Moser P.,Pierre Fabre
European Neuropsychopharmacology | Year: 2014
Many lines of evidence suggest that schizophrenia has a major developmental component and that environmental factors that disrupt key stages of development, such as maternal stress during pregnancy as a result of infection or malnutrition, can increase the risk of developing schizophrenia in later life. This review examines how non-clinical neurodevelopmental models pertinent to schizophrenia have been evaluated for their ability to reproduce behavioural deficits related to the negative symptoms of schizophrenia. The more frequently used are the prenatal application of the mitotoxic agent methylazoxymethanol, prenatal immune challenge and the neonatal ventral hippocampus lesion model. In general they have been extensively evaluated in models considered relevant to positive symptoms of schizophrenia. In contrast, very few studies have examined tests related to negative symptoms and, when they have, it has almost exclusively been a social interaction model. Other aspects related to negative symptoms such as anhedonia, affective flattening and avolition have almost never been studied. Further studies examining other components of negative symptomatology are needed to more clearly associate these deficits with a schizophrenia-like profile as social withdrawal is a hallmark of many disorders. Although there are no truly effective treatments for negative symptoms, better characterisation with a broader range of drugs used in schizophrenia will be necessary to better evaluate the utility of these models. In summary, developmental models of schizophrenia have been extensively studied as models of positive symptoms but, given the unmet need in the clinic, the same effort now needs to be made with regard to negative symptoms. © 2013 Elsevier B.V. and ECNP.
Kollman J.M.,Howard Hughes Medical Institute |
Merdes A.,Pierre Fabre |
Mourey L.,CNRS Institute of Pharmacology and Structural Biology |
Agard D.A.,Howard Hughes Medical Institute
Nature Reviews Molecular Cell Biology | Year: 2011
Microtubule nucleation is regulated by the γ-tubulin ring complex (γTuRC) and related γ-tubulin complexes, providing spatial and temporal control over the initiation of microtubule growth. Recent structural work has shed light on the mechanism of γTuRC-based microtubule nucleation, confirming the long-standing hypothesis that the γTuRC functions as a microtubule template. The first crystallographic analysis of a non-γ-tubulin γTuRC component (γ-tubulin complex protein 4 (GCP4)) has resulted in a new appreciation of the relationships among all γTuRC proteins, leading to a refined model of their organization and function. The structures have also suggested an unexpected mechanism for regulating γTuRC activity via conformational modulation of the complex component GCP3. New experiments on γTuRC localization extend these insights, suggesting a direct link between its attachment at specific cellular sites and its activation. © 2011 Macmillan Publishers Limited. All rights reserved.
Beck A.,Pierre Fabre
Discovery medicine | Year: 2010
Monoclonal antibodies (mAbs) and derivatives are currently the fastest growing class of therapeutic molecules. More than 30 G-type immunoglobulins (IgG) and related agents have been approved over the past 25 years mainly for cancers and inflammatory diseases. In oncology, mAbs are often combined with cytotoxic drugs to enhance their therapeutic efficacy. Alternatively, small anti-neoplastic molecules can be chemically conjugated to mAbs, used both as carriers (increased half-life) and as targeting agents (selectivity). Potential benefits of antibody-drug conjugates (ADCs), strategies, and development challenges are discussed in this review. Several examples of ADCs are presented with emphasis on three major molecules currently in late clinical development as well as next generation thio-mAbs conjugates with improved therapeutic index.
Beck A.,Pierre Fabre |
Reichert J.M.,Landes Bioscience
mAbs | Year: 2012
Therapeutic properties of antibodies frequently depend on the composition of their glycans. Most of the currently approved antibodies are produced in mammalian cell lines, which yield mixtures of different glycoforms that are close to those of humans, but not fully identical. Glyco-engineering is being developed as a method to control the composition of carbohydrates and to enhance the pharmacological properties of mAbs. The recent approval in Japan of mogamulizumab (POT ELIGEO® ), the first glyco-engineered antibody to reach the market, is a landmark in the field of therapeutic antibodies. Mogamulizumab is a humanized mAb derived from Kyowa Hakko Kirin's POT ELLIGENT® technology, which produces antibodies with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity. The approval was granted March 30, 2012 by the Japanese Ministry of Health, Labour and Welfare for patients with relapsed or refractory CCR4- positive adult Tcell leukemia-lymphoma.
Bardin L.,Pierre Fabre
Behavioural Pharmacology | Year: 2011
Serotonin [5-hydroxytryptamine (5-HT)] in the central nervous system and in the periphery has long been considered to have an important role in the control of pain, for example, through descending inhibition. In recent years, considerable research efforts have focused on the role played by 5-HT on acute or chronic pain states as well as on the identification of the respective 5-HT receptors involved. However, preclinical studies have reported conflicting observations, and numerous important questions remain unanswered. The purpose of this study is to provide an analysis of the recent developments in understanding the role of 5-HT both within the periphery and at the level of the spinal dorsal horn. We discuss the inhibitory or facilitatory influences exerted by 5-HT, through the descending 5-HT pathway, on spinal processing of nociceptive information in pathological pain states. Evidence with regard to the possible implication of the 5-HT 1A, 5-HT 2A, 5-HT 3, and 5-HT 7 receptors in pain modulation is also reviewed. Recent studies (both behavioral and clinical, relevant to these targets) have indeed demonstrated that 5-HT 1A and 5-HT 7 receptor agonists or 5-HT 2A and 5-HT 3 receptor antagonists may be promising therapeutic agents for the treatment of pain states. © 2010 Lippincott Williams & Wilkins.