scholarly journals Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Drugs ◽  
2020 ◽  
Author(s):  
Jerold Chun ◽  
Gavin Giovannoni ◽  
Samuel F. Hunter
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Profile ◽  
Receptor Signalling ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate

scholarly journals COVID-19 Vaccination Reactogenicity in Persons With Multiple Sclerosis

2021 ◽  
Vol 9 (1) ◽  
pp. e1104
Author(s):  
Farren Basil Shaw Briggs ◽  
Farrah J. Mateen ◽  
Hollie Schmidt ◽  
Keisha M. Currie ◽  
Heather M. Siefers ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Injection Site ◽  
Safety Information ◽  
Vaccine Dose ◽  
Research Network ◽  
Severe Reaction ◽  
Cross Sectional ◽  
Convenience Sample ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate

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.

Delayed fingolimod-associated asystole

2011 ◽  
Vol 17 (11) ◽  
pp. 1387-1389 ◽  
Author(s):  
Patricio S Espinosa ◽  
Joseph R Berger
Keyword(s):  
Multiple Sclerosis ◽  
Lymph Nodes ◽  
Disability Progression ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate

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.

scholarly journals Ozanimod to Treat Relapsing Forms of Multiple Sclerosis: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

2020 ◽  
Vol 12 (3) ◽  
pp. 89-108
Author(s):  
Grace Lassiter ◽  
Carlie Melancon ◽  
Tyler Rooney ◽  
Anne-Marie Murat ◽  
Jessica S. Kaye ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Drug Efficacy ◽  
Receptor Modulator ◽  
Increased Risk ◽  
Relapsing Remitting ◽  
The Us ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
Us Fda ◽  
Reversible Encephalopathy

Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing–remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators.

Clinical immunology of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis

Neurology ◽  
2011 ◽  
Vol 76 (Issue 8, Supplement 3) ◽  
pp. S20-S27 ◽  
Author(s):  
M. Mehling ◽  
T. A. Johnson ◽  
J. Antel ◽  
L. Kappos ◽  
A. Bar-Or
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Immunology ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate

FTY720 on the way from the base camp to the summit of the mountain: relevance for remyelination

2012 ◽  
Vol 18 (3) ◽  
pp. 258-263 ◽  
Author(s):  
M Kipp ◽  
S Amor
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Potential ◽  
Oral Disease ◽  
S1p Receptors ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System

FTY720 (fingolimod; Gilenya®), a sphingosine 1-phosphate (S1P) receptor modulator, is the first oral disease-modifying therapy to be approved for the treatment of relapsing–remitting multiple sclerosis. FTY720 is rapidly converted in vivo to the active S-fingolimod-phosphate, which binds to S1P receptors. This action inhibits egress of lymphocytes from the lymph nodes, preventing entry into the blood and thus infiltration into the central nervous system. More recent studies, however, convincingly show that FTY720 crosses the blood–brain barrier, where it is thought to act on S1P receptors on cells within the central nervous system, such as astrocytes, oligodendrocytes or microglia. Here we discuss the evidence showing that FTY720 also plays a role in remyelination and repair within the brain. While the mechanisms of action still require firm elucidation, it is clear that FTY720 could also be reparative, extending its therapeutic potential for multiple sclerosis.

scholarly journals FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis

2022 ◽  
Author(s):  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
Aran Groves ◽  
Manisha Ray ◽  
Arjun Saha ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Metabolic Pathways ◽  
Type I ◽  
Rna Seq ◽  
Autoimmune Encephalomyelitis ◽  
Altered Expression ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor

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.

Ozanimod for the treatment of relapsing forms of multiple sclerosis

2021 ◽  
Author(s):  
Andrea M Kuczynski ◽  
Jiwon Oh
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Side Effects ◽  
Receptor Subtypes ◽  
Efficacy And Safety ◽  
S1p Receptors ◽  
Receptor Modulator ◽  
Wide Range ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Multiple sclerosis (MS) is an inflammatory disease that causes chronic neurological disability in young adults. Modulation of sphingosine 1-phosphate (S1P) receptors, a group of receptors that, among other things, regulate egression of lymphocytes from lymph nodes, has proven to be effective in treating relapsing MS. Fingolimod, the first oral S1P receptor modulator, has demonstrated potent efficacy and tolerability, but can cause undesirable side effects due to its interaction with a wide range of S1P receptor subtypes. This review will focus on ozanimod, a more selective S1P receptor modulator, which has recently received approval for relapsing MS. We summarize ozanimod’s mechanism of action, and efficacy and safety from clinical trials that demonstrate its utility as another treatment option for relapsing MS.

Fingolimod (FTY720), the Sphingosine 1-Phosphate Receptor Modulator, as a New Therapeutic Drug in Multiple Sclerosis

2011 ◽  
Vol 31 (2) ◽  
pp. 167-174 ◽  
Author(s):  
Kenji Chiba ◽  
Hirotoshi Kataoka ◽  
Noriyasu Seki ◽  
Yasuhiro Maeda ◽  
Kunio Sugahara
Keyword(s):  
Multiple Sclerosis ◽  
Therapeutic Drug ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate

scholarly journals Does Siponimod Exert Direct Effects in the Central Nervous System?

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1771 ◽  
Author(s):  
Markus Kipp
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Direct Interaction ◽  
Active Role ◽  
Progressive Multiple Sclerosis ◽  
Receptor Subtypes ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System

The modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes in lymph nodes. Different sphingosine 1-phosphate receptor subtypes are expressed in the brain and spinal cord, and their pharmacological effects may improve disease development and neuropathology. Siponimod (BAF312) is a novel sphingosine 1-phosphate receptor modulator that has recently been approved for the treatment of active secondary progressive multiple sclerosis (MS). In this review article, we summarize recent evidence suggesting that the active role of siponimod in patients with progressive MS may be due to direct interaction with central nervous system cells. Additionally, we tried to summarize our current understanding of the function of siponimod and discuss the effects observed in the case of MS.

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