab calibration standards ranged from 0.125 to 40 mg/l. Low, middle and high quality controls were spiked at 0.2, 4 and 8 mg/l, respectively. The limits of quantification were established to be 0.125 and 10 mg/l for LLOQ and ULOQ, respectively. No cross-reactivity with anti-VEGF or anti-EGFR was detected. Conclusion: This in-house-developed ELISA is sensitive, accurate, reproducible and suitable for pharmacokinetic studies of ramucirumab.

Objectives: Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation., Methods: A total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX-). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration., Results: We analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group and 26/55 (47.3%) in the MTX- group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX- group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ≤W26 was significantly associated with adalimumab long-term maintenance (p=0.04)., Conclusion: MTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance., Competing Interests: Competing interests: EDu was invited to attend international congresses by Roche and UCB; she has acted as a consultant and given lectures on behalf of her institution for BMS and Abbvie. eDe participated on behalf of her institution in clinical trials sponsored by Abbvie, Roche, BMS, Novartis, Pfizer, UCB and Sanofi; she has given lectures for Abbvie, BMS, Janssen, Pfizer, UCB, Novartis; she has acted as a consultant for BMS and UCB, Novartis; she has been invited to attend international congresses by MSD, Roche, BMS Abbvie and Novartis. FLG has been invited to attend an international congress by Abbvie, Pfizer. LA was invited to attend international congress by Abbvie, Novartis, Pfizer and UCB. EL has received speaker and consultant fees from Amgen, Expanscience, Lilly, and MSD; and research grants from Abbvie, Amgen, Lilly, MSD and UCB. GC was invited to attend international congress by Abbvie. VD-P has received speaker and consultant fees from MSD, BMS, UCB, Roche; and research grants from Roche-Chugai. EG has participated on behalf of his institution in clinical trials sponsored by Roche, Lilly, Novartis, Amgen, and BMS; she has acted as a consultant and given lectures for Abbvie, BMS, MSD, Pfizer, Roche, UCB, Novartis; she has been invited to attend international congresses by MSD, Roche, Novartis and BMS. BLG has participated on behalf of his institution in clinical trials sponsored by Roche, Lilly, Novartis, Pfizer, UCB and MSD; he has acted as a consultant and given lectures for Abbvie, BMS, Janssen, MSD, Pfizer, Sanofi-Genzyme, UCB, Novartis; he has been invited to attend international congresses by MSD, Roche, Abbvie, Sanofi and Pfizer. EP was invited to attend an international congress by Buhlmann. GP reports grants received by his research team from Novartis, Roche Pharma, Sanofi-Genzyme, Chugai, Pfizer and Shire, outside of the submitted work. DT has acted as a consultant and given lectures for Sanofi, Amgen, PG participated on behalf of his institution in clinical trials sponsored by Abbvie, Roche, BMS, Boehringer, Lilly, Novartis, Pfizer, UCB, Janssen and MSD; he has acted as a consultant and given lectures for Abbvie, Biogaran, BMS, Hospira, Janssen, MSD, Pfizer, Sanofi-Genzyme, UCB; he has been invited to attend international congresses by MSD, Roche, BMS and Abbvie. DM has acted as a consultant and given lectures on behalf of his institution for Pfizer and Novartis; he has been invited to attend an international congress by Janssen-Cilag. His institution received grants for research from the non-governmental organisation Lions Club Tours Val de France. TR, MS, AP, CD, AdV, TA, AM and HW declared that they have no disclosure with the manuscript., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Zika virus (ZIKV) is an emerging mosquito-borne virus of medical concern. ZIKV infection may represent a serious disease, causing neonatal microcephaly and neurological disorders. Nowadays, there is no approved antiviral against ZIKV. Several indigenous or endemic medicinal plants from Mascarene archipelago in Indian Ocean have been found able to inhibit ZIKV infection. The purpose of our study was to determine whether essential oil (EO) from Reunion Island medicinal plant Ayapana triplinervis , whose thymohydroquinone dimethyl ether (THQ) is the main component has the potential to prevent ZIKV infection in human cells. Virological assays were performed on human epithelial A549 cells infected with either GFP reporter ZIKV or epidemic viral strain. Zebrafish assay was employed to evaluate the acute toxicity of THQ in vivo. We showed that both EO and THQ inhibit ZIKV infection in human cells with IC 50 values of 38 and 45 µg/mL, respectively. At the noncytotoxic concentrations, EO and THQ reduced virus progeny production by 3-log. Time-of-drug-addition assays revealed that THQ could act as viral entry inhibitor. At the antiviral effective concentration, THQ injection in zebrafish does not lead to any signs of stress and does not impact fish survival, demonstrating the absence of acute toxicity for THQ. From our data, we propose that THQ is a new potent antiviral phytocompound against ZIKV, supporting the potential use of medicinal plants from Reunion Island as a source of natural and safe antiviral substances against medically important mosquito-borne viruses.

Background: Brain metastases are challenging daily practice in oncology and remain a compartmental problem since most anti-cancer drugs do not cross the blood-brain barrier at relevant pharmacological concentrations., Methods: In a young woman with HER2-overexpressing breast cancer resistant to standard treatments, at the time of brain metastases progression, a ventricular reservoir was implanted for intrathecal drug injections and detailed pharmacokinetic studies., Results: A first association of intrathecal trastuzumab with intravenous cisplatin was offered to the patient. For trastuzumab, the mean cerebrospinal fluid trough concentration of 53.4 mg/L reached relevant levels, enabling the stabilization of the metastases. Adding intravenous cisplatin was not beneficial, since the cerebrospinal fluid exposure was almost undetectable under 0.08 mg/L. We then offered the patient an intrathecal combination of trastuzumab and methotrexate, because of their in vitro synergic cytotoxicity. The cerebrospinal fluid peak of methotrexate was 1037 µmol/L at 2 h, and the concentrations remained above the theoretical therapeutic concentration. After 2 months of this drug combination, we obtained an excellent response on the brain metastases., Conclusion: Our preliminary study supports the interest of a compartmental approach through a direct administration of drugs into the cerebrospinal fluid for the treatment of breast cancer brain metastases.

Supercritical Fluid Chromatography (SFC) has known a strong regain of interest for the last 10 years, especially in the field of pharmaceutical analysis. Besides the development and validation of the SFC method in one individual laboratory, it is also important to demonstrate its applicability and transferability to various laboratories around the world. Therefore, an inter-laboratory study was conducted and published for the first time in SFC, to assess method reproducibility, and evaluate whether this chromatographic technique could become a reference method for quality control (QC) laboratories. This study involved 19 participating laboratories from 4 continents and 9 different countries. It included 5 academic groups, 3 demonstration laboratories at analytical instrument companies, 10 pharmaceutical companies and 1 food company. In the initial analysis of the study results, consistencies within- and between-laboratories were deeply examined. In the subsequent analysis, the method reproducibility was estimated taking into account variances in replicates, between-days and between-laboratories. The results obtained were compared with the literature values for liquid chromatography (LC) in the context of impurities determination. Repeatability and reproducibility variances were found to be similar or better than those described for LC methods, and highlighted the adequacy of the SFC method for QC analyses. The results demonstrated the excellent and robust quantitative performance of SFC. Consequently, this complementary technique is recognized on equal merit to other chromatographic techniques., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objectives: The pharmacokinetics of infliximab are highly variable and influence clinical response in chronic inflammatory diseases. The goal of this study was to build a Bayesian model allowing predictions of upcoming infliximab concentrations and dosing regimen adjustment, using only one concentration measurement and information regarding the last infliximab infusion., Methods: This retrospective study was based on data from 218 patients treated with infliximab in Tours University Hospital who were randomly assigned to learning (two-thirds) or validation (one-third) data subsets. One-compartment pharmacokinetic and time since last dose (TLD) models were built and compared using learning and validation subsets. From these models, Bayesian pharmacokinetic and TLD models using one concentration measurement (1C-PK and 1C-TLD) were designed. The predictive performances of the 1C-TLD model were tested on two external validation cohorts., Results: Pharmacokinetic and TLD models described the data satisfactorily and provided accurate parameter estimations. Comparable predictions of infliximab concentrations were obtained from pharmacokinetic versus TLD models, as well as from Bayesian 1C-PK versus 1C-TLD models. The 1C-TLD model showed satisfactory prediction of future infliximab concentrations and provided satisfactory predictions of infliximab steady-state concentration for up to three upcoming visits after a blood sample., Conclusions: Accurate individual concentration predictions can be obtained using a single infliximab concentration measurement and information regarding only the last infusion. The 1C-TLD model may help to optimize the dosing regimen of infliximab in routine therapeutic drug monitoring.

Background: Contrast-enhanced MRI is often used for diagnosis and follow-up of children with inflammatory bowel disease., Objective: To compare the accuracy of diffusion-weighted MRI (DWI) to contrast-enhanced MRI in children with known or suspected inflammatory bowel disease., Materials and Methods: This retrospective, consecutive study included 55 children. We used ileo-colonoscopy and histology as the reference standard from the terminal ileum to the rectum, and contrast-enhanced MRI as the reference standard proximal to the terminal ileum. DWI and contrast-enhanced MRI sequences were independently reviewed and compared per patient and per segment to these reference standards and to the follow-up for each child., Results: We obtained endoscopic data for 340/385 colonic and ileal segments (88%). The rate of agreement per segment between DWI and endoscopy was 64%, and the rate of agreement between contrast-enhanced MRI and endoscopy was 59%. Per patient, sensitivity and specificity of bowel wall abnormalities as compared to the endoscopy were 87% and 100% for DWI, and 70% and 100% for contrast-enhanced MRI, respectively. Positive and negative predictive values were, respectively, 100% and 57% for DWI, and 96% and 41% for contrast-enhanced MRI. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of DWI compare to contrast-enhanced MRI in the segments proximal to the terminal ileum were 90%, 98%, 90%, 98% and 96%, respectively., Conclusion: The diagnostic performance of DWI is competitive to that of contrast-enhanced MRI in children with known or suspected inflammatory bowel disease.

Purpose: Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT)., Methods: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics., Results: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease., Conclusions: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing., Registration Identification: ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: Panitumumab is a monoclonal antibody directed against EGFR that is approved for the treatment of metastatic colorectal cancer. To investigate its pharmacokinetics and concentration-response relationship, a validated assay is required., Results: An ELISA assay was developed and validated according to international recommendations. Six calibrators (ranging from 0.1 to 20 mg/l) plus one anchor point (50 mg/l) and three quality controls (0.45, 2 and 8 mg/l) were defined. The limit of detection, lower limit of quantification and upper limit of quantification were 0.033, 0.112 and 10 mg/l, respectively., Conclusion: This method is validated and can be used to study pharmacokinetics of panitumumab or to perform therapeutic drug monitoring.

Monoclonal antibodies (mAbs) may be used as biopharmaceuticals to treat various diseases, ranging from oncology to inflammatory and cardiovascular affections. Trustworthy analytical methods are necessary to study their pharmacokinetics, both during their development and in post-marketing studies. Because biopharmaceuticals are macromolecules, ligand-binding assays (both immunoassays and bioassays) are methods of choice to measure their concentrations. Immunoassays are based on the capture of biopharmaceuticals by their target, which may be a circulating or membrane antigen or by an antibody recognizing their structure. Bioassays measure the activity of the biopharmaceutical in a specific in vitro test. A number of techniques have been reported, but their limits of detection and quantification vary widely. Anti-drug antibodies (ADA) against biopharmaceuticals are often formed and sometimes interfere with clinical efficacy. Accurate and reliable detection of ADA is therefore necessary. Binding of ADA is dependent on affinity and avidity, which makes quantification challenging. In this review, we discuss the benefits and limitations of each method to determine mAb levels and carefully compare ADA assays.

Aim: Eculizumab is a monoclonal antibody toward C5 fraction of the complement system. It is approved to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. To perform pharmacokinetic studies and therapeutic drug monitoring, a validated assay is required., Materials & Methods: An indirect ELISA with recombinant human C5 sensitized microtiter plates were developed., Results: The assay allows the measurement of free eculizumab concentration in human serum. The LOD, LLOQ and ULOQ were 0.091, 0.25 and 82.35 mg/l, respectively. The assay meets EMA and US FDA guidelines criteria for the validation of a ligand-binding assay., Conclusion: This method is validated and can be used in PK and PK-PD studies as well as to perform therapeutic drug monitoring of free eculizumab.

Aims: Rituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients., Methods: In a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis., Results: A two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7 l and 0.56 l day -1 , respectively. Distribution and elimination half-lives were 0.9 days and 17.3 days, respectively. As expected, the central volume of distribution increased with body surface area (P = 0.012) and was higher in male than in female (P = 0.004). We found that the elimination rate constant (k 10 ) increased with CD19+ count (P = 0.00022) and IgG concentration (P = 7.4 × 10 -8 ), and that k 10 decreased with time (P = 0.00015), partly explained by a change in target-antigen amount., Conclusions: The association between CD19+ count and k 10 may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k 10 may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab., (© 2017 The British Pharmacological Society.)

The immunogenicity of infliximab and adalimumab is a major concern because patients may develop Abs also called antidrug Abs (ADA), directed against these anti-TNF-α Abs after just a few weeks of treatment. These ADAs can lead to a decrease in biologic concentration, which is associated with lower treatment efficacy. Our aim was to study the involvement of immune complexes and neonatal Fc receptor (FcRn) in the emergence of ADAs in the case of anti-TNF-α Abs. Wild type and FcRn knockout mice were injected once with either infliximab or adalimumab, alone or preincubated with TNF-α. Adalimumab cross-reacts with murine TNF-α whereas infliximab is species specific. When injected alone, only adalimumab elicited a humoral response. By preforming immune complexes with TNF-α, an anti-infliximab response was elicited. Surprisingly, both wild type and FcRn knockout mice were able to mount an immune response against anti-TNF-α Abs, suggesting that immune complexes are a major determinant of this immunization., (Copyright © 2017 by The American Association of Immunologists, Inc.)

BRAF inhibitors (BRAFi), a targeted therapy, are used to treat metastatic late-stage melanomas harbouring the BRAF-V600 mutation (found in about 50% of melanomas). The targeted therapy is generally maintained until tumour progression or major toxicity occurs, although responses are often limited in time. It is unknown whether melanoma patients achieving a complete response with targeted therapy can safely discontinue treatment. We retrospectively observed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a complete response and those with an incomplete response combined with surgical removal of the remaining tumours. We also evaluated the effectiveness of BRAFi in these patients after recurrence. In 11 patients, the best response was diagnosed after a median BRAFi treatment duration of 105 (29-341) days. The median follow-up after BRAFi initiation was 769 (435-1765) days. Recurrence was observed in all 11 patients (100%), median: 82 (27-322) days. Five patients achieved a complete response, with a median progression-free survival after cessation of 136.5 (34-322) days versus 82 (27-144) days for six patients with an incomplete response combined with surgical removal of remaining tumours. Baseline characteristics and time to best response and to discontinuation did not influence the rate of relapse. Subsequently, eight patients were rechallenged with a BRAFi. The median progression-free survival time after BRAFi rechallenge was 222.5 (15-425) days. The three remaining patients received treatments other than BRAFi. Our findings may be valuable with respect to ongoing clinical trials of combinations of targeted therapies and immunomodulatory antibodies.

The standard four-rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti-ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange-based regimen received two infusions of rituximab 375 mg m -2 within 4 days, and a third dose at day +15 of the first infusion if peripheral B cells were still detectable. Primary endpoint was the assessment of the time required to platelet count recovery from the first plasma exchange. Three patients died after the first rituximab administration. In the remaining patients, the B cell-driven treatment hastened remission and ADAMTS13 activity recovery as a result of rapid anti-ADAMTS13 depletion in a similar manner to the standard four-rituximab infusions schedule. The 1-year relapse-free survival was also comparable between both groups. A rituximab regimen based on B cell depletion is feasible and provides comparable results than with the four-rituximab infusions schedule. This regimen could represent a new standard in TTP. This trial was registered at www.clinicaltrials.gov (NCT00907751). Am. J. Hematol. 91:1246-1251, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ 35 S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca 2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1 neo-/- mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities., Competing Interests: Organizations from whom the authors have received compensation for professional services: Guy Griebel, employee of Sanofi; Philippe Pichat, employee of Sanofi; Vanessa Naimoli, former employee of Sanofi; Lisa Potestio, former employee of Sanofi; Robert Featherstone, former employee of Sanofi; Sukhveen Sahni, former employee of Sanofi; Henry Defex, former employee of Sanofi; Christophe Desvignes, employee of Sanofi; Franck Slowinski, employee of Sanofi; Xavier Vigé, employee of Sanofi; Olivier E. Bergis, employee of Sanofi; Rosy Sher, former employee of Sanofi; Raymond Kosley, former employee of Sanofi; Sathapana Kongsamut, former employee of Sanofi; Mark D. Black, former employee of Sanofi; Geoffrey B. Varty, former employee of Sanofi. Drs Kosley and Sher are inventors on a patent covering the main product described in this report.

Background: Adalimumab is a therapeutic antibody used for treating inflammatory diseases. To understand interindividual PK variability, there is a need to develop and validate an assay to measure serum adalimumab concentrations., Methods: An ELISA was developed on microtiter plates coated with TNF-α. Seven nonzero adalimumab standards ranging from 0.05 to 50 mg/l and three quality controls (0.2, 2.5 and 7 mg/l) were tested for their intra and interday precision on six occasions., Results: The LOD, LLOQ and ULOQ of the assay were 0.022, 0.073 and 9 mg/l, respectively., Conclusion: This method is accurate, reproducible and may be useful for PK studies and for therapeutic drug monitoring of adalimumab.

We report a very rare case of complex upper extralobar pulmonary sequestration, detected during pregnancy and resected early because the diagnosis was uncertain (possibility of a teratoma). At 2 months, the upper left pulmonary lesion was completely removed by thoracoscopy. Pathology concluded an extralobar sequestration associated with a duplication cyst of mixed bronchogenic and esophageal type. The postoperative course was uneventful. The early thoracoscopic approach in this type of antenatally diagnosed lesion was a good option.