scholarly journals Abuse and dependence potential of sphingosine-1-phosphate (S1P) receptor modulators used in the treatment of multiple sclerosis: a review of literature and public data

2021 ◽  
Author(s):  
Kerri A. Schoedel ◽  
Carine Kolly ◽  
Anne Gardin ◽  
Srikanth Neelakantham ◽  
Kasra Shakeri-Nejad
Keyword(s):  
Multiple Sclerosis ◽  
Prescription Drugs ◽  
Subjective Effects ◽  
Review Of Literature ◽  
Dependence Potential ◽  
Public Data ◽  
Sphingosine 1 Phosphate ◽  
The Usa ◽  
S1p Receptor ◽  
Receptor Modulators

AbstractAbuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally.

scholarly journals Sphingosine-1-phosphate Receptor Modulators in Multiple Sclerosis

2018 ◽  
Vol 13 (1) ◽  
pp. 25 ◽  
Author(s):  
Patrick Vermersch
Keyword(s):  
Multiple Sclerosis ◽  
Oral Disease ◽  
Receptor Subtypes ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
S1p Receptor ◽  
Phase Ii And Iii ◽  
Receptor Modulators ◽  
Term Data

The introduction of oral disease modifying therapies has transformed the treatment landscape for patients with multiple sclerosis (MS). Fingolimod (Gilenya®, Novartis, Basel, Switzerland), the first oral therapy to be approved, has demonstrated clinical efficacy as a result of modulation of subtype 1 sphingosine-1-phosphate (S1P1) receptors. This leads to retention of lymphocytes in the lymph nodes, preventing their entry into the central nervous system. However, fingolimod can cause adverse effects as a result of its interaction with other S1P receptor subtypes, which are expressed in numerous tissues, including cardiac myocytes. More selective S1P receptor agents are currently in phase II and III clinical development. Siponimod, ozanimod, ponesimod and amiselimod have demonstrated efficacy with improved safety profiles compared with fingolimod. While more long-term data are needed, these selective S1P receptor modulators appear to be promising options for the treatment of MS and other disorders associated with autoimmunity and inflammation.

scholarly journals Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1290 ◽  
Author(s):  
Alessandra Musella ◽  
Antonietta Gentile ◽  
Livia Guadalupi ◽  
Francesca Romana Rizzo ◽  
Francesca De Vito ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Ex Vivo ◽  
The United States ◽  
Neuroprotective Effects ◽  
Local Inflammatory Response ◽  
Electrophysiological Studies ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Receptor Modulators

Future treatments of multiple sclerosis (MS), a chronic autoimmune neurodegenerative disease of the central nervous system (CNS), aim for simultaneous early targeting of peripheral immune function and neuroinflammation. Sphingosine-1-phosphate (S1P) receptor modulators are among the most promising drugs with both “immunological” and “non-immunological” actions. Selective S1P receptor modulators have been recently approved for MS and shown clinical efficacy in its mouse model, the experimental autoimmune encephalomyelitis (EAE). Here, we investigated the anti-inflammatory/neuroprotective effects of ozanimod (RPC1063), a S1P1/5 modulator recently approved in the United States for the treatment of MS, by performing ex vivo studies in EAE brain. Electrophysiological experiments, supported by molecular and immunofluorescence analysis, revealed that ozanimod was able to dampen the EAE glutamatergic synaptic alterations, through attenuation of local inflammatory response driven by activated microglia and infiltrating T cells, the main CNS-cellular players of EAE synaptopathy. Electrophysiological studies with selective S1P1 (AUY954) and S1P5 (A971432) agonists suggested that S1P1 modulation is the main driver of the anti-excitotoxic activity mediated by ozanimod. Accordingly, in vivo intra-cerebroventricular treatment of EAE mice with AUY954 ameliorated clinical disability. Altogether these results strengthened the relevance of S1P1 agonists as immunomodulatory and neuroprotective drugs for MS therapy.

scholarly journals Novel Multiple Sclerosis Agents-Induced Cardiotoxicity

2021 ◽  
Author(s):  
Zaki Al-Yafeai ◽  
Hamzah Abduljabbar ◽  
Alexander Carvajal-Gonzalez ◽  
Muhammed Arvas ◽  
Shaun Patel ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Signal Analysis ◽  
Cardiovascular Complications ◽  
Reporting Odds Ratio ◽  
New Agents ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Artery Disease ◽  
Receptor Modulators

Background: Emerging novel therapeutics have been developed to hamper the progression of multiple sclerosis. However, the adverse events related to these new agents remain largely unknown. Therefore, we sought to investigate the cardiovascular complications of these drugs. Methods: Utilizing data from the U.S. Food and Drug Administration Adverse Events Reporting System, we comprehensively evaluated the cardiovascular complications of the newly FDA approved anti-multiple sclerosis agents. Disproportionality signal analysis was conducted by measuring reporting odds ratio (ROR) with 95% confidence interval of all the cardiovascular adverse events adverse events since approval till 2021. Results: After vetting the newly approved agents for multiple sclerosis, CD20 and CD25 inhibitors and sphingosine-1-phosphate receptors agonists were the latest approved medications for multiple sclerosis since 2015. Two CD20 (ocrelizumab, ofatumumab) and one CD25 inhibitors (daclizumab) were significantly associated with multiple cardiovascular adverse events. Among all the cardiotoxic events; coronary artery disease, cardiac failure and atrial fibrillation were the most predominant among CD20 or CD25 blockers. Interestingly, Sphingosine-1-phosphate receptors agonists showed much fewer reported cardiac adverse events. However, fingolimod and siponimod were associated with significant bradycardia. Conclusions: Our data revealed the new agents prescribed for multiple sclerosis have cardiotoxic effects, including not only the known adverse effects observed effects for S1P receptor modulators but also undefined cardiovascular complications associated with CD20 and CD25 inhibitors. These findings potentially instigate further studies to personalize prescribing these agents for multiple sclerosis based on patient cardiovascular profile.

scholarly journals Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis

CNS Drugs ◽  
2015 ◽  
Vol 29 (7) ◽  
pp. 565-575 ◽  
Author(s):  
Adnan M. Subei ◽  
Jeffrey A. Cohen
Keyword(s):  
Multiple Sclerosis ◽  
Sphingosine 1 Phosphate ◽  
Receptor Modulators

scholarly journals Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders

2019 ◽  
Vol 59 (1) ◽  
pp. 149-170 ◽  
Author(s):  
Jerold Chun ◽  
Yasuyuki Kihara ◽  
Deepa Jonnalagadda ◽  
Victoria A. Blaho
Keyword(s):  
Multiple Sclerosis ◽  
Drug Targets ◽  
Science Studies ◽  
Lessons Learned ◽  
Fungal Metabolites ◽  
Organ Systems ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
Disease Stages ◽  
Receptor Modulators

Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration–approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS). These dual actions represent a more general theme for S1P and likely other LP receptor modulators. Fingolimod's direct CNS activities likely contribute to its efficacy in MS, with particular relevance to treating progressive disease stages and forms that involve neurodegeneration. The evolving understanding of fingolimod's MOA has provided strategies for developing next-generation compounds with superior attributes, suggesting new ways to target S1P as well as other LP receptor modulators for novel therapeutics in the CNS and other organ systems.

Mechanism of action of s1p receptor modulators in multiple sclerosis: The double requirement

2020 ◽  
Vol 176 (1-2) ◽  
pp. 100-112
Author(s):  
Régis Bordet ◽  
William Camu ◽  
Jérôme De Seze ◽  
David-Axel Laplaud ◽  
Jean-Christophe Ouallet ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mechanism Of Action ◽  
S1p Receptor ◽  
Receptor Modulators
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