FTY720 (fingolimod) for relapsing multiple sclerosis

References

• Pugliatti M, Rosati G, Carton H et al. The epidemiology of multiple sclerosis in Europe. Eur. J. Neurol.13(7), 700–722 (2006).
   PubMed Web of Science ®Google Scholar
• Compston A, Coles A. Multiple sclerosis. Lancet359(9313), 1221–1231 (2002).
   PubMed Web of Science ®Google Scholar
• Goodin DS, Frohman EM, Garmany GP Jr et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology58(2), 169–178 (2002).
   PubMed Web of Science ®Google Scholar
• Ransohoff RM. Natalizumab for multiple sclerosis. N. Engl. J. Med.356(25), 2622–2629 (2007).
   PubMed Web of Science ®Google Scholar
• Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs19(3), 239–252 (2005).
   PubMed Web of Science ®Google Scholar
• Fujita T, Inoue K, Yamamoto S et al. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J. Antibiot. (Tokyo)47(2), 208–215 (1994).
   PubMed Web of Science ®Google Scholar
• Adachi K, Kohara T, Nakao N et al. Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: discovery of a novel immunosuppressant, FTY720. Bioorg. Med. Chem. Lett.5(8), 853–856 (1995).
   Web of Science ®Google Scholar
• Martini S, Peters H, Bohler T, Budde K. Current perspectives on FTY720. Expert Opin. Investig. Drugs16(4), 505–518 (2007).
   PubMed Web of Science ®Google Scholar
• Budde K, Schutz M, Glander P et al. FTY720 (fingolimod) in renal transplantation. Clin. Transplant.20(Suppl. 17), 17–24 (2006).
   PubMed Web of Science ®Google Scholar
• Salvadori M, Budde K, Charpentier B et al. FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia. Am. J. Transplant.6(12), 2912–2921 (2006).
   PubMed Web of Science ®Google Scholar
• Tedesco-Silva H, Pescovitz MD, Cibrik D et al. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation82(12), 1689–1697 (2006).
   PubMed Web of Science ®Google Scholar
• Kappos L, Antel J, Comi G et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med.355(11), 1124–1140 (2006).
   PubMed Web of Science ®Google Scholar
• Mandala S, Hajdu R, Bergstrom J et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science296(5566), 346–349 (2002).
   PubMed Web of Science ®Google Scholar
• Brinkmann V, Davis MD, Heise CE et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem.277(24), 21453–21457 (2002).
   PubMed Web of Science ®Google Scholar
• Albert R, Hinterding K, Brinkmann V et al. Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer. J. Med. Chem.48(16), 5373–5377 (2005).
   PubMed Web of Science ®Google Scholar
• Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol. Ther.115(1), 84–105 (2007).
   PubMed Web of Science ®Google Scholar
• Spiegel S, Cuvillier O, Edsall LC et al. Sphingosine-1-phosphate in cell growth and cell death. Ann. NY Acad. Sci.845, 11–18 (1998).
   PubMed Web of Science ®Google Scholar
• Spiegel S, Milstien S. Sphingolipid metabolites: members of a new class of lipid second messengers. J. Membr. Biol.146(3), 225–237 (1995).
   PubMed Web of Science ®Google Scholar
• Hla T. Signaling and biological actions of sphingosine 1-phosphate. Pharmacol. Res.47(5), 401–407 (2003).
   PubMed Web of Science ®Google Scholar
• Lee MJ, Van Brocklyn JR, Thangada S et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science.279(5356), 1552–1555 (1998).
   PubMed Web of Science ®Google Scholar
• Lee JF, Zeng Q, Ozaki H et al. Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity. J. Biol. Chem.281(39), 29190–29200 (2006).
   PubMed Web of Science ®Google Scholar
• Allende ML, Yamashita T, Proia RL. G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood102(10), 3665–3667 (2003).
   PubMed Web of Science ®Google Scholar
• Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S, Proia RL. Essential role for sphingosine kinases in neural and vascular development. Mol. Cell. Biol.25(24), 11113–11121 (2005).
   PubMed Web of Science ®Google Scholar
• Saba JD. Lysophospholipids in development: miles apart and edging in. J. Cell. Biochem.92(5), 967–992 (2004).
   PubMed Web of Science ®Google Scholar
• Hannun YA, Luberto C, Argraves KM. Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochemistry40(16), 4893–4903 (2001).
   PubMed Web of Science ®Google Scholar
• Le Stunff H, Milstien S, Spiegel S. Generation and metabolism of bioactive sphingosine-1-phosphate. J. Cell. Biochem.92(5), 882–899 (2004).
   PubMed Web of Science ®Google Scholar
• Murata N, Sato K, Kon J et al. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem. J.352(Pt 3), 809–815 (2000).
   PubMed Web of Science ®Google Scholar
• Sanchez T, Hla T. Structural and functional characteristics of S1P receptors. J. Cell. Biochem.92(5), 913–922 (2004).
   PubMed Web of Science ®Google Scholar
• Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat. Rev. Immunol.5(7), 560–570 (2005).
   PubMed Web of Science ®Google Scholar
• Hu W, Mahavadi S, Huang J, Li F, Murthy KS. Characterization of S1P1 and S1P2 receptor function in smooth muscle by receptor silencing and receptor protection. Am. J. Physiol. Gastrointest. Liver. Physiol.291(4), G605–G610 (2006).
   PubMed Web of Science ®Google Scholar
• Graler MH, Grosse R, Kusch A, Kremmer E, Gudermann T, Lipp M. The sphingosine 1-phosphate receptor S1P4 regulates cell shape and motility via coupling to Gi and G12/13. J. Cell. Biochem.89(3), 507–519 (2003).
   PubMed Web of Science ®Google Scholar
• Rosen H, Sanna G, Alfonso C. Egress: a receptor-regulated step in lymphocyte trafficking. Immunol. Rev.195, 160–177 (2003).
   PubMed Web of Science ®Google Scholar
• Lo CG, Xu Y, Proia RL, Cyster JG. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J. Exp. Med.201(2), 291–301 (2005).
   PubMed Web of Science ®Google Scholar
• Matloubian M, Lo CG, Cinamon G et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature427(6972), 355–360 (2004).
   PubMed Web of Science ®Google Scholar
• Allende ML, Dreier JL, Mandala S, Proia RL. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem.279(15), 15396–15401 (2004).
   PubMed Web of Science ®Google Scholar
• von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med.343(14), 1020–1034 (2000).
   PubMed Web of Science ®Google Scholar
• Schwab SR, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science309(5741), 1735–1739 (2005).
   PubMed Web of Science ®Google Scholar
• Brinkmann V, Baumruker T. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr. Opin. Pharmacol.6(3), 244–250 (2006).
   PubMed Web of Science ®Google Scholar
• Sanna MG, Wang SK, Gonzalez-Cabrera PJ et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat. Chem. Biol.2(8), 434–441 (2006).
   PubMed Web of Science ®Google Scholar
• Wei SH, Rosen H, Matheu MP et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nat. Immunol.6(12), 1228–1235 (2005).
   PubMed Web of Science ®Google Scholar
• McVerry BJ, Garcia JG. Endothelial cell barrier regulation by sphingosine 1-phosphate. J. Cell. Biochem.92(6), 1075–1085 (2004).
   PubMed Web of Science ®Google Scholar
• Rosen H, Sanna MG, Cahalan SM, Gonzalez-Cabrera PJ. Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends Immunol.28(3), 102–107 (2007).
   PubMed Web of Science ®Google Scholar
• Tolle M, Levkau B, Keul P et al. Immunomodulator FTY720 Induces eNOS-dependent arterial vasodilatation via the lysophospholipid receptor S1P3. Circ. Res.96(8), 913–920 (2005).
   PubMed Web of Science ®Google Scholar
• Coussin F, Scott RH, Wise A, Nixon GF. Comparison of sphingosine 1-phosphate-induced intracellular signaling pathways in vascular smooth muscles: differential role in vasoconstriction. Circ. Res.91(2), 151–157 (2002).
   PubMed Web of Science ®Google Scholar
• Peters SL, Alewijnse AE. Sphingosine-1-phosphate signaling in the cardiovascular system. Curr. Opin. Pharmacol.7(2), 186–192 (2007).
   PubMed Web of Science ®Google Scholar
• Chiba K, Hoshino Y, Suzuki C et al. FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant Proc.28(2), 1056–1059 (1996).
   PubMed Web of Science ®Google Scholar
• Hoshino Y, Suzuki C, Ohtsuki M, Masubuchi Y, Amano Y, Chiba K. FTY720, a novel immunosuppressant possessing unique mechanisms. II. Long-term graft survival induction in rat heterotopic cardiac allografts and synergistic effect in combination with cyclosporine A. Transplant Proc.28(2), 1060–1061 (1996).
   PubMed Web of Science ®Google Scholar
• Chiba K, Yanagawa Y, Masubuchi Y et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J. Immunol.160(10), 5037–5044 (1998).
   PubMed Web of Science ®Google Scholar
• Yanagawa Y, Masubuchi Y, Chiba K. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats, III. Increase in frequency of CD62L-positive T cells in Peyer's patches by FTY720-induced lymphocyte homing. Immunology.95(4), 591–594 (1998).
   PubMed Web of Science ®Google Scholar
• Chiba K, Yanagawa Y, Kataoka H, Kawaguchi T, Ohtsuki M, Hoshino Y. FTY720, a novel immunosuppressant, induces sequestration of circulating lymphocytes by acceleration of lymphocyte homing. Transplant Proc.31(1–2), 1230–1233 (1999).
   PubMed Web of Science ®Google Scholar
• Xie JH, Nomura N, Koprak SL, Quackenbush EJ, Forrest MJ, Rosen H. Sphingosine-1-phosphate receptor agonism impairs the efficiency of the local immune response by altering trafficking of naive and antigen-activated CD4+ T cells. J. Immunol.170(7), 3662–3670 (2003).
   PubMed Web of Science ®Google Scholar
• Del Rio ML, Pabst O, Ramirez P, Penuelas-Rivas G, Forster R, Rodriguez-Barbosa JI. The thymus is required for the ability of FTY720 to prolong skin allograft survival across different histocompatibility MHC barriers. Transpl. Int.20(10), 895–903 (2007).
   PubMed Web of Science ®Google Scholar
• Graler MH, Goetzl EJ. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J.18(3), 551–553 (2004).
   PubMed Web of Science ®Google Scholar
• Liu CH, Thangada S, Lee MJ, Van Brocklyn JR, Spiegel S, Hla T. Ligand-induced trafficking of the sphingosine-1-phosphate receptor EDG-1. Mol. Biol. Cell.10(4), 1179–1190 (1999).
   PubMed Web of Science ®Google Scholar
• Singer, II, Tian M, Wickham LA et al. Sphingosine-1-phosphate agonists increase macrophage homing, lymphocyte contacts, and endothelial junctional complex formation in murine lymph nodes. J. Immunol.175(11), 7151–7161 (2005).
   PubMed Web of Science ®Google Scholar
• Baumruker T, Billich A, Brinkmann V. FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis. Expert Opin. Investig. Drugs16(3), 283–289 (2007).
   PubMed Web of Science ®Google Scholar
• Yanagawa Y, Sugahara K, Kataoka H, Kawaguchi T, Masubuchi Y, Chiba K. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J. Immunol.160(11), 5493–5499 (1998).
   PubMed Web of Science ®Google Scholar
• Maki T, Gottschalk R, Monaco AP. Prevention of autoimmune diabetes by FTY720 in nonobese diabetic mice. Transplantatio74(12), 1684–1686 (2002).
   PubMed Web of Science ®Google Scholar
• Hwang MW, Matsumori A, Furukawa Y et al. FTY720, a new immunosuppressant, promotes long-term graft survival and inhibits the progression of graft coronary artery disease in a murine model of cardiac transplantation. Circulation100(12), 1322–1329 (1999).
   PubMed Web of Science ®Google Scholar
• Kurose S, Ikeda E, Tokiwa M, Hikita N, Mochizuki M. Effects of FTY720, a novel immunosuppressant, on experimental autoimmune uveoretinitis in rats. Exp. Eye Res.70(1), 7–15 (2000).
   PubMed Web of Science ®Google Scholar
• Fujino M, Funeshima N, Kitazawa Y et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther.305(1), 70–77 (2003).
   PubMed Web of Science ®Google Scholar
• Kataoka H, Sugahara K, Shimano K et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell. Mol. Immunol.2(6), 439–448 (2005).
   PubMed Web of Science ®Google Scholar
• Pinschewer DD, Ochsenbein AF, Odermatt B, Brinkmann V, Hengartner H, Zinkernagel RM. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J. Immunol.164(11), 5761–5770 (2000).
   PubMed Web of Science ®Google Scholar
• Brinkmann V, Pinschewer D, Chiba K, Feng L. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol. Sci.21(2), 49–52 (2000).
   PubMed Web of Science ®Google Scholar
• Chiba K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol. Ther.108(3), 308–319 (2005).
   PubMed Web of Science ®Google Scholar
• Payne SG, Oskeritzian CA, Griffiths R et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood109(3), 1077–1085 (2007).
   PubMed Web of Science ®Google Scholar
• Kalyvas A, David S. Cytosolic phospholipase A2 plays a key role in the pathogenesis of multiple sclerosis-like disease. Neuron41(3), 323–335 (2004).
   PubMed Web of Science ®Google Scholar
• Sanchez T, Estrada-Hernandez T, Paik JH et al. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J. Biol. Chem.278(47), 47281–47290 (2003).
   PubMed Web of Science ®Google Scholar
• Peng X, Hassoun PM, Sammani S et al. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am. J. Respir. Crit. Care Med.169(11), 1245–1251 (2004).
   PubMed Web of Science ®Google Scholar
• Czeloth N, Bernhardt G, Hofmann F, Genth H, Forster R. Sphingosine-1-phosphate mediates migration of mature dendritic cells. J. Immunol.175(5), 2960–2967 (2005).
   PubMed Web of Science ®Google Scholar
• Lan YY, De Creus A, Colvin BL et al. The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo. Am. J. Transplant.5(11), 2649–2659 (2005).
   PubMed Web of Science ®Google Scholar
• Muller H, Hofer S, Kaneider N et al. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur. J. Immunol.35(2), 533–545 (2005).
   PubMed Web of Science ®Google Scholar
• Dev KK, Mullershausen F, Mattes H et al. Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol. Ther.117(1), 77–93 (2008).
   PubMed Web of Science ®Google Scholar
• Pebay A, Toutant M, Premont J et al. Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades. Eur. J. Neurosci.13(12), 2067–2076 (2001).
   Web of Science ®Google Scholar
• Chae SS, Proia RL, Hla T. Constitutive expression of the S1P1 receptor in adult tissues. Prostaglandins Other Lipid Mediat.73(1–2), 141–150 (2004).
   PubMed Web of Science ®Google Scholar
• Mullershausen F, Craveiro LM, Shin Y et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J. Neurochem.102(4), 1151–1161 (2007).
   PubMed Web of Science ®Google Scholar
• Jaillard C, Harrison S, Stankoff B et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J. Neurosci.25(6), 1459–1469 (2005).
   PubMed Web of Science ®Google Scholar
• Miron VE, Jung CG, Kim HJ, Kennedy TE, Soliven B, Antel JP. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann. Neurol.63(1), 61–71 (2008).
   PubMed Web of Science ®Google Scholar
• Saini HS, Coelho RP, Goparaju SK et al. Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors. J. Neurochem.95(5), 1298–1310 (2005).
   PubMed Web of Science ®Google Scholar
• Novgorodov AS, El-Alwani M, Bielawski J, Obeid LM, Gudz TI. Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J.21(7), 1503–1514 (2007).
   PubMed Web of Science ®Google Scholar
• Yamagata K, Tagami M, Torii Y et al. Sphingosine 1-phosphate induces the production of glial cell line-derived neurotrophic factor and cellular proliferation in astrocytes. Glia41(2), 199–206 (2003).
   PubMed Web of Science ®Google Scholar
• Sorensen SD, Nicole O, Peavy RD et al. Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol. Pharmacol.64(5), 1199–1209 (2003).
   PubMed Web of Science ®Google Scholar
• Rouach N, Pebay A, Meme W et al. S1P inhibits gap junctions in astrocytes: involvement of G and Rho GTPase/ROCK. Eur. J. Neurosci.23(6), 1453–1464 (2006).
   PubMed Web of Science ®Google Scholar
• Sato K, Tomura H, Igarashi Y, Ui M, Okajima F. Exogenous sphingosine 1-phosphate induces neurite retraction possibly through a cell surface receptor in PC12 cells. Biochem. Biophys. Res. Commun.240(2), 329–334 (1997).
   PubMed Web of Science ®Google Scholar
• MacLennan AJ, Devlin BK, Marks L, Gaskin AA, Neitzel KL, Lee N. Antisense studies in PC12 cells suggest a role for H218, a sphingosine 1-phosphate receptor, in growth-factor-induced cell-cell interaction and neurite outgrowth. Dev. Neurosci.22(4), 283–295 (2000).
   PubMed Web of Science ®Google Scholar
• Toman RE, Payne SG, Watterson KR et al. Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension. J. Cell Biol.166(3), 381–392 (2004).
   PubMed Web of Science ®Google Scholar
• Kimura A, Ohmori T, Ohkawa R et al. Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells25(1), 115–124 (2007).
   PubMed Web of Science ®Google Scholar
• Harada J, Foley M, Moskowitz MA, Waeber C. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J. Neurochem.88(4), 1026–1039 (2004).
   PubMed Web of Science ®Google Scholar
• Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol.47(6), 707–717 (2000).
   PubMed Web of Science ®Google Scholar
• Brück W, Kuhlmann T, Stadelmann C. Remyelination in multiple sclerosis. J. Neurol. Sci.206(2), 181–185 (2003).
   PubMed Web of Science ®Google Scholar
• Franklin RJ. Why does remyelination fail in multiple sclerosis? Nat. Rev. Neurosci.3(9), 705–714 (2002).
   PubMed Web of Science ®Google Scholar
• Dubois-Dalcq M, Ffrench-Constant C, Franklin RJ. Enhancing central nervous system remyelination in multiple sclerosis. Neuron48(1), 9–12 (2005).
   PubMed Web of Science ®Google Scholar
• Coelho RP, Payne SG, Bittman R, Spiegel S, Sato-Bigbee C. The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J. Pharmacol. Exp. Ther.323(2), 626–635 (2007).
   PubMed Web of Science ®Google Scholar
• Jung CG, Kim HJ, Miron VE et al. Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia55(16), 1656–1667 (2007).
   PubMed Web of Science ®Google Scholar
• Balatoni B, Storch MK, Swoboda EM et al. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res. Bull.74(5), 307–316 (2007).
   PubMed Web of Science ®Google Scholar
• Sofroniew MV. Reactive astrocytes in neural repair and protection. Neuroscientist11(5), 400–407 (2005).
   PubMed Web of Science ®Google Scholar
• Budde K, Schmouder RL, Brunkhorst R et al. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J. Am. Soc. Nephrol.13(4), 1073–1083 (2002).
   PubMed Web of Science ®Google Scholar
• Budde K, Schmouder RL, Nashan B et al. Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am. J. Transplant.3(7), 846–854 (2003).
   PubMed Web of Science ®Google Scholar
• Kovarik JM, Schmouder R, Barilla D, Wang Y, Kraus G. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br. J. Clin. Pharmacol.57(5), 586–591 (2004).
   PubMed Web of Science ®Google Scholar
• Kahan BD, Karlix JL, Ferguson RM et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, Phase I study. Transplantation76(7), 1079–1084 (2003).
   PubMed Web of Science ®Google Scholar
• Skerjanec A, Tedesco H, Neumayer HH et al. FTY720, a novel immunomodulator in de novo kidney transplant patients: pharmacokinetics and exposure-response relationship. J. Clin. Pharmacol.45(11), 1268–1278 (2005).
   PubMed Web of Science ®Google Scholar
• Kovarik JM, Schmouder R, Barilla D, Riviere GJ, Wang Y, Hunt T. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J. Clin. Pharmacol.44(5), 532–537 (2004).
   PubMed Web of Science ®Google Scholar
• Hofmann M, Brinkmann V, Zerwes HG. FTY720 preferentially depletes naive T cells from peripheral and lymphoid organs. Int. Immunopharmacol.6(13–14), 1902–1910 (2006).
   PubMed Web of Science ®Google Scholar
• Berard M, Tough DF. Qualitative differences between naive and memory T cells. Immunology106(2), 127–138 (2002).
   PubMed Web of Science ®Google Scholar
• Bohler T, Waiser J, Schuetz M, Neumayer HH, Budde K. FTY720 exerts differential effects on CD4+ and CD8+ T-lymphocyte subpopulations expressing chemokine and adhesion receptors. Nephrol. Dial. Transplant.19(3), 702–713 (2004).
   PubMed Web of Science ®Google Scholar
• Schuurman HJ, Menninger K, Audet M et al. Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation, given alone or in combination with cyclosporine or RAD. Transplantation.74(7), 951–960 (2002).
   PubMed Web of Science ®Google Scholar
• Brinkmann V, Cyster JG, Hla T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am. J. Transplant.4(7), 1019–1025 (2004).
   PubMed Web of Science ®Google Scholar
• Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science291(5512), 2413–2417 (2001).
   PubMed Web of Science ®Google Scholar
• Clemens JJ, Davis MD, Lynch KR, Macdonald TL. Synthesis of para-alkyl aryl amide analogues of sphingosine-1-phosphate: discovery of potent S1P receptor agonists. Bioorg. Med. Chem. Lett.13(20), 3401–3404 (2003).
   PubMed Web of Science ®Google Scholar
• Fujita T, Hirose R, Yoneta M et al. Potent immunosuppressants, 2-alkyl-2-aminopropane-1,3-diols. J. Med. Chem.39(22), 4451–4459 (1996).
   PubMed Web of Science ®Google Scholar
• Parrill AL, Wang D, Bautista DL et al. Identification of Edg1 receptor residues that recognize sphingosine 1-phosphate. J. Biol. Chem.275(50), 39379–39384 (2000).
   PubMed Web of Science ®Google Scholar
• Kiuchi M, Adachi K, Kohara T et al. Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J. Med. Chem.43(15), 2946–2961 (2000).
   PubMed Web of Science ®Google Scholar
• Kovarik JM, Hartmann S, Bartlett M et al. Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects. Biopharm. Drug Dispos.28(2), 97–104 (2007).
   PubMed Web of Science ®Google Scholar
• Kovarik JM, Schmouder RL, Slade AJ. Overview of FTY720 clinical pharmacokinetics and pharmacology. Ther. Drug. Monit.26(6), 585–587 (2004).
   PubMed Web of Science ®Google Scholar
• Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett.554(1–2), 189–193 (2003).
   PubMed Web of Science ®Google Scholar
• Kharel Y, Lee S, Snyder AH et al. Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J. Biol. Chem.280(44), 36865–36872 (2005).
   PubMed Web of Science ®Google Scholar
• Zemann B, Kinzel B, Muller M et al. Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood107(4), 1454–1458 (2006).
   PubMed Web of Science ®Google Scholar
• Park SI, Felipe CR, Machado PG et al. Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients. Braz. J. Med. Biol. Res.38(5), 683–694 (2005).
   PubMed Web of Science ®Google Scholar
• Kovarik JM, Schmouder RL, Serra D et al. FTY720 pharmacokinetics in mild to moderate hepatic impairment. J. Clin. Pharmacol.45(4), 446–452 (2005).
   PubMed Web of Science ®Google Scholar
• Kovarik JM, Schmouder RL, Hartmann S et al. Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function. J. Clin. Pharmacol.46(2), 149–156 (2006).
   PubMed Web of Science ®Google Scholar
• Meno-Tetang GM, Li H, Mis S et al. Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in rats after oral and intravenous doses. Drug Metab. Dispos.34(9), 1480–1487 (2006).
   PubMed Web of Science ®Google Scholar
• Foster CA, Howard LM, Schweitzer A et al. 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. J. Pharmacol. Exp. Ther.323(2), 469–475 (2007).
   PubMed Web of Science ®Google Scholar
• Billich A, Bornancin F, Devay P, Mechtcheriakova D, Urtz N, Baumruker T. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J. Biol. Chem.278(48), 47408–47415 (2003).
   PubMed Web of Science ®Google Scholar
• Zimmerlin AG, Patten CJ. Role of CYP4F in the metabolic clearance of FTY720: prediction of low drug to drug interaction potential [abstract]. Transplantation69(Suppl.), S191 (2000).
   PubMedGoogle Scholar
• Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet360(9340), 1155–1162 (2002).
   PubMed Web of Science ®Google Scholar
• Kahan BD. Update on pharmacokinetic/pharmacodynamic studies with FTY720 and sirolimus. Ther. Drug Monit.24(1), 47–52 (2002).
   PubMed Web of Science ®Google Scholar
• Kovarik JM, Hsu CH, Skerjanec A, Riviere GJ, Schmouder R. FTY720 disposition is not affected by demographic or clinical factors in de novo kidney transplant patients. Am. J. Transplant.5(Suppl. 3), 332 (2003).
   Google Scholar
• Kovarik JM, Slade A, Voss B et al. Ethnic sensitivity study of fingolimod in white and Asian subjects. Int. J. Clin. Pharmacol. Ther.45(2), 98–109 (2007).
   PubMed Web of Science ®Google Scholar
• Chiba K, Matsuyuki H, Maeda Y, Sugahara K. Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell. Mol. Immunol.3(1), 11–19 (2006).
   PubMed Web of Science ®Google Scholar
• Rausch M, Hiestand P, Foster CA, Baumann DR, Cannet C, Rudin M. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J. Magn. Reson. Imaging.20(1), 16–24 (2004).
   PubMed Web of Science ®Google Scholar
• Webb M, Tham CS, Lin FF et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J. Neuroimmunol.153(1–2), 108–121 (2004).
   PubMed Web of Science ®Google Scholar
• Schubart A, Seabrook T, Rausch M et al. CNS mediated effects of FTY720 (fingolimod) in EAE. Neurology60(Suppl. 1), A315 (2007).
   Google Scholar
• Kappos L, Antel J, Comi G et al. Oral fingolimod (FTY720) in relapsing multiple sclerosis: 24-month results of the Phase II study. Multiple Sclerosis12(1 Suppl.), S101 (2006).
   PubMedGoogle Scholar
• Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet352(9139), 1498–1504 (1998).
   PubMed Web of Science ®Google Scholar
• Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann. Neurol.39(3), 285–294 (1996).
   PubMed Web of Science ®Google Scholar
• The IFNB Multiple Sclerosis Study Group. Interferon β-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology43(4), 655–661 (1993).
   PubMed Web of Science ®Google Scholar
• Paty DW, Li DK. Interferon β-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology43(4), 662–667 (1993).
   PubMed Web of Science ®Google Scholar
• Johnson KP, Brooks BR, Cohen JA et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer Multiple Sclerosis Study Group. Neurology45(7), 1268–1276 (1995).
   PubMed Web of Science ®Google Scholar
• Hartung HP, Gonsette R, Konig N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet360(9350), 2018–2025 (2002).
   PubMed Web of Science ®Google Scholar
• Polman CH, O’Connor PW, Havrdova E et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med.354(9), 899–810 (2006).
   PubMed Web of Science ®Google Scholar
• Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a misnomer reviewed. Intern. Med. J.35(2), 83–90 (2005).
   PubMed Web of Science ®Google Scholar
• Oppenheimer F, Mulgaonkar S, Ferguson R et al. Impact of long-term therapy with FTY720 or mycophenolate mofetil on cardiac conduction and rhythm in stable adult renal transplant patients. Transplantation83(5), 645–648 (2007).
   PubMed Web of Science ®Google Scholar
• Schmouder R, Serra D, Wang Y et al. FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J. Clin. Pharmacol.46(8), 895–904 (2006).
   PubMed Web of Science ®Google Scholar
• Mulgaonkar S, Tedesco H, Oppenheimer F et al. FTY720/cyclosporine regimens in de novo renal transplantation: a 1-year dose-finding study. Am. J. Transplant.6(8), 1848–1857 (2006).
   PubMed Web of Science ®Google Scholar
• Sanna MG, Liao J, Jo E et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem.279(14), 13839–13848 (2004).
   PubMed Web of Science ®Google Scholar
• Koyrakh L, Roman MI, Brinkmann V, Wickman K. The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I. Am. J. Transplant.5(3), 529–536 (2005).
   PubMed Web of Science ®Google Scholar
• Tedesco-Silva H, Mourad G, Kahan BD et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation79(11), 1553–1560 (2005).
   PubMed Web of Science ®Google Scholar
• Roviezzo F, Di Lorenzo A, Bucci M et al. Sphingosine-1-phosphate/sphingosine kinase pathway is involved in mouse airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol.36(6), 757–762 (2007).
   PubMed Web of Science ®Google Scholar
• Pfaff M, Powaga N, Akinci S et al. Activation of the SPHK/S1P signalling pathway is coupled to muscarinic receptor-dependent regulation of peripheral airways. Respir. Res.6, 48 (2005).
   PubMed Web of Science ®Google Scholar
• Massberg S, von Andrian UH. Fingolimod and sphingosine-1-phosphate – modifiers of lymphocyte migration. N. Engl. J. Med.355(11), 1088–1091 (2006).
   PubMed Web of Science ®Google Scholar