19
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      An update of teriflunomide for treatment of multiple sclerosis

      review-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          There are a number of oral agents emerging as potential disease-modifying agents in multiple sclerosis (MS). Among these investigational agents, teriflunomide has shown promise in large, multicenter, phase III clinical trials with respect to safety and efficacy in relapsing MS patients, and is the latest disease-modifying agent approved for use in MS patients in the United States. This review will summarize teriflunomide’s historical development, clinical pharmacology, studies in animals, clinical trials, and safety data, and will end with a discussion of the role of teriflunomide in MS in the context of existing treatment options.

          Most cited references24

          • Record: found
          • Abstract: found
          • Article: not found

          Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential antirheumatic activity--I. Disease modifying action on adjuvant arthritis of the rat.

          The new isoxazol derivative, N-(4-Trifluoro-methylphenyl)-5-methylisoxazol-4-carboxamide (HWA 486) has been investigated as to its disease modifying activity on adjuvant arthritis of the Lewis rat. This compound was able to prevent the onset of the adjuvant disease, provided the therapy was started within the first 12 days after its induction, reflecting properties similar to that of immunosuppressive agents. If therapy started later than 12 days, the substance was still able to reduce the degree of inflammation and arrest its progress as long as it was administered, i.e. termination of the therapy, after the establishment of adjuvant arthritis, allowed the disease to progress, a property similar to classical anti-inflammatory agents such as indomethacin. The stimulation of lymphocytes from adjuvant arthritic rats with ConA, PHA, and LPS was suppressed. Treatment of these animals with HWA 486 returned the mitogenic response to normal values. However, the lymphocytes from non-diseased animals were not affected by treatment with this substance. Cyclophosphamide, on the other hand, which also can prevent the establishment of the disease, reduces the proliferative response to mitogens in healthy animals. The characteristics of HWA 486 distinguish it from either classical anti-inflammatory drugs, such as phenylbutazone, or classical immunosuppressive agents, such as cyclophosphamide.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            An aggregation sensing reporter identifies leflunomide and teriflunomide as polyglutamine aggregate inhibitors.

            Intracellular protein aggregation is a common pathologic feature in neurodegenerative diseases such as Huntington' disease, amyotrophic lateral sclerosis and Parkinson' disease. Although progress towards understanding protein aggregation in vitro has been made, little of this knowledge has translated to patient therapy. Moreover, mechanisms controlling aggregate formation and catabolism in cellulo remain poorly understood. One limitation is the lack of tools to quantitatively monitor protein aggregation and disaggregation. Here, we developed a protein-aggregation reporter that uses huntingtin exon 1 containing 72 glutamines fused to the N-terminal end of firefly luciferase (httQ72-Luc). httQ72-Luc fails to aggregate unless seeded by a non-luciferase-containing polyglutamine (polyQ) protein such as Q80-cfp. Upon co-aggregation, httQ72-luc becomes insoluble and loses its enzymatic activity. Using httQ72-Luc with Q80(CFP/YFP) as seeds, we screened the Johns Hopkins Clinical Compound Library and identified leflunomide, a dihydroorotate dehydrogenase inhibitor with immunosuppressive and anti-psoriatic activities, as a novel drug that prevents polyQ aggregation. Leflunomide and its active metabolite teriflunomide inhibited protein aggregation independently of their known role in pyrimidine biosynthesis, since neither uridine treatment nor other pyrimidine biosynthesis inhibitors affected polyQ aggregation. Inducible cell line and cycloheximide-chase experiments indicate that these drugs prevent incorporation of expanded polyQ into an aggregate. This study demonstrates the usefulness of luciferase-based protein aggregate reporters for high-throughput screening applications. As current trials are under-way for teriflunomide in the treatment of multiple sclerosis, we propose that this drug be considered a possible therapeutic agent for polyQ diseases.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Immunological basis for the development of tissue inflammation and organ-specific autoimmunity in animal models of multiple sclerosis.

              Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) that has shaped our understanding of autoimmune tissue inflammation in the central nervous system (CNS). Major therapeutic approaches to MS have been first validated in EAE. Nevertheless, EAE in all its modifications is not able to recapitulate the full range of clinical and histopathogenic aspects of MS. Furthermore, autoimmune reactions in EAE-prone rodent strains and MS patients may differ in terms of the relative involvement of various subsets of immune cells. However, the role of specific molecules that play a role in skewing the immune response towards pathogenic autoreactivity is very similar in mice and humans. Thus, in this chapter, we will focus on the identification of a novel subset of inflammatory T cells, called Th17 cells, in EAE and their interplay with other immune cells including protective regulatory T cells (T-regs). It is likely that the discovery of Th17 cells and their relationship with T-regs will change our understanding of organ-specific autoimmune diseases in the years to come.
                Bookmark

                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2013
                2013
                26 April 2013
                : 9
                : 177-190
                Affiliations
                [1 ]Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
                [2 ]Division of Neurology, St Michael’s Hospital, Toronto, ON, Canada
                Author notes
                Correspondence: Paul W O’Connor, The MS Clinic at St Michael’s Hospital, Shuter 3-003, 30 Bond Street, Toronto, ON M5B 1W8, Canada, Tel +1 416 864 5830, Fax +1 416 864 5147, Email oconnorp@ 123456smh.ca
                Article
                tcrm-9-177
                10.2147/TCRM.S30947
                3673963
                23761970
                e2b0fcf8-8fdd-425e-9b99-e88998d29114
                © 2013 Oh and O’Connor, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                Categories
                Review

                Medicine
                teriflunomide,multiple sclerosis,clinical trials,review
                Medicine
                teriflunomide, multiple sclerosis, clinical trials, review

                Comments

                Comment on this article