Document Detail


Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis.
MedLine Citation:
PMID:  21520239     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jeffrey A Cohen; Jerold Chun
Related Documents :
15176169 - Counter-regulatory balance: atopic dermatitis in patients undergoing infliximab infusio...
24108579 - Extracellular haemoglobin upregulates and binds to tissue factor on macrophages: implic...
10515369 - Chronic allograft rejection. do the th2 cells preferentially induced by indirect alloan...
16081849 - Human bronchial epithelium controls th2 responses by th1-induced, nitric oxide-mediated...
11754819 - Il-25 induces il-4, il-5, and il-13 and th2-associated pathologies in vivo.
8724829 - Differentiation of subsets of cd4+ and cd8+ t cells.
10573189 - Redistribution of cytochrome c is not an essential requirement in c2-ceramide induced a...
17624419 - Regulatory role of vitamins e and c on extracellular matrix components of the vascular ...
16329649 - Induction of immunity and inflammation by interleukin-12 family members.
Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Annals of neurology     Volume:  69     ISSN:  1531-8249     ISO Abbreviation:  Ann. Neurol.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-04-26     Completed Date:  2011-06-24     Revised Date:  2011-12-01    
Medline Journal Info:
Nlm Unique ID:  7707449     Medline TA:  Ann Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  759-77     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 American Neurological Association.
Affiliation:
Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA. cohenj@ccf.org
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Central Nervous System / drug effects,  immunology
Clinical Trials as Topic
Disease Models, Animal
Drug-Induced Liver Injury
Heart Diseases / chemically induced
Humans
Immunosuppressive Agents / adverse effects*,  pharmacology
Infection / chemically induced
Liver Diseases
Lymphocytes / physiology
Lysophospholipids / metabolism
Multiple Sclerosis / drug therapy*,  immunology,  pathology
Propylene Glycols / adverse effects*,  pharmacology
Receptors, Lysosphingolipid / metabolism
Respiration Disorders / chemically induced
Sphingosine / adverse effects,  analogs & derivatives*,  metabolism,  pharmacology
Chemical
Reg. No./Substance:
0/Immunosuppressive Agents; 0/Lysophospholipids; 0/Propylene Glycols; 0/Receptors, Lysosphingolipid; 123-78-4/Sphingosine; 162359-55-9/fingolimod; 26993-30-6/sphingosine 1-phosphate
Comments/Corrections
Comment In:
Ann Neurol. 2011 Oct;70(4):673-4; author reply 674   [PMID:  22028236 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Neuronal cell death in neonatal hypoxia-ischemia.
Next Document:  Subthalamic neuronal firing in obsessive-compulsive disorder and Parkinson disease.