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

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 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 Comprehensive assessment of vascular lesions in predicting cardiovascular events in atherosclerosis and carbohydrate metabolism disorders

2019 ◽  
Vol 2 (21) ◽  
pp. 22-27
Author(s):  
A. A. Tarasov ◽  
M. A. Gordeeva ◽  
S. I. Davydov ◽  
E. A. Reznikova ◽  
A. R. Babaeva
Keyword(s):  
Diabetes Mellitus ◽  
Adverse Events ◽  
Cardiovascular Events ◽  
Cardiovascular Complications ◽  
High Rate ◽  
Vascular Lesions ◽  
Type I ◽  
Tnf Α ◽  
Circulating Markers ◽  
Artery Disease

The article presents the results of a cluster analysis of the contribution of immune inflammationmarkers and endothelial dysfunction (ED) to the cardiovascular complicationsfrequency and severity in cohorts of patients with asymptomatic atherosclerosis (AAS), coronary artery disease (CAD), tyepe 2 diabetes mellitus (T2DM) and metabolic syndrome (MS) during 3 years of prospective observation. A comparative analysis of the spectrum of the examined markers was performed depending on the stage of the development of the disease, the presence of T2DM and the MS. It was revealed that the greatest contribution to the cardiovascular complications development in AAS is provided by such circulating markers of ED and immune inflammation as ET-1, IL-1β, TNF-α, total autoantibodies to type I and III collagen (a-Coll) and to Chondroitine-sulfate (a-ChS). With IHD, the greatest contribution is provided by ET-1, eNOs, antibodies a-Coll and also IL-6 and vWf.In T2DM patients without CAD, a profile of markers associated with the high rate of adverse events includes ET-1, eNOs, IL-6, a-Coll and antibodies against hyaluronic acid (a-HA). In a cohort of patients with chronic CAD in the setting of T2DM, a profile of markers associated with the development of adverse events includes vWf, TNF-α, as well as the level of eNOs, IL-6, a-Coll, a-HA and CRP. In the cases of AAS without concomitant MS, the greatest contribution is due to the increase in the level of ET-1, vWf, a-Coll and a-ChS content; in the presence of MS — IL-1β, TNF-α, a-Coll, anti-ChS, anti-HA and CRP. In CAD without MS profile of markers associated with the development of adverse events, includes ET-1, eNOs and a-HA, the presence of the MS — a-Coll, ET-1 and IL-6 levels.

scholarly journals Risk of bronchospasm and coronary arteriospasm with sugammadex use: a post marketing analysis

2019 ◽  
Vol 10 ◽  
pp. 204209861986907 ◽  
Author(s):  
Pushkar Aggarwal
Keyword(s):  
Adverse Event ◽  
Adverse Events ◽  
Signal Analysis ◽  
Proportional Reporting Ratio ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Reporting Odds Ratio ◽  
Potential Association ◽  
Chi Squared ◽  
Post Marketing

Introduction: Sugammadex is used for the reversal of neuromuscular blockade caused by rocuronium bromide and vecuronium bromide. As part of the post licensing phase of drug development, adverse events related to the use of sugammadex are still being uncovered and being reported. The potential association between sugammadex and adverse events bronchospasm and coronary arteriospasm using a retrospective pharmacovigilance signal analysis was carried out. Methods: Food and Drug Administration’s Adverse Event Reporting System database was used to run disproportionality analyses to investigate the potential association of sugammadex with bronchospasm or coronary arteriospasm. In this analysis we report the adverse event signal using frequentist methods of Relative reporting ratio (RRR), proportional reporting ratio (PRR), reporting odds ratio (ROR) and the Bayesian based Information Component metric. Results: A statistically significant disproportionality signal is found between sugammadex and bronchospasm ( n = 44; chi-squared = 2993.87; PRR = 71.95 [95% CI: 54.00–95.85]) and sugammadex and coronary arteriospasm ( n = 6; chi-squared = 209.39; PRR = 43.82 [95% CI: 19.73–97.33]) as per Evans criteria. Both statistically significant disproportionality signals persisted when stratified by gender. Based upon dynamic cumulative PRR graph, the PRR value has steadily increased and the 95% CI narrowed since December 2012. Conclusion: The results of the pharmacovigilance analysis highlight a statistically significant disproportionality signal between sugammadex usage and bronchospasm and coronary arteriospasm adverse events. Physicians need to be aware of these adverse events when using sugammadex. The results of the pharmacovigilance signal analysis highlight a statistically significant disproportionality signal between sugammadex usage and bronchospasm and coronary arteriospasm adverse events. Physicians need to be aware of these adverse events when using sugammadex.

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
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