JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 6, 2007; DOI: 10.1124/jpet.107.127183

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.107.127183v1
jpet.107.127183v2
323/2/469    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Foster, C. A.
Right arrow Articles by Billich, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Foster, C. A.
Right arrow Articles by Billich, A.


Received for publication June 25, 2007.
Revised August 2, 2007.
Accepted for publication August 3, 2007.

Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the CNS during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis

Carolyn A. Foster 1, Laurence M. Howard 1, Alain Schweitzer 2, Elke Persohn 2, Peter C. Hiestand 1, Balazs Balatoni 3, Roland Reuschel 1, Christian Beerli 1, Manuela Schwartz 4, Andreas Billich 5*

1 Novartis Institutes for Biomedical Research 2 Novartis Pharma 3 Novartis Hungary Healthcare 4 Evangelisches Krankenhaus Wien 5 Novartis Institutes for BioMedical Research

* Address correspondence to: E-mail: andreas.billich{at}novartis.com

Abstract

FTY720 is an oral sphingosine-1-phosphate receptor modulator under development for the treatment of multiple sclerosis (MS). The drug is phosphorylated in vivo by sphingosine kinase 2 to its bioactive form (FTY720-P). While treatment with FTY720 is accompanied by a reduction of the peripheral lymphocyte count, its efficacy in MS and experimental autoimmune encephalomyelitis (EAE) may be due to additional, direct effects in the central nervous system (CNS). We now show that FTY720 localizes to the CNS white matter, preferentially along myelin sheaths. Brain trough levels of FTY720 and FTY720 P in rat EAE are of the same magnitude and dose-dependently increase; they are in the range of 40 to 540 ng/g in the brain tissue at efficacious doses and exceed blood concentrations several fold. In a rat model of chronic EAE, prolonged treatment with 0.03 mg/kg was efficacious, but limiting the dosing period failed to prevent EAE despite a significant decrease in blood lymphocytes. FTY720 effectiveness is likely due to a culmination of mechanisms involving reduction of autoreactive T cells, neuroprotective influence of FTY720-P in the CNS, and inhibition of inflammatory mediators in the brain.


Key words: CNS, FTY720, experimental autoimmune encephalomyelitis, immunomodulation, multiple sclerosis, sphingosine kinase


This article has been cited by other articles:


Home page
 BrainHome page
D. Wheeler, V. V. R. Bandaru, P. A. Calabresi, A. Nath, and N. J. Haughey
A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis
Brain, November 1, 2008; 131(11): 3092 - 3102.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
V. E. Miron, J. A. Hall, T. E. Kennedy, B. Soliven, and J. P. Antel
Cyclical and Dose-Dependent Responses of Adult Human Mature Oligodendrocytes to Fingolimod
Am. J. Pathol., October 1, 2008; 173(4): 1143 - 1152.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.