Mangafodipir Protects against Hepatic Ischemia-Reperfusion Injury in Mice

Mangafodipir is a contrast agent used in magnetic resonance imaging that concentrates in the liver and displays pleiotropic antioxidant properties. Since reactive oxygen species are involved in ischemia-reperfusion damages, we hypothesized that the use of mangafodipir could prevent liver lesions in a mouse model of hepatic ischemia reperfusion injury. Mangafodipir (MnDPDP) was compared to ischemic preconditioning and intermittent inflow occlusion for the prevention of hepatic ischemia-reperfusion injury in the mouse.Mice were subjected to 70% hepatic ischemia (continuous ischemia) for 90 min. Thirty minutes before the ischemic period, either mangafodipir (10 mg/kg) or saline was injected intraperitoneally. Those experimental groups were compared with one group of mice preconditioned by 10 minutes' ischemia followed by 15 minutes' reperfusion, and one group with intermittent inflow occlusion. Hepatic ischemia-reperfusion injury was evaluated by measurement of serum levels of aspartate aminotransferase (ASAT) activity, histologic analysis of the livers, and determination of hepatocyte apoptosis (cytochrome c release, caspase 3 activity). The effect of mangafodipir on the survival rate of mice was studied in a model of total hepatic ischemia.<0.01), and by higher rates of survival in treated than in untreated animals (P<0.001). The level of protection by mangafodipir was similar to that observed following intermittent inflow occlusion and higher than after ischemic preconditioning.Mangafodipir is a potential new preventive treatment for hepatic ischemia-reperfusion injury

Rôle des cytokines dans l'immunité bronchique au cours de la mucoviscidose

PARIS-BIUP (751062107) / SudocSudocFranceF

Quantification of infliximab and adalimumab in human plasma by a liquid chromatography tandem mass spectrometry kit and comparison with two ELISA methods

International audienceBackground: This study compared the performance of plasma infliximab and adalimumab quantification using a commercially available kit (mAbXmise kit) and mass spectrometry readout to that of two ELISA methods in patients treated for inflammatory bowel disease. Methods and results: The mAbXmise method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was linear from 2 to 100 mu g/ml. It was validated according to international guidelines. Regarding cross-validation for infliximab (n = 70), the mean bias with LC-MS/MS assay was approximately threefold higher with the commercial ELISA assay compared with the in-house ELISA (-6.1 vs -1.8 mu g/ml, respectively). The mean bias between the LC-MS/MS assay and in-house ELISA was -1.2 mu g/ml for adalimumab (n = 35). Conclusion: The LC-MS/MS method is a powerful alternative to immunoassays to monitor concentrations of infliximab and adalimumab

Effects of successive switches to different biosimilars infliximab on immunogenicity in chronic inflammatory diseases in daily clinical practice

International audienceObjective: To evaluatre the risk of immunogenicity in patients with chronic inflammatory diseases who experienced successive non-medical swiches to different biosimilars infliximab.Patients and methods: Observational study over a 3-year observation period assessing the risk of immunogenicity in i) patients in maintenance therapy with innovator infliximab who were successively switched to CT-P13, then to SB2 (cohort-1) and ii) biologic-naive patients initiated with CT-P13 before being switched to SB2 (cohort-2). A propotion meta-analysis was also performed, integrating our results to 16 additional studies.Results: Cohort-1 included 265 patients who switched to CT-P13, and 140 patients were subsequently switched to SB2. Among the 235 anti-drug antibody (ADA)-free patients at baseline, 20 patients (8.5%) developed ADA over the 3-year observation period (rate of 3 for 100 patient years). Cohort-2 included 44 patients, of whom 29 subsequently switched to SB2. A total of 11 patients (25%) developed ADA within 3 years (rate of 14 for 100 patients years). We found no influence of the number of biosimilars infliximab received on ADA deveopment in both cohorts. The risk of treatment discontinuation was significantly higher in patients with positive ADA in both cohorts. The meta-analysis including our data exposed an incidence of immunogenicity of 4.7% (95% CI 3.5-6.1%) after the switch from innovator infliximab to biosimilar infliximab and 21.1% (95% CI 13.1-30.3%) in patients initiating biosimilar infliximab.Conclusion: Immunogenicity was not favored by successive non-medical switches to biosimilars infliximab in our study, but was associated with treatment discontinuation

Whole blood versus serum hydroxychloroquine levels for drug monitoring of patients with systemic lupus erythematosus : prehole blood versus serum hydroxychloroquine levels for drug monitoring of patients with systemic lupus erythematosus : preliminary results of a pharmacological study.

International audienceBackground: In order to assess the pharmacokinetic/pharmacodynamic relationship of hydroxychloroquine (HCQ) in patients with systemic lupus erythematosus (SLE), HCQ levels have been measured in whole blood as well as in serum but both methods have never been compared. In addition, cut offs for non-adherence (classically 200ng/ml but also 100 ng/mL) have been established only in whole blood. Objectives: The aims of this study were (1) to compare these two pharmacological approaches, and (2) since it would be very interesting to retrospectively assess severe non-adherence in clinical trials or in large cohort of patients in which only serum samples are usually available, to determine if serum HCQ level cut offs could be established for identification of severe non-adherent patients. Methods: The HCQ and desethylchloroquine (DCQ) levels were measured in serum and whole blood from 573 SLE patients. The risk factors for active SLE (SLEDAI score >4) were identified using multiple logistic regression. HCQ serum level was also measured in 51 non-adherent patients (whole blood HCQ level <200 ng/mL). Results: The mean HCQ and DCQ levels were 916 ± 449 and 116 ± 55 ng/mL in whole blood, respectively; and 469 ± 223 and 63 ± 31 ng/mL in serum, respectively. The mean ratio of serum/whole blood level for HCQ and DCQ were 0.53 ± 0.15 and 0.57 ± 0.21, respectively. A strong positive correlation was found between serum and whole blood levels of HCQ (rho=0.837 [CI95% 0.810-0.860], p<0.0001), and DCQ (rho=0.771 [CI95% 0.736-0.802], p<0.0001). In the multivariate analysis, only corticosteroids (p=0.044), immunosuppressant (p=0.027), HCQ whole blood level (p=0.023) and hemoglobin (p=0.009) were identified as an independent risk factor of active SLE but serum HCQ level was not. Given the mean ratio of serum/whole blood level for HCQ was 0.53, we extrapolated that serum HCQ level cut offs of 106 and 53 ng/mL would correspond to the previously used cut-off of 200 and 100 ng/mL of HCQ in whole blood. Using HCQ serum level cut off of 106 ng/mL, 43 of 51 patients (84%) with blood HCQ levels <200 ng/mL would also have been considered as non-adherent. The positive and negative predictive value of HCQ serum level < 106 ng/ml to detect non-adherence were 96.6% and 63.6%, respectively. Of these 51 patients, 25 patients (49%) exhibited HCQ whole blood concentration below 100 ng/mL. Using HCQ serum level cut off of 53 ng/mL, 23 of 25 patients (92%) with HCQ whole blood level<100 ng/mL, would also have been considered as non-adherent. The positive and negative predictive value of HCQ serum level < 53 ng/ml to detect non-adherence were 82.1% and 90.9%. Conclusion: Our data support the use of whole blood rather than serum as the matrix for drug monitoring of HCQ levels in SLE patients. However, when whole blood is not available, our results support the use of HCQ serum level to assess non-adherence with a cut off of 106 ng/mL corresponding to 200 ng/ml in whole bloo

Prevention of hepatocytes apoptosis following reperfusion injury.

<p>The mitochondrial/cytosol cytochrome c ratio (A) and caspase-3 activities were measured in the livers of the various experimental groups and controls. Caspase-3 like activities were expressed as Units per mg of proteins. Bars represent means ± SEM, nine mice in each group.</p

Prevention of lipid peroxidation following ischemia-reperfusion of the liver using on mangafodipir and intermittent clamping.

<p>The concentrations of 4-hydroxyalkenals (4-HNE) and malondialdehyde (MDA) were measured spectrophotometrically in whole liver homogenates. The level of lipid peroxidation was expressed as the amounts of 4-HNE + MDA per mg of proteins. Bars represent means ± SEM; nine mice in each group.</p