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https://www.readbyqxmd.com/read/29779852/treatment-of-progressive-multiple-sclerosis-challenges-and-promising-perspectives
#1
REVIEW
E Maillart
Management of progressive multiple sclerosis (MS) is one of the main challenges of the new century. Based on our knowledge of pathophysiology, three therapeutic strategies are proposed: anti-inflammatory (ocrelizumab, siponimod…); remyelinating (opicinumab); and neuroprotective (high-dose biotin, ibudilast, simvastatin…). Nevertheless, despite recent promising positive clinical trials, new methodological approaches for therapeutic protocols with adaptable outcomes to assess progression are still needed.
May 17, 2018: Revue Neurologique
https://www.readbyqxmd.com/read/29735753/metabolism-and-disposition-of-siponimod-a-novel-selective-s1p1-s1p5-agonist-in-healthy-volunteers-and-in-vitro-identification-of-human-cytochrome-p450-enzymes-involved-in-its-oxidative-metabolism
#2
Ulrike Glaenzel, Yi Jin, Robert Nufer, Wenkui Li, Kirsten Schroer, Sylvie Adam-Stitah, Sjoerd Peter van Marle, Eric Legangneux, Hubert Borell, Alexander David James, Axel Meissner, Gian Camenisch, Anne Gardin
Siponimod, a next generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism and excretion of a single oral dose of [14 C]siponimod 10 mg in four healthy male subjects. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29627873/disease-modifying-treatment-in-progressive-multiple-sclerosis
#3
REVIEW
John Robert Ciotti, Anne Haney Cross
PURPOSE OF REVIEW: Multiple sclerosis (MS) is an immune-mediated disorder that affects the central nervous system (CNS), often first affecting people in early adulthood. Although most MS patients have a relapsing-remitting course (RRMS) at disease onset, a substantial proportion later develop chronic progression, termed secondary progressive MS (SPMS). Approximately 10% of MS patients experience chronic progression from disease onset, termed primary progressive multiple sclerosis (PPMS)...
April 7, 2018: Current Treatment Options in Neurology
https://www.readbyqxmd.com/read/29576505/siponimod-versus-placebo-in-secondary-progressive-multiple-sclerosis-expand-a-double-blind-randomised-phase-3-study
#4
Ludwig Kappos, Amit Bar-Or, Bruce A C Cree, Robert J Fox, Gavin Giovannoni, Ralf Gold, Patrick Vermersch, Douglas L Arnold, Sophie Arnould, Tatiana Scherz, Christian Wolf, Erik Wallström, Frank Dahlke
BACKGROUND: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS. METHODS: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries...
March 22, 2018: Lancet
https://www.readbyqxmd.com/read/29556671/induction-of-hemangiosarcoma-in-mice-after-chronic-treatment-with-s1p-modulator-siponimod-and-its-lack-of-relevance-to-rat-and-human
#5
Francois Pognan, J Andreas Mahl, Maria Papoutsi, David Ledieu, Marc Raccuglia, Diethilde Theil, Sarah B Voytek, Patrick J Devine, Katie Kubek-Luck, Natalie Claudio, Andre Cordier, Annabelle Heier, Carine Kolly, Andreas Hartmann, Salah-Dine Chibout, Page Bouchard, Christian Trendelenburg
A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional antagonist, while no such tumors were observed in rats under the same treatment conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 and 75 mg/kg/day) in vivo mechanistic studies, vascular endothelial cell (VEC) activation was observed in both species, but VEC proliferation and persistent increases in circulating placental growth factor 2 (PLGF2) were only seen in the mouse...
March 19, 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29500302/oral-therapies-for-multiple-sclerosis
#6
Simon Faissner, Ralf Gold
Multiple sclerosis treatment faces tremendous changes owing to the approval of new medications, some of which are available as oral formulations. Until now, the four orally available medications, fingolimod, dimethylfumarate (BG-12), teriflunomide, and cladribine have received market authorization, whereas laquinimod is still under development. Fingolimod is a sphingosine-1-phosphate inhibitor, which is typically used as escalation therapy and leads to up to 60% reduction of the annualized relapse rate, but might also have neuroprotective properties...
March 2, 2018: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29310513/sphingosine-1-phosphate-receptor-subtype-1-s1pr1-as-a-therapeutic-target-for-brain-trauma
#7
Salvatore Cuzzocrea, Timothy Doyle, Michela Campolo, Irene Paterniti, Emanuela Esposito, Susan Farr, Daniela Salvemini
Traumatic brain injury (TBI) provokes secondary pathological mechanisms, including ischemic and inflammatory processes. The new research in sphingosine 1-phosphate (S1P) receptor modulators has opened the door for an effective mechanism of reducing central nervous system (CNS) inflammatory lesion activity. Thus, the aim of this study was to characterize the immunomodulatory effect of the functional S1PR1 antagonist siponimod in Phase III clinical trials for autoimmune disorders and of the competitive S1PR1 antagonist TASP0277308 in preclinical development in an in vivo model of TBI in mice...
January 8, 2018: Journal of Neurotrauma
https://www.readbyqxmd.com/read/29273968/in-vitro-studies-and-in-silico-predictions-of-fluconazole-and-cyp2c9-genetic-polymorphism-impact-on-siponimod-metabolism-and-pharmacokinetics
#8
Yi Jin, Hubert Borell, Anne Gardin, Mike Ufer, Felix Huth, Gian Camenisch
PURPOSE: The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism. METHODS: In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism...
April 2018: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29205338/s1p-receptor-antagonists-fingolimod-and-siponimod-do-not-improve-the-outcome-of-experimental-autoimmune-myasthenia-gravis-mice-after-disease-onset
#9
Andreas Pelz, Hanne Schaffert, Radharani Diallo, Falk Hiepe, Andreas Meisel, Siegfried Kohler
Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigue in the presence of circulating antibodies against components of the neuromuscular junction. Most patients have a good prognosis, but some are refractory to standard-of-care immunosuppressive treatment and suffer from recurrent myasthenic crises. Functional sphingosine-1-phosphate (S1P) antagonists like fingolimod and siponimod (BAF312) are successfully used for the treatment of multiple sclerosis, and fingolimod was shown to prevent the development of myasthenic symptoms in experimental autoimmune myasthenia gravis (EAMG), the standard model of MG...
March 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29138536/spotlight-on-siponimod-and-its-potential-in-the-treatment-of-secondary-progressive-multiple-sclerosis-the-evidence-to-date
#10
REVIEW
Alberto Gajofatto
Siponimod (BAF312) is a synthetic molecule belonging to the sphingosine-1-phosphate (S1P) modulator family, which has putative neuroprotective properties and well-characterized immunomodulating effects mediated by sequestration of B and T cells in secondary lymphoid organs. Compared to fingolimod (ie, precursor of the S1P modulators commercially available for the treatment of relapsing-remitting [RR] multiple sclerosis [MS]), siponimod exhibits selective affinity for types 1 and 5 S1P receptor, leading to a lower risk of adverse events that are mainly induced by S1P3 receptor activation, such as bradycardia and vasoconstriction...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29110882/substantial-disease-exacerbation-in-a-patient-with-relapsing-remitting-multiple-sclerosis-after-withdrawal-from-siponimod
#11
Tomasz Litwin, Łukasz Smoliński, Anna Członkowka
Among patients with multiple sclerosis, discontinuing highly effective disease-modifying treatments can potentially lead to severe disease recurrence, especially cessation of natalizumab and fingolimod. Similar to fingolimod, siponimod is a sphingosine-1-phosphate receptor modulator that inhibits the egress of a lymphocyte subpopulation from lymph nodes. In the present case report, we describe a patient with MS who experienced substantial disease exacerbation after withdrawal from siponimod.
January 2018: Neurologia i Neurochirurgia Polska
https://www.readbyqxmd.com/read/28990207/a-review-of-bioanalytical-quantitative-methods-for-selected-sphingosine-1-phosphate-receptor-modulators
#12
REVIEW
Ranjeet Prasad Dash, Nuggehally R Srinivas, Rana Rais
Sphingosine 1-phosphate (S1P1 ) modulators provide an emerging therapeutic approach for various autoimmune disorders such as multiple sclerosis and psoriasis. Fingolimod is the first approved orally active, selective and potent drug of this class. Other drugs belonging to this class include siponimod, ponesimod, ceralifimod, amiselimod, CS-0777 and GSK2018682. However, owing to the high protein binding, polarity and zwitter-ionic nature of the phosphate metabolite of parent drugs, it becomes challenging to optimize the extraction method for this class of compounds...
January 2018: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28955715/impact-of-siponimod-on-vaccination-response-in-a-randomized-placebo-controlled-study
#13
Mike Ufer, Kasra Shakeri-Nejad, Anne Gardin, Zhenzhong Su, Ines Paule, Thomas C Marbury, Eric Legangneux
OBJECTIVE: To evaluate effects of siponimod on response to T-cell-dependent (influenza) and T-cell-independent (pneumococcal polysaccharide vaccine [PPV-23]) vaccinations in healthy participants. METHODS: In this double-blind, placebo-controlled, parallel-group study, each participant underwent a 7-week treatment period and received intramuscular injections of influenza and PPV-23 vaccines (day 21). Participants were randomized to 4 treatment groups (N = 30 each) and received placebo or siponimod 2 mg once daily in concomitant, interrupted, or preceding fashion...
November 2017: Neurology® Neuroimmunology & Neuroinflammation
https://www.readbyqxmd.com/read/28812220/sphingosine-1-phosphate-receptor-modulators-for-the-treatment-of-multiple-sclerosis
#14
REVIEW
Burhan Z Chaudhry, Jeffrey A Cohen, Devon S Conway
Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability...
October 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/28752787/the-xenopus-tadpole-an-in-vivo-model-to-screen-drugs-favoring-remyelination
#15
Abdelkrim Mannioui, Quentin Vauzanges, Jean Baptiste Fini, Esther Henriet, Somya Sekizar, Loris Azoyan, Jean Léon Thomas, David Du Pasquier, Carine Giovannangeli, Barbara Demeneix, Catherine Lubetzki, Bernard Zalc
BACKGROUND: In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely. OBJECTIVE: A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules. METHODS: In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes...
July 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/28283111/is-multiple-sclerosis-a-length-dependent-central-axonopathy-the-case-for-therapeutic-lag-and-the-asynchronous-progressive-ms-hypotheses
#16
REVIEW
Gavin Giovannoni, Gary Cutter, Maria Pia Sormani, Shibeshih Belachew, Robert Hyde, Harold Koendgen, Volker Knappertz, Davorka Tomic, David Leppert, Robert Herndon, Claudia A M Wheeler-Kingshott, Olga Ciccarelli, David Selwood, Elisabetta Verdun di Cantogno, Ali-Frederic Ben-Amor, Paul Matthews, Daniele Carassiti, David Baker, Klaus Schmierer
Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms...
February 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/27934627/characterization-and-prediction-of-cardiovascular-effects-of-fingolimod-and-siponimod-using-a-systems-pharmacology-modeling-approach
#17
Nelleke Snelder, Bart A Ploeger, Olivier Luttringer, Dean F Rigel, Randy L Webb, David Feldman, Fumin Fu, Michael Beil, Liang Jin, Donald R Stanski, Meindert Danhof
Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action (i.e., primary hemodynamic response variable) of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once-daily fingolimod (0, 0.1, 0.3, 1, 3, and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats...
February 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27566665/siponimod-baf312-prevents-synaptic-neurodegeneration-in-experimental-multiple-sclerosis
#18
Antonietta Gentile, Alessandra Musella, Silvia Bullitta, Diego Fresegna, Francesca De Vito, Roberta Fantozzi, Eleonora Piras, Francesca Gargano, Giovanna Borsellino, Luca Battistini, Anna Schubart, Georgia Mandolesi, Diego Centonze
BACKGROUND: Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients...
August 26, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27443658/pharmacokinetics-safety-and-tolerability-of-siponimod-baf312-in-subjects-with-different-levels-of-hepatic-impairment-a-single-dose-open-label-parallel-group-study%C3%A2
#19
Kasra Shakeri-Nejad, Vassilios Aslanis, Uday Kiran Veldandi, Anne Gardin, Andreas Zaehringer, Angela Dodman, Zhenzhong Su, Eric Legangneux
OBJECTIVE: To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS). METHODS: This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI...
January 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27380540/safety-and-efficacy-of-siponimod-baf312-in-patients-with-relapsing-remitting-multiple-sclerosis-dose-blinded-randomized-extension-of-the-phase-2-bold-study
#20
RANDOMIZED CONTROLLED TRIAL
Ludwig Kappos, David K B Li, Olaf Stüve, Hans-Peter Hartung, Mark S Freedman, Bernhard Hemmer, Peter Rieckmann, Xavier Montalban, Tjalf Ziemssen, Brian Hunter, Sophie Arnould, Erik Wallström, Krzysztof Selmaj
IMPORTANCE: This dose-blinded extension of the phase 2 BOLD (BAF312 on MRI Lesion Given Once Daily) Study in relapsing-remitting multiple sclerosis provides evidence on disease activity and safety of a range of siponimod doses for up to 24 months. OBJECTIVE: To assess the safety and efficacy of siponimod for up to 24 months during the dose-blinded extension of the BOLD Study. DESIGN, SETTING, AND PARTICIPANTS: At extension baseline in a randomized clinical trial, patients taking siponimod continued at the originally assigned dose and patients taking placebo were rerandomized to the 5 siponimod doses...
September 1, 2016: JAMA Neurology
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