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https://www.readbyqxmd.com/read/27890706/the-sphingosine-1-phosphate-receptor-a-novel-therapeutic-target-for-multiple-sclerosis-and-other-autoimmune-diseases
#1
REVIEW
Yang Mao-Draayer, Jeffrey Sarazin, David Fox, Elena Schiopu
Multiple sclerosis (MS) is a prototype autoimmune disease of the central nervous system (CNS). Currently, there is no drug that provides a cure for MS. To date, all immunotherapeutic drugs target relapsing remitting MS (RR-MS); it remains a daunting medical challenge in MS to develop therapy for secondary progressive MS (SP-MS). Since the approval of the non-selective sphingosine-1-phosphate (S1P) receptor modulator FTY720 (fingolimod [Gilenya®]) for RR-MS in 2010, there have been many emerging studies with various selective S1P receptor modulators in other autoimmune conditions...
November 23, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27864936/effect-of-sphingosine-kinase-modulators-on-interleukin-1%C3%AE-release-sphingosine-1-phosphate-receptor-1-expression-and-experimental-autoimmune-encephalomyelitis
#2
Mark Barbour, Melissa McNaughton, Stephanie D Boomkamp, Neil MacRitchie, Hui-Rong Jiang, Nigel J Pyne, Susan Pyne
BACKGROUND AND PURPOSE: The sphingosine analogue, FTY720 (Gilenya(R) ) alleviates clinical disease progression in multiple sclerosis. Here we variously assessed the effects of an azide analogue of (S)-FTY720 vinylphosphonate (compound 5; a sphingosine kinase 1 activator), (R)-FTY720 methyl ether (ROMe, a sphingosine kinase 2 inhibitor) and RB-020 (a sphingosine kinase 1 inhibitor and sphingosine kinase 2 substrate) on IL-1β formation, sphingosine 1-phosphate levels and S1P1 expression...
November 16, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27699272/effects-of-sphingosine-1-phosphate-receptor-1-phosphorylation-in-response-to-fty720-during-neuroinflammation
#3
Hsing-Chuan Tsai, Yingxiang Huang, Christopher S Garris, Monica A Moreno, Christina W Griffin, May H Han
Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human S1PR1 variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defective S1pr1 gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG35-55-immunized and Th17-mediated experimental autoimmune encephalomyelitis (EAE) models...
June 16, 2016: JCI Insight
https://www.readbyqxmd.com/read/27663260/to-fingolimod-and-beyond-the-rich-pipeline-of-drug-candidates-that-target-s1p-signaling
#4
REVIEW
Wee Siong Chew, Wei Wang, Deron R Herr
Sphingosine 1-phosphate (S1P) is an extracellular lipid signaling molecule that acts as a selective, high-affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on S1P receptors, primarily on S1P receptor 1 (S1P1)...
November 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27645342/cryptococcal-meningitis-after-fingolimod-discontinuation-in-a-patient-with-multiple-sclerosis
#5
Melanie D Ward, David E Jones, Myla D Goldman
Fingolimod (Gilenya, Novartis) is an oral sphingosine-1-phosphate analogue used in the treatment of relapsing multiple sclerosis (MS). Fingolimod treatment is associated with relative lymphopenia and was associated with an increased risk of herpes infection in clinical trials. In the post-marketing setting, fingolimod has been associated with several cases of cryptococcal meningitis, recently prompting an update to its prescribing information. To date, all cases have been associated with active treatment with fingolimod...
September 2016: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/27611691/preclinical-metabolism-pharmacokinetics-and-in-vivo-analysis-of-new-blood-brain-barrier-penetrant-fingolimod-analogues-fty720-c2-and-fty720-mitoxy
#6
Julius O Enoru, Barbara Yang, Sesha Krishnamachari, Ernesto Villanueva, William DeMaio, Adiba Watanyar, Ramesh Chinnasamy, Jeffrey B Arterburn, Ruth G Perez
Parkinson's disease (PD) is a neurodegenerative aging disorder in which postmortem PD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A) enzymatic activity loss. Based on our translational research, we began evaluating the PD-repurposing-potential of an anti-inflammatory, neuroprotective, and PP2A stimulatory oral drug that is FDA-approved for multiple sclerosis, FTY720 (fingolimod, Gilenya®). We also designed two new FTY720 analogues, FTY720-C2 and FTY720-Mitoxy, with modifications that affect drug potency and mitochondrial localization, respectively...
2016: PloS One
https://www.readbyqxmd.com/read/27528608/fty720-fingolimod-reduces-synucleinopathy-and-improves-gut-motility-in-a53t-mice-contributions-of-pro-brain-derived-neurotrophic-factor-pro-bdnf-and-mature-bdnf
#7
Guadalupe Vidal-Martínez, Javier Vargas-Medrano, Carolina Gil-Tommee, David Medina, Nathan T Garza, Barbara Yang, Ismael Segura-Ulate, Samantha J Dominguez, Ruth G Perez
Patients with Parkinson's disease (PD) often have aggregated α-synuclein (aSyn) in enteric nervous system (ENS) neurons, which may be associated with the development of constipation. This occurs well before the onset of classic PD motor symptoms. We previously found that aging A53T transgenic (Tg) mice closely model PD-like ENS aSyn pathology, making them appropriate for testing potential PD therapies. Here we show that Tg mice overexpressing mutant human aSyn develop ENS pathology by 4 months. We then evaluated the responses of Tg mice and their WT littermates to the Food and Drug Administration-approved drug FTY720 (fingolimod, Gilenya) or vehicle control solution from 5 months of age...
September 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27502119/study-design-of-pangaea-2-0-a-non-interventional-study-on-rrms-patients-to-be-switched-to-fingolimod
#8
Tjalf Ziemssen, Raimar Kern, Christian Cornelissen
BACKGROUND: The therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased due to the approval of new substances that now supplement traditional first-line agents, demanding a paradigm shift in the assessment of disease activity and treatment response in clinical routine. Here, we report the study design of PANGAEA 2.0 (Post-Authorization Non-interventional GermAn treatment benefit study of GilEnyA in MS patients), a non-interventional study in patients with relapsing-remitting MS (RRMS) identify patients with disease activity and monitor their disease course after treatment switch to fingolimod (Gilenya®), an oral medication approved for patients with highly active RRMS...
August 8, 2016: BMC Neurology
https://www.readbyqxmd.com/read/27439747/effects-of-fingolimod-administration-in-a-genetic-model-of-cognitive-deficits
#9
D Becker-Krail, A Q Farrand, H A Boger, A Lavin
Notwithstanding recent advances, cognitive impairments are among the most difficult-to-treat symptoms in neuropsychiatric disorders. Deficits in information processing contributing to memory and sociability impairments are found across neuropsychiatric-related disorders. Previously, we have shown that mutations in the DTNBP1 gene (encoding dystrobrevin-binding protein 1 [dysbindin-1]) lead to abnormalities in synaptic glutamate release in the prefrontal cortex (PFC) and hippocampus and to cognitive deficits; glutamatergic transmission is important for cortical recurrent excitation that allows information processing in the PFC...
July 20, 2016: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/27258401/from-natural-product-to-the-first-oral-treatment-for-multiple-sclerosis-the-discovery-of-fty720-gilenya%C3%A2
#10
REVIEW
Frédéric J Zécri
Multiple sclerosis is a devastating chronic autoimmune disease affecting women and men of all ages. Inflammation of the central nervous system causes demyelination and ultimately neuropsychological dysfunction. Myriocin, a natural product with strong immunosuppressant activity was interrogated leading to a new class of immunomodulator with a unique mode of action. In this review, we will summarize these findings, the mechanism hypothesis and discuss the data's ultimately leading to the approval of Gilenya™ as the first oral treatment for multiple sclerosis...
June 2016: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/27006700/fingolimod-in-the-treatment-of-relapsing-remitting-multiple-sclerosis-long-term-experience-and-an-update-on-the-clinical-evidence
#11
REVIEW
Bhupendra O Khatri
Since the approval in 2010 of fingolimod 0.5 mg (Gilenya; Novartis Pharma AG, Basel, Switzerland) in the USA as an oral therapy for relapsing forms of multiple sclerosis, long-term clinical experience with this therapy has been increasing. This review provides a summary of the cumulative dataset from clinical trials and their extensions, plus postmarketing studies that contribute to characterizing the efficacy and safety profile of fingolimod in patients with relapsing forms of multiple sclerosis. Data from the controlled, phase III, pivotal studies [FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis), FREEDOMS II and TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis)] in relapsing-remitting multiple sclerosis have shown that fingolimod has a robust effect on clinical and magnetic resonance imaging outcomes...
March 2016: Therapeutic Advances in Neurological Disorders
https://www.readbyqxmd.com/read/26990079/ozanimod-rpc1063-is-a-potent-sphingosine-1-phosphate-receptor-1-s1p1-and-receptor-5-s1p5-agonist-with-autoimmune-disease-modifying-activity
#12
F L Scott, B Clemons, J Brooks, E Brahmachary, R Powell, H Dedman, H G Desale, G A Timony, E Martinborough, H Rosen, E Roberts, M F Boehm, R J Peach
BACKGROUND AND PURPOSE: Sphingosine1-phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P1 receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non-selective S1P modulator, FTY720 (fingolimod, Gilenya™)...
June 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/26985316/identification-and-preclinical-pharmacology-of-bms-986104-a-differentiated-s1p1-receptor-modulator-in-clinical-trials
#13
T G Murali Dhar, Hai-Yun Xiao, Jenny Xie, Lois D Lehman-McKeeman, Dauh-Rurng Wu, Marta Dabros, Xiaoxia Yang, Tracy L Taylor, Xia D Zhou, Elizabeth M Heimrich, Rochelle Thomas, Kim W McIntyre, Bethanne Warrack, Hong Shi, Paul C Levesque, Jia L Zhu, James Hennan, Praveen Balimane, Zheng Yang, Anthony M Marino, Georgia Cornelius, Celia J D'Arienzo, Arvind Mathur, Ding Ren Shen, Mary Ellen Cvijic, Luisa Salter-Cid, Joel C Barrish, Percy H Carter, Alaric J Dyckman
Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model...
March 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26981780/ruxolitinib-synergizes-with-dmf-to-kill-via-bim-bad-induced-mitochondrial-dysfunction-and-via-reduced-sod2-trx-expression-and-ros
#14
Mehrad Tavallai, Laurence Booth, Jane L Roberts, William P McGuire, Andrew Poklepovic, Paul Dent
We determined whether the myelofibrosis drug ruxolitinib, an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could interact with the multiple sclerosis drug dimethyl-fumarate (DMF) to kill tumor cells; studies used the in vivo active form of the drug, mono-methyl fumarate (MMF). Ruxolitinib interacted with MMF to kill brain, breast, lung and ovarian cancer cells, and enhanced the lethality of standard of care therapies such as paclitaxel and temozolomide. MMF also interacted with other FDA approved drugs to kill tumor cells including Celebrex® and Gilenya®...
April 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/26950691/potential-anti-tumor-effects-of-fty720-associated-with-pp2a-activation-a-brief-review
#15
Ion Cristóbal, Juan Madoz-Gúrpide, Rebeca Manso, Paula González-Alonso, Federico Rojo, Jesús García-Foncillas
FTY720 (Fingolimod, Gilenya (†) ) is an FDA-approved immunosuppressant currently used in the treatment of multiple sclerosis. However, a large number of studies over the last few years have shown that FTY720 shows potent antitumor properties that suggest its potential usefulness as a novel anticancer agent. Interestingly, the restoration of protein phosphatase 2A (PP2A) activity mediated by FTY720 could play a key role in its antitumor effects. Taking into account that PP2A inactivation is a common event that determines poor outcome in several tumor types, FTY720 could serve as an alternative therapeutic strategy for cancer patients with such alterations...
June 2016: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/26899449/role-of-dimethyl-fumarate-in-oxidative-stress-of-multiple-sclerosis-a-review
#16
A Suneetha, K Raja Rajeswari
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS affecting both white and grey matter. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis. Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment...
April 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/26890887/canadian-experience-with-fingolimod-adherence-to-treatment-and-monitoring
#17
Yves Lapierre, Paul O'Connor, Virginia Devonshire, Mark S Freedman, Marcelo Kremenchutzky, Michael Yeung, Robyn Schecter
BACKGROUND: The Canadian GILENYA® Go ProgramTM provides education and support to people with relapsing-remitting multiple sclerosis during fingolimod treatment. METHODS: Data were collected and analyzed from the time of the first individual enrolled in March 2011 to March 31, 2014. Individuals were excluded if they withdrew from the program prior to receiving the first dose, or had not completed the first dose observation (FDO) at the time of data cut-off. Reports of adverse effects were validated with a database of adverse events reported to Novartis Pharmaceuticals Canada Inc...
March 2016: Canadian Journal of Neurological Sciences. le Journal Canadien des Sciences Neurologiques
https://www.readbyqxmd.com/read/26856942/the-management-and-outcomes-of-fingolimod-first-dose-cardiac-monitoring-in-uk-patients-with-relapsing-remitting-multiple-sclerosis
#18
Joe Datt, Laura Baldock, Emily Pull, Bryn Webber
BACKGROUND: Patients initiated on Gilenya (fingolimod) require cardiovascular monitoring for 6h after the first dose. Novartis has engaged an independent provider (Regent's Park Heart Clinics [RPHC]) to provide a first dose observation (FDO) service to UK neurologists. OBJECTIVES: To describe routinely-documented clinical observations (heart rate [HR], blood pressure [BP], cardiac rhythm [CR]) and outcomes from the RPHC fingolimod FDO service. METHODS: Pseudonymised data (clinical observations pre-dose and for 6h after the first dose and any requirement for extended monitoring) were collected retrospectively from RPHC records for the first 850 RPHC FDO episodes (undertaken Jul-2012 to Jan-2015)...
January 2016: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/26513477/akp-11-a-novel-s1p1-agonist-with-favorable-safety-profile-attenuates-experimental-autoimmune-encephalomyelitis-in-rat-model-of-multiple-sclerosis
#19
Devadoss J Samuvel, Nishant Saxena, Jasdeep S Dhindsa, Avtar K Singh, Gurmit S Gill, Damian W Grobelny, Inderjit Singh
Sphingosine-1-phosphate receptor 1 (S1P1) mediated regulation of lymphocyte egress from lymphoid organs is recognized as the mechanism of FTY720 (Fingolimod, Gilenya) efficacy in relapsing-remitting forms of multiple sclerosis (RRMS). In this study we describe a novel S1P1 agonist AKP-11, next generation of S1P1 agonist, with immunomodulatory activities in cell culture model and for therapeutic efficacy against an animal model of MS, i.e. experimental autoimmune encephalomyelitis (EAE) but without the adverse effects observed with FTY720...
2015: PloS One
https://www.readbyqxmd.com/read/26199353/assessing-pml-risk-under-immunotherapy-if-all-you-have-is-a-hammer-everything-looks-like-a-nail
#20
Jeroen Van Schependom, Jeroen Gielen, Jorne Laton, Guy Nagels
Recently, three progressive multifocal leukoencephalopathy (PML) cases have been reported in multiple sclerosis (MS) patients, two treated with fingolimod (Gilenya, Novartis), the third with dimethyl fumarate (Tecfidera, Biogen). Because our immunotherapeutic arsenal in MS and other diseases is increasing, and because PML is a very serious health risk, it is of interest to the clinical community to show how we can assess this risk in a statistically sound way. The null-hypothesis for this analysis was that there is no elevated risk for PML in patients treated with one of these recent drugs, compared to the incidence in the general population...
March 2016: Multiple Sclerosis: Clinical and Laboratory Research
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