Journal ArticleDOI
Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis
Jeffrey A. Cohen,Jerold Chun +1 more
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TLDR
Findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti‐inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS.Abstract:
Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod-phosphate (fingolimod-P), is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod-P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P₁ S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti-inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10x the approved 0.5 mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies.read more
Citations
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Journal ArticleDOI
Sphingosine-1-Phosphate and Lymphocyte Egress from Lymphoid Organs
Jason G. Cyster,Susan R. Schwab +1 more
TL;DR: Current understanding of how Sphingosine-1-phosphate promotes exit from the secondary lymphoid organs and thymus is summarized and how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression is examined.
Journal ArticleDOI
The Concise Guide to PHARMACOLOGY 2013/14: G Protein‐Coupled Receptors
Stephen P.H. Alexander,Helen E. Benson,Elena Faccenda,Adam J. Pawson,Joanna L. Sharman,Michael Spedding,John A. Peters,Anthony J. Harmar +7 more
Journal ArticleDOI
An update on the biology of sphingosine 1-phosphate receptors.
Victoria A. Blaho,Timothy Hla +1 more
TL;DR: This review will focus on the most recent advances in S1PRs, as they become attractive therapeutic targets in several diseases, such as chronic inflammatory pathologies, autoimmunity, and cancer.
Journal ArticleDOI
Multiple Sclerosis: Current and Emerging Disease-Modifying Therapies and Treatment Strategies
TL;DR: The available evidence supporting risk-benefit profiles for available and emerging DMTs is reviewed, including those currently in use (sequential monotherapy, escalation therapy, and induction and maintenance therapy) and others that may soon become feasible (combination approaches and "personalized medicine").
Journal ArticleDOI
Immune interventions in stroke
TL;DR: Preliminary results suggest that the use of drugs that modify disease in multiple sclerosis might accomplish these goals in ischaemic and haemorrhagic stroke and further elucidation of the immune mechanisms involved in stroke is likely to lead to successful immune interventions.
References
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Journal ArticleDOI
Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance
TL;DR: This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice.
Journal ArticleDOI
Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
Mehrdad Matloubian,Charles G. Lo,Guy Cinamon,Matthew J. Lesneski,Ying Xu,Volker Brinkmann,Maria L. Allende,Richard L. Proia,Jason G. Cyster +8 more
TL;DR: It is established that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
Journal ArticleDOI
A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis
Ludwig Kappos,Ernst Wilhelm Radue,Paul O'Connor,Chris H. Polman,Reinhard Hohlfeld,Peter A. Calabresi,Krzysztof Selmaj,Catherine Agoropoulou,Malgorzata Leyk,Lixin Zhang-Auberson,Pascale Burtin +10 more
TL;DR: Both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI and were superior to placebo with regard to MRI-related measures.
Journal ArticleDOI
Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
Jeffrey A. Cohen,Frederik Barkhof,Giancarlo Comi,Hans Peter Hartung,Bhupendra Khatri,Xavier Montalban,Jean Pelletier,Ruggero Capra,Paolo Gallo,Guillermo Izquierdo,Klaus Tiel-Wilck,Ana de Vera,James Jin,Tracy Stites,Stacy Wu,Shreeram Aradhye,Ludwig Kappos +16 more
TL;DR: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a.
Journal ArticleDOI
Sphingosine-1-phosphate: an enigmatic signalling lipid
Sarah Spiegel,Sheldon Milstien +1 more
TL;DR: The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions.