Absorption and Disposition of the Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) in Healthy Volunteers: A Case of Xenobiotic Biotransformation Following Endogenous Metabolic Pathways

2010 ◽  
Vol 39 (2) ◽  
pp. 199-207 ◽  
Author(s):  
Markus Zollinger ◽  
Hans-Peter Gschwind ◽  
Yi Jin ◽  
Claudia Sayer ◽  
Frédéric Zécri ◽  
...  
2014 ◽  
Vol 3 (3) ◽  
pp. 170-178 ◽  
Author(s):  
Jianfeng Xu ◽  
Frank Gray ◽  
Alex Henderson ◽  
Kirsty Hicks ◽  
Jiansong Yang ◽  
...  

2022 ◽  
Author(s):  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
Aran Groves ◽  
Manisha Ray ◽  
Arjun Saha ◽  
...  

FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analogue approved for multiple sclerosis (MS) therapy, which can functionally antagonize the S1P receptor, S1P1. Vitamin B12 (B12) deficiency produces neurological manifestations resembling MS. Here, we report a new mechanism where FTY720 suppresses neuroinflammation by regulating B12 metabolic pathways. Nuclear RNA-seq of c-Fos-activated astrocytes (called ieAstrocytes) from experimental autoimmune encephalomyelitis (EAE) spinal cords identified up-regulation of CD320, a transcobalamin 2 (TCN2)-B12 receptor, by S1P1 inhibition. CD320 was reduced in MS plaques. Deficiency of CD320 or dietary B12 worsened EAE and eliminated FTY720 efficacy, while concomitantly down-regulating type I interferon signaling. TCN2 functioned as a chaperone for FTY720 and sphingosine, which induced astrocytic CD320 internalization. An accompanying paper identified a requirement for astrocyte sphingosine kinases in FTY720 efficacy and its altered expression in MS brains, molecularly linking MS and B12 deficiency that can be accessed by sphingolipid/fingolimod metabolic pathways.


2019 ◽  
Vol 139 (11) ◽  
pp. 2381-2384.e3 ◽  
Author(s):  
Markus Thieme ◽  
Katja Bieber ◽  
Tanya Sezin ◽  
Melanie Wannick ◽  
Yask Gupta ◽  
...  

2021 ◽  
Vol 9 (1) ◽  
pp. e1104
Author(s):  
Farren Basil Shaw Briggs ◽  
Farrah J. Mateen ◽  
Hollie Schmidt ◽  
Keisha M. Currie ◽  
Heather M. Siefers ◽  
...  

Background and ObjectivesThere are limited data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine reactogenicity in persons with multiple sclerosis (PwMS) and how reactogenicity is affected by disease-modifying therapies (DMTs). The objective of this retrospective cross-sectional study was to generate real-world multiple sclerosis–specific vaccine safety information, particularly in the context of specific DMTs, and provide information to mitigate specific concerns in vaccine hesitant PwMS.MethodsBetween 3/2021 and 6/2021, participants in iConquerMS, an online people-powered research network, reported SARS-CoV-2 vaccines, experiences of local (itch, pain, redness, swelling, or warmth at injection site) and systemic (fever, chills, fatigue, headache, joint pain, malaise, muscle ache, nausea, allergic, and other) reactions within 24 hours (none, mild, moderate, and severe), DMT use, and other attributes. Multivariable models characterized associations between clinical factors and reactogenicity.ResultsIn 719 PwMS, 64% reported experiencing a reaction after their first vaccination shot, and 17% reported a severe reaction. The most common reactions were pain at injection site (54%), fatigue (34%), headache (28%), and malaise (21%). Younger age, being female, prior SARS-CoV-2 infection, and receiving the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vs BNT162b2 (Pfizer-BioNTech) vaccine were associated with experiencing a reaction after the first vaccine dose. Similar relationships were observed for a severe reaction, including higher odds of reactions among PwMS with more physical impairment and lower odds of reactions for PwMS on an alpha4-integrin blocker or sphingosine-1-phosphate receptor modulator. In 442 PwMS who received their second vaccination shot, 74% reported experiencing a reaction, whereas 22% reported a severe reaction. Reaction profiles after the second shot were similar to those reported after the first shot. Younger PwMS and those who received the mRNA-1273 (Moderna) vs BNT162b2 vaccine reported higher reactogenicity after the second shot, whereas those on a sphingosine-1-phosphate receptor modulator or fumarate were significantly less likely to report a reaction.DiscussionSARS-CoV-2 vaccine reactogenicity profiles and the associated factors in this convenience sample of PwMS appear similar to those reported in the general population. PwMS on specific DMTs were less likely to report vaccine reactions. Overall, the short-term vaccine reactions experienced in the study population were mostly self-limiting, including pain at the injection site, fatigue, headache, and fever.


2010 ◽  
Vol 30 (5) ◽  
pp. 419-424 ◽  
Author(s):  
Kenji Chiba ◽  
Hirotoshi Kataoka ◽  
Yasuhiro Maeda ◽  
Noriyasu Seki ◽  
Kunio Sugahara

2011 ◽  
Vol 17 (11) ◽  
pp. 1387-1389 ◽  
Author(s):  
Patricio S Espinosa ◽  
Joseph R Berger

Oral fingolimod (Gilenya) is a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes. Fingolimod reduces relapses and delays disability progression in patients with relapsing forms of multiple sclerosis (MS). We report a patient with MS who developed asystole and sustained bradycardia 21 hours after the first dose of fingolimod.


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