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      Laquinimod in the treatment of multiple sclerosis: a review of the data so far

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          Abstract

          Laquinimod (ABR-215062) is a new orally available carboxamide derivative, which is currently developed for relapsing remitting (RR) and chronic progressive (CP) forms of multiple sclerosis (MS; RRMS or CPMS) as well as neurodegenerative diseases. Its mechanism of action may comprise immunomodulatory effects on T-cells, monocytes, and dendritic cells as well as neuroprotective effects with prominent actions on astrocytes. Laquinimod was tested in Phase II and III clinical trials in RRMS at different dosages ranging from 0.1 to 0.6 mg/day. The compound was well tolerated, yet at the dosages tested only led to moderate effects on the reduction of relapse rates as primary study endpoint in Phase III trials. In contrast, significant effects on brain atrophy and disease progression were observed. While there were no significant safety signals in the clinical trials, the Committee for Medicinal Products for Human Use (CHMP) refused marketing authorization for RRMS based on the assessment of the risk–benefit ratio with regard to data from animal studies. At present, the compound is further tested in RRMS as well as CPMS and Huntington’s disease at different concentrations. Results from these trials will further inform about the clinical benefit of laquinimod in patient cohorts with a persisting, but still insufficiently met need for safe and at the same time effective oral compounds with neuroprotective effects.

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          Most cited references 23

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          Clinical relevance of brain volume measures in multiple sclerosis.

          Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA [Structural Image Evaluation using Normalization of Atrophy]). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.
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            Pathology of multiple sclerosis and related inflammatory demyelinating diseases.

            This article provides a comprehensive overview of the pathology of multiple sclerosis (MS), including recent insights into its molecular neuropathology and immunology. It shows that all clinical manifestations of relapsing and progressive MS display the same basic features of pathology, such as chronic inflammation, demyelination in the white and gray matter, and diffuse neurodegeneration within the entire central nervous system. However, the individual components of the pathological spectrum vary quantitatively between early relapsing and late progressive MS. Widespread confluent and plaque-like demyelination with oligodendrocyte destruction is the unique pathological hallmark of the disease, but axonal injury and neurodegeneration are additionally present and in part extensive. Remyelination of existing lesions may occur in MS brains; it is extensive in a subset of patients, while it fails in others. Active tissue injury in MS is always associated with inflammation, consistent with T-cell and macrophage infiltration and microglia activation. Recent data suggest that oxidative injury and subsequent mitochondrial damage play a major pathogenetic role in neurodegeneration. Finally we discuss similarities and differences of the pathology between classical MS and other inflammatory demyelinating diseases, such as neuromyelitis optica, concentric sclerosis, or acute disseminated encephalomyelitis.
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              Multiple sclerosis: Prospects and promise.

              We have entered a golden era in multiple sclerosis (MS) research. Two decades ago, our understanding of the disease was largely descriptive and there were no approved therapies to modify the natural history of MS. Today, delineation of immune pathways relevant to MS have been clarified; a comprehensive map of genes that influence risk compiled; clues to environmental triggers identified; noninvasive in vivo monitoring of the MS disease process has been revolutionized by high-field MRI; and many effective therapies for the early, relapsing, component of MS now exist. However, major challenges remain. We still have no useful treatment for progressive MS (the holy grail of MS research), no means to repair injured axons or protect neurons, and extremely limited evidence to guide treatment decisions. Recent advances have set in place a foundation for development of increasingly selective immunotherapy for patients; application of genetic and genomic discoveries to improve therapeutic options; development of remyelination or neuroprotection therapies for progressive MS; and integrating clinical, imaging and genomic data for personalized medicine. MS has now advanced from the backwaters of autoimmune disease research to the front-line, and definitive answers, including cures, are now realistic goals for the next decade. Many of the breakthrough discoveries in MS have also resulted from meaningful interactions across disciplines, and especially from translational and basic scientists working closely with clinicians, highlighting that the clinical value of discoveries are most often revealed when ideas developed in the laboratory are tested at the bedside. Copyright © 2013 American Neurological Association.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                14 March 2016
                : 10
                : 1111-1118
                Affiliations
                [1 ]Department of Neurology, University Hospital Essen, Essen, Germany
                [2 ]Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
                Author notes
                Correspondence: Jan Thöne, Department of Neurology, University Hospital Essen, Hufelandstrasse 55, D-45147 Essen, Germany, Email jan_thoene@ 123456gmx.de
                Article
                dddt-10-1111
                10.2147/DDDT.S55308
                4798201
                27042003
                © 2016 Thöne and Linker. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Pharmacology & Pharmaceutical medicine

                neuroprotection, demyelination, axonal damage, abr-215062

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