AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

International audienceAGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human

Nouvelle politique antibiotique au CHU de Nancy en 2006 (de l'analyse pharmaceutique à l'équipe opérationnelle infectiologue/pharmacien)

NANCY1-SCD Pharmacie-Odontologie (543952101) / SudocSudocFranceF

Evaluation of effects of an operational multidisciplinary team on antibiotic use in the medium to long term at a French university hospital

International audienc

Pharmaceutical algorithms set in a real time clinical decision support targeting high-alert medications applied to pharmaceutical analysis

International audienceBackground: Pharmaceutical analysis of the prescription has to prop up the quality of patients' medication management in a context of medication's risk acculturation. But this activity remains highly variable. Medication-related clinical decision support may succeed in reducing adverse drug events and healthcare costs.Purpose: This study aims to present AVICENNE as a real time medication-related clinical decision support (rt-CDS) applied to pharmaceutical analysis and its ability to detect Drug related problems (DRP) consecutively resolved by pharmacists. Basic procedures A Medication-related rt-CDS is created by integrating the software PharmaClass® (Keenturtle), 5 health data streams on the patient and Pharmaceutical algorithms (PA). PA are created by modeling the pharmaceutical experiment about DRP and the thread of their criticality. They are partially encoded as computerized rules in Pharmaclass® allowing alerts' issue. An observational prospective study is conducted during 9-months among 1000 beds in 2 health facilities. The first step is to identify alerts as DRP; their resolution follows with clear guidelines worked out for the pharmaceutical analysis. A basis on predictive positive values (PPV) of the PA is being built today helping to know the performance of DRP detection and resolution. Main findings 71 PA are encoded as rules into Pharmaclass®: 40 targeted serious adverse drug events. 1508 alerts are analyzed by pharmacists. Among them 921 DRPs were characterized and 540 pharmaceutical interventions transmitted of which 219 were accepted by prescribers. Three PPV are defined depending on software, pharmacist and patient. Principal conclusion Clinical pharmacy societies should host, share and update a national corpus of PA and exploit its educational interest

Soluble Mucosal Addressin Cell Adhesion Molecule 1 and Retinoic Acid are Potential Tools for Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Treated with Vedolizumab: A Proof of Concept Study

International audienceBackground: Vedolizumab (VDZ), a humanized monoclonal antibody targeting α4β7 integrin, is effective in induction and maintenance therapy in patients with inflammatory bowel disease (IBD) who have not adequately responded to standard therapies, and high levels of vedolizumab trough levels (VTL) have been associated with clinical remission. The α4β7 integrin binds to endothelial MAdCAM-1 and is up-regulated by retinoic acid (RA). Aim: To determine the relations between soluble MAdCAM-1 (sMAdCAM-1) and RA concentrations with clinical remission during VDZ maintenance therapy. Methods: In a retrospective study performed in IBD patients treated with VDZ we measured VTL, sMAdCAM-1 and RA concentrations. Results: Among the 62 included patients (38 Crohn's disease) 24 relapsed and 38 stayed in remission between weeks 10 to 30 after VDZ initiation. During this maintenance therapy, median values of VTL and RA were 15.4 \textmug/mL and 0.97 ng/mL, whereas sMAdCAM-1 was undetectable (\textless 0.41 ng/mL) in 67.3% of samples. The positive predictive value (PPV) of undetectable sMAdCAM-1 for clinical remission was 80.0% with a corresponding sensitivity of 74.6%. On multivariate analysis undetectable sMAdCAM-1 and high VTL (\textgreater 19 \textmug/mL) were independently associated with clinical remission (OR=7.5, p=0.006 and OR=2.2, p=0.045, respectively). The combination of sMAdCAM-1 \textless 0.41 ng/mL and VTL \textgreater 19 \textmug/mL was the best pharmacokinetic profile with a PPV of 95.2%. Median values of sMAdCAM-1 and RA were significantly higher (p=0.0001) before VDZ therapy than during the follow-up (sMAdCAM-1: 40.5 vs \textless 0.41 ng/mL; RA: 1.7 vs 0.97 ng/mL). Only RA \textgreater 1.86 ng/mL before VDZ therapy was predictive of clinical remission during the follow-up (AUROC=80.7%). Conclusions: Undetectable sMAdCAM-1 appears strongly associated with clinical remission during VDZ maintenance therapy. Combination of undetectable sMAdCAM-1 with high VTL is also potentially interesting for therapeutic drug monitoring. Baseline RA concentrations are predictive of clinical remission. These findings need to be confirmed in further prospective studies

Theranostic gadolinium-based nanoparticles AGuIX®: in vivo imaging and safety evaluation

International audienceIntroductionA new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy.1 These nanoparticles consist of a polysiloxane network surrounded by Gd chelates. Nanoparticles, which contain high-Z contrast agents such as Gd-based nanoparticles, increase the sensitivity of the tumor to radiation. Owing to their small size (3 +/- 0.1 nm), AGuIX® typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes.2 Multi-imaging properties and safety evaluation of the Gd-based nanoparticles have been investigated before their clinical transfer. MethodsGd-based nanoparticles have been administrated to rats-bearing tumor and non-human primates for MRI and PET investigations. In parallel, regulatory investigations have been performed on both rodents and non-human primates

In-depth Exploration of Cerebrospinal Fluid by Combining Peptide Ligand Library Treatment and Label-free Protein Quantification*

Cerebrospinal fluid (CSF) is the biological fluid in closest contact with the brain and thus contains proteins of neural cell origin. Hence, CSF is a biochemical window into the brain and is particularly attractive for the search for biomarkers of neurological diseases. However, as in the case of other biological fluids, one of the main analytical challenges in proteomic characterization of the CSF is the very wide concentration range of proteins, largely exceeding the dynamic range of current analytical approaches. Here, we used the combinatorial peptide ligand library technology (ProteoMiner) to reduce the dynamic range of protein concentration in CSF and unmask previously undetected proteins by nano-LC-MS/MS analysis on an LTQ-Orbitrap mass spectrometer. This method was first applied on a large pool of CSF from different sources with the aim to better characterize the protein content of this fluid, especially for the low abundance components. We were able to identify 1212 proteins in CSF, and among these, 745 were only detected after peptide library treatment. However, additional difficulties for clinical studies of CSF are the low protein concentration of this fluid and the low volumes typically obtained after lumbar puncture, precluding the conventional use of ProteoMiner with large volume columns for treatment of patient samples. The method has thus been optimized to be compatible with low volume samples. We could show that the treatment is still efficient with this miniaturized protocol and that the dynamic range of protein concentration is actually reduced even with small amounts of beads, leading to an increase of more than 100% of the number of identified proteins in one LC-MS/MS run. Moreover, using a dedicated bioinformatics analytical work flow, we found that the method is reproducible and applicable for label-free quantification of series of samples processed in parallel

Theranostic gadolinium-based nanoparticles AGuIX®: in vivo imaging and safety evaluation

International audienceIntroductionA new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy.1 These nanoparticles consist of a polysiloxane network surrounded by Gd chelates. Nanoparticles, which contain high-Z contrast agents such as Gd-based nanoparticles, increase the sensitivity of the tumor to radiation. Owing to their small size (3 +/- 0.1 nm), AGuIX® typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes.2 Multi-imaging properties and safety evaluation of the Gd-based nanoparticles have been investigated before their clinical transfer. MethodsGd-based nanoparticles have been administrated to rats-bearing tumor and non-human primates for MRI and PET investigations. In parallel, regulatory investigations have been performed on both rodents and non-human primates

Approaches to Integrating Biomarkers Into Clinical Trials and Care Pathways as Targets for the Treatment of Inflammatory Bowel Diseases

International audienceBACKGROUND & AIMS:There is no consensus on the best way to integrate biomarkers into inflammatory bowel disease (IBD) research and clinical practice. The International Organization for the Study of Inflammatory Bowel Disease aimed to outline biomarker definitions, categories, and operating properties required for their use in registration trials and clinical practice. Using fecal calprotectin as an example, we provide a framework for biomarker development and validation in patients with IBD.METHODS:We reviewed international society guidelines, regulatory agency guidance documents, and standardized reporting guidelines for biomarkers, in combination with publications on fecal calprotectin levels in patients with IBD. We assessed the validity of fecal calprotectin to serve as a surrogate biomarker of IBD activity and outlined a framework for further validation and development of biomarkers.RESULTS:No endpoints have been fully validated as surrogates of risk of disease complications; mucosal healing is the most valid endpoint used to determine risk of disease complications. Fecal level of calprotectin has not been validated as a biomarker for IBD activity because of lack of technical and clinical reliability, assessment of performance when used as a replacement for endoscopy, and assessment of responsiveness to changes in disease states. The level of fecal calprotectin can be used only as a prognostic factor for disease recurrence in patients in remission after medical or surgical treatment.CONCLUSIONS:We reviewed guidelines, regulatory documents, and publications to identify properties required for the development of biomarkers of IBD activity and areas in need of clarification from regulatory agencies and societies. We propose a path forward for research of biomarkers for IBD.Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved