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Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-03-2015 | Award Amount: 6.00M | Year: 2016

Up to 70% of cardiovascular events are not prevented by current therapeutic regimens. In search for additional, innovative strategies, immune cells have been recognized as key players contributing to atherosclerotic plaque progression and destabilization. Particularly the role of innate immune cells is of major interest, following the recent paradigm shift that innate immunity, considered to be incapable of learning ability, does exhibit a memory feature transduced via epigenetic modulation. Compelling evidence shows that atherosclerotic factors promote immune cell migration by pre-activation of innate immune cells. In this project called REPROGRAM, we aim to prove that innate immune cell activation via epigenetic reprogramming perpetuates the upheld systemic inflammatory state in cardiovascular disease which is common in other chronic inflammatory diseases. This opens a new therapeutic area in which epigenetic modulation of innate immune cells effectively decreases systemic inflammation impacting on chronic inflammation as well as the development of co-morbidities. The integrated use of in vitro, ex vivo and in vivo studies, including cells, mice and patients, allows translation from in vitro mechanisms to diseases (molecule-to-man) and extrapolation to cohorts (man-to-mass), enabling us to demonstrate relevance and therapeutic potential of targeting trained immunity in cardiovascular and chronic inflammatory diseases. Enforced by the promising data in oncology, the future prospects for epigenetic interventions in cardiovascular and chronic inflammatory diseases are eminent, attested by the large residual cardiovascular disease burden and the huge societal impact of other chronic inflammatory diseases. The REPROGRAM consortium consisting of key opinion leaders in the field of cardiovascular (systems) biology, immunology, epigenetic therapies and rheumatoid arthritis, with a large intersectoral network, guarantees rapid translation of early mechanistic discoveries


Sharman J.L.,Queens Medical Research Institute | Mpamhanga C.P.,Queens Medical Research Institute | Spedding M.,Institute Of Recherches Internationales Servier | Staels B.,University of Lille Nord de France | And 3 more authors.
Nucleic Acids Research | Year: 2011

The IUPHAR database is an established online reference resource for several important classes of human drug targets and related proteins. As well as providing recommended nomenclature, the database integrates information on the chemical, genetic, functional and pathophysiological properties of receptors and ion channels, curated and peer-reviewed from the biomedical literature by a network of experts. The database now includes information on 616 gene products from four superfamilies in human and rodent model organisms: G protein-coupled receptors, voltage- and ligand-gated ion channels and, in a recent update, 49 nuclear hormone receptors (NHRs). New data types for NHRs include details on co-regulators, DNA binding motifs, target genes and 3D structures. Other recent developments include curation of the chemical structures of approximately 2000 ligand molecules, providing electronic descriptors, identifiers, link-outs and calculated molecular properties, all available via enhanced ligand pages. The interface now provides intelligent tools for the visualization and exploration of ligand structure-activity relationships and the structural diversity of compounds active at each target. The database is freely available at http://www.iuphar-db.org. © The Author(s) 2010.


Castanho A.,University of Strasbourg | Bothorel B.,University of Strasbourg | Seguin L.,Institute Of Recherches Internationales Servier | Mocaer E.,Institute Of Recherches Internationales Servier | Pevet P.,University of Strasbourg
Chronobiology International | Year: 2014

Depression and biological rhythms disturbances are strongly associated. Agomelatine is an antidepressant with melatoninergic MT1-MT2 agonist and serotoninergic 5-HT2c antagonist properties. Both melatonin and 5-HT are known to modulate circadian rhythmicity controlled by the endogenous clock located in the suprachiasmatic nuclei (SCN). The aim of the present study was to compare the effect of an acute injection of agomelatine (Ago), melatonin (MLT) or an antagonist 5-HT2c (S32006), on the rhythms of two robust clock outputs: the pineal MLT secretion and the body temperature rhythm (Tc). Daily endogenous MLT profiles were measured using transpineal microdialysis over 4 consecutive days in rats maintained on a 12 h light/12 h dark cycle. Simultaneously, Tc was recorded. The drugs were injected subcutaneously at three doses (1, 2.5 or 5 mg/kg) at the onset of darkness. Both Ago and MLT, at the dose of 2.5 mg/kg, increased the amplitude of the peak of MLT secretion and this effect was observed 2 d after injection. Moreover, both drugs induced a dose-dependent advance of the rhythm onset which resulted in lengthening of the MLT peak. S32006 had no effect on the rhythm of MLT. Ago, MLT and S32006 increased the amplitude of the rhythm of Tc. These data suggest a central action of Ago, directly on the SCN, via melatoninergic receptors responsible for both the increased amplitude of MLT rhythm and the phase advance. The increase in the amplitude of the body temperature could involve both MLT agonist and/or 5-HT2c antagonist properties of Ago. © 2014 Informa Healthcare USA, Inc.


Pertinez H.,University of Liverpool | Chenel M.,Institute Of Recherches Internationales Servier | Aarons L.,University of Manchester
Pharmaceutical Research | Year: 2013

Purpose: To develop a physiologically based pharmacokinetic (PBPK) model to describe the disposition of Strontium - a bone seeking agent approved in 2004 (as its Ranelate salt) for treatment of osteoporosis in post-menopausal women. Methods: The model was developed using plasma and bone exposure data obtained from ovariectomised (OVX) female rats - a preclinical model for post-menopausal osteoporosis. The final PBPK model incorporated elements from literature models for bone seeking agents allowing for description of the heterogeneity of bone tissue and also for a physiological description of bone remodelling processes. The model was implemented in MATLAB in open and closed loop configurations, and fittings of the model to exposure data to estimate certain model parameters were carried out using nonlinear regression, treating data with a naïve-pooled approach. Results: The PBPK model successfully described plasma and bone exposure of Strontium in OVX rats with parameter estimates and model behaviour in keeping with known aspects of the distribution and incorporation of Strontium into bone. Conclusions: The model describes Strontium exposure in a physiologically rationalized manner and has the potential for future uses in modelling the PK-PD of Strontium, and/or other bone seeking agents, and for scaling to model human Strontium bone exposure. © 2013 Springer Science+Business Media New York.


Stein D.J.,University of Cape Town | Picarel-Blanchot F.,Institute Of Recherches Internationales Servier | Kennedy S.H.,University of Toronto
Human Psychopharmacology | Year: 2013

Objectives Anxiety in major depression is associated with increased morbidity. The antidepressant, agomelatine, which acts as an agonist at melatonin MT1 and MT2 receptors and as an antagonist at serotonin 5-HT2C receptors, has demonstrated efficacy and safety in both major depression and generalized anxiety disorder. Here, we investigated the efficacy of agomelatine in anxious depression. Methods Data from three placebo-controlled short-term trials of agomelatine and three comparative studies of agomelatine versus fluoxetine, sertraline, and venlafaxine were pooled. Effects of agomelatine on anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale in four studies (one vs placebo and three vs active comparator) and with the Hamilton Depression Rating Scale (HAMD) anxiety subscore in all six studies. Anxiolytic and antidepressant efficacies of agomelatine were assessed in patients with more severe anxiety symptoms at baseline (score ≥5 on HAMD anxiety subscore). Results Agomelatine had a significantly greater effect on anxiety symptoms than both placebo and a number of comparator antidepressants. In more anxious depressed patients, agomelatine had a significantly greater effect on anxiety and depressive symptoms than both placebo and comparator antidepressants. Conclusion Once-a-day oral agomelatine is a new, efficacious alternative option for the treatment of anxiety in patients with major depression. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd.


Bertrand J.,University Paris Diderot | Comets E.,University Paris Diderot | Chenel M.,Institute Of Recherches Internationales Servier | Mentre F.,University Paris Diderot
Biometrics | Year: 2012

Nonlinear mixed effects models allow investigating individual differences in drug concentration profiles (pharmacokinetics) and responses. Pharmacogenetics focuses on the genetic component of this variability. Two tests often used to detect a gene effect on a pharmacokinetic parameter are (1) the Wald test, assessing whether estimates for the gene effect are significantly different from 0 and (2) the likelihood ratio test comparing models with and without the genetic effect. Because those asymptotic tests show inflated type I error on small sample size and/or with unevenly distributed genotypes, we develop two alternatives and evaluate them by means of a simulation study. First, we assess the performance of the permutation test using the Wald and the likelihood ratio statistics. Second, for the Wald test we propose the use of the F-distribution with four different values for the denominator degrees of freedom. We also explore the influence of the estimation algorithm using both the first-order conditional estimation with interaction linearization-based algorithm and the stochastic approximation expectation maximization algorithm. We apply these methods to the analysis of the pharmacogenetics of indinavir in HIV patients recruited in the COPHAR2-ANRS 111 trial. Results of the simulation study show that the permutation test seems appropriate but at the cost of an additional computational burden. One of the four F-distribution-based approaches provides a correct type I error estimate for the Wald test and should be further investigated. © 2011, The International Biometric Society.


Galizzi J.-P.,Institute Of Recherche Servier | Lockhart B.P.,Institute Of Recherche Servier | Bril A.,Institute Of Recherches Internationales Servier
Drug Metabolism and Drug Interactions | Year: 2013

Translational research is a continuum between clinical and basic research where the patient is the center of the research process. It brings clinical research to a starting point for the drug discovery process, permitting the generation of a more robust pathophysiological hypothesis essential for a better selection of drug targets and candidate optimization. It also establishes the basis of early proof for clinical concept studies, preferably in phase I, for which biomarkers and surrogate endpoints can often be used. Systems biology is a prerequisite approach to translational research where technologies and expertise are integrated and articulated to support efficient and productive realization of this concept. The first component of systems biology relies on omics-based technologies and integrates the changes in variables, such as genes, proteins and metabolites, into networks that are responsible for an organism' s normal and diseased state. The second component of systems biology is in the domain of computational methods, where simulation and modeling create hypotheses of signaling pathways, transcription networks, physiological processes or even cell- or organism-based models. The simulations aim to show the origin of perturbations of the system that lead to pathological states and what treatment could be achieved to ameliorate or normalize the system. This review discusses how translational research and systems biology together could improve global understanding of drug targets, suggest new targets and approaches for therapeutics, and provide a deeper understanding of drug effects. Taken together, these types of analyses can lead to new therapeutic options while improving the safety and efficacy of new and existing medications.


Hubert S.,Agency for Science, Technology and Research Singapore | Abastado J.-P.,Agency for Science, Technology and Research Singapore | Abastado J.-P.,Institute Of Recherches Internationales Servier
Medecine/Sciences | Year: 2014

Metastasis is the main cause of cancer-related death. While the development of clinically detectable metastases occurs only at late time points, recent data obtained in mice and humans indicate that cancer cell dissemination is an early event in the progression of several types of cancer. However, disseminated cancer cells can remain dormant for prolonged periods of time. Then, how do cancer cells acquire the ability to disseminate so early? What are the selective pressures driving their dissemination? What are the signals controlling dormancy and why do some cancer cells eventually escape these controls? The present review presents our current understanding on these questions and how this novel paradigm could be translated to the clinic. © 2014 médecine/sciences-Inserm.


Howe W.M.,University of Michigan | Ji J.,University of Michigan | Parikh V.,Temple University | Williams S.,University of Michigan | And 3 more authors.
Neuropsychopharmacology | Year: 2010

Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective α4Β2* nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction with the increased task demands implemented by distractor presentation, the selective agonist, but not nicotine, enhanced the detection of signals during the post-distractor recovery period. This effect is consistent with the hypothesis that second-long increases in cholinergic activity (transients) mediate the detection of cues and that nAChR agonists augment such transients. Electrochemical recordings of prefrontal cholinergic transients evoked by S 38232 and nicotine indicated that the α4Β2* nAChR agonist evoked cholinergic transients that were characterized by a faster rise time and more rapid decay than those evoked by nicotine. Blockade of the α7 nAChR sharpens nicotine-evoked transients; therefore, we determined the effects of co-administration of nicotine and the α7 nAChR antagonist methyllycaconitine on dSAT performance. Compared with vehicle and nicotine alone, this combined treatment significantly enhanced the detection of signals. These results indicate that compared with nicotine, α4Β2* nAChR agonists significantly enhance attentional performance and that the dSAT represents a useful behavioral screening tool. The combined behavioral and electrochemical evidence supports the hypothesis that nAChR agonist-evoked cholinergic transients, which are characterized by rapid rise time and fast decay, predict robust drug-induced enhancement of attentional performance. © 2010 Nature Publishing Group All rights reserved.


Pelletier J.-P.,University of Montréal | Kapoor M.,University of Montréal | Fahmi H.,University of Montréal | Lajeunesse D.,University of Montréal | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective: To explore the disease-modifying effect, under therapeutic conditions, of strontium ranelate (SrRan) on the progression of joint structural changes and on the major pathophysiological pathways in an experimental osteoarthritis dog model. Methods: Dogs underwent sectioning of the anterior cruciate ligament, and 4 weeks after surgery received oral treatment of SrRan 25, 50 or 75 mg/kg per day, or placebo for 12 weeks. Methods included macroscopy, picrosirius red staining, histology, subchondral bone histomorphometry, quantitative PCR, and ELISA for CTX-II level in serum. Strontium plasma and synovial fluid levels were also measured. Results: At steady state, strontium blood exposures were within the clinical therapeutic range of osteoarthritis patients and correlated with strontium concentrations in synovial fluid. SrRan treatment significantly reduced the osteoarthritis cartilage lesions at all doses tested (p≤0.05). Significantly better preservation of the collagen network was also found in SrRan-treated dogs at 50 and 75 mg/kg per day (p=0.03). The osteoarthritis subchondral bone thickening observed in osteoarthritis-placebo dogs was significantly reduced by SrRan at 50 mg/kg per day (p=0.02). The increased gene expression levels of MMP-1, MMP-13 and cathepsin K in osteoarthritis cartilage were all significantly reduced by SrRan at 75 mg/kg per day (p≤0.03) as were, in osteoarthritis synovium, IL-1β at 50 and 75 mg/kg per day (p=0.05) and MMP-3 at all doses tested (p≤0.02). The serum level of CTX-II was reduced (p≤0.04) by SrRan at 16 weeks in dogs treated with 50 and 75 mg/kg per day. Conclusions: This study is the first to demonstrate in vivo in an animal model that SrRan reduced the progression of osteoarthritis structural changes. The inhibition of several key proteases as well as IL-1β may have contributed to the beneficial effect of SrRan.

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