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https://www.readbyqxmd.com/read/29274026/clinical-and-demographic-profile-of-patients-receiving-fingolimod-in-clinical-practice-in-germany-and-the-benefit-risk-profile-of-fingolimod-after-1-year-of-treatment-initial-results-from-the-observational-noninterventional-study-pangaea
#1
Tjalf Ziemssen, Michael Lang, Björn Tackenberg, Stephan Schmidt, Holger Albrecht, Luisa Klotz, Judith Haas, Christoph Lassek, Jennie Medin, Christian Cornelissen
The population with multiple sclerosis receiving treatment in clinical practice differs from that in randomized controlled trials (RCTs). An assessment of the real-world benefit-risk profile of therapies is needed. This analysis used data from the large, noninterventional, observational German study Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) to assess prospectively baseline characteristics and outcomes after 12 months (± 90 days) of fingolimod treatment. Patients were divided into 2 cohorts: fingolimod starter [first received fingolimod in PANGAEA (n = 3315)] and previous study [received fingolimod before enrollment in PANGAEA in RCTs (n = 875), some of whom also had baseline data at entry into RCTs (n = 505)]...
December 22, 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/29226621/cenerimod-a-novel-selective-s1p1-receptor-modulator-with-unique-signaling-properties
#2
Luca Piali, Magdalena Birker-Robaczewska, Cyrille Lescop, Sylvie Froidevaux, Nicole Schmitz, Keith Morrison, Christopher Kohl, Markus Rey, Rolf Studer, Enrico Vezzali, Patrick Hess, Martine Clozel, Beat Steiner, Martin H Bolli, Oliver Nayler
Sphingosine-1-phosphate receptor 1 (S1P1 ) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues. S1P1 receptor modulation may thus offer potential to treat various autoimmune diseases. The first nonselective S1P1-5 receptor modulator FTY720/fingolimod/Gilenya® has successfully demonstrated clinical efficacy in relapsing forms of multiple sclerosis. However, cardiovascular, hepatic, and respiratory side-effects were reported and there is a need for novel S1P1 receptor modulators with better safety profiles...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29127024/the-sphingosine-1-phosphate-receptor-modulator-fingolimod-as-a-therapeutic-agent-recent-findings-and-new-perspectives
#3
REVIEW
Andrea Huwiler, Uwe Zangemeister-Wittke
The immunomodulatory drug fingolimod (FTY720, Gilenya(R)) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P1 subtype by induction of receptor downregulation. Since S1P1 is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression...
November 7, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28738875/effects-of-fty720-on-brain-neurogenic-niches-in-vitro-and-after-kainic-acid-induced-injury
#4
Raffaela Cipriani, Juan Carlos Chara, Alfredo Rodríguez-Antigüedad, Carlos Matute
BACKGROUND: FTY720 (fingolimod, Gilenya™) is an oral, blood-brain barrier (BBB)-passing drug approved as immunomodulatory treatment for relapsing-remitting form of the multiple sclerosis (MS). In addition, FTY720 exerts several effects in the central nervous system (CNS), ranging from neuroprotection to reduction of neuroinflammation. However, the neurogenic and oligodendrogenic potential of FTY720 has been poorly investigated. In this study, we assessed the effect of FTY720 on the production of new neurons and oligodendrocytes from neural stem/precursor cells both in vitro and in vivo...
July 24, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28299825/fingolimod-gilenya-%C3%A2-in-multiple-sclerosis-bradycardia-atrioventricular-blocks-and-mild-effect-on-the-qtc-interval-something-to-do-with-the-l-type-calcium-channel
#5
Sylvie Pilote, Chantale Simard, Benoit Drolet
Cardiac arrhythmias and ECG abnormalities including bradycardia, prolongation of the QT interval, and atrioventricular (AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing-remitting form of multiple sclerosis. This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo, and (iii) in vivo. (i) Patch-clamp experiments in whole cell configuration were performed on Cav 1...
August 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28240814/an-engineered-macroencapsulation-membrane-releasing-fty720-to-precondition-pancreatic-islet-transplantation
#6
Daniel T Bowers, Claire E Olingy, Preeti Chhabra, Linda Langman, Parker H Merrill, Ritu S Linhart, Michael L Tanes, Dan Lin, Kenneth L Brayman, Edward A Botchwey
Macroencapsulation is a powerful approach to increase the efficiency of extrahepatic pancreatic islet transplant. FTY720, a small molecule that activates signaling through sphingosine-1-phosphate receptors, is immunomodulatory and pro-angiogenic upon sustained delivery from biomaterials. While FTY720 (fingolimod, Gilenya) has been explored for organ transplantation, in the present work the effect of locally released FTY720 from novel nanofiber-based macroencapsulation membranes is explored for islet transplantation...
February 27, 2017: Journal of Biomedical Materials Research. Part B, Applied Biomaterials
https://www.readbyqxmd.com/read/28153532/fty720-fingolimod-reverses-%C3%AE-synuclein-induced-downregulation-of-brain-derived-neurotrophic-factor-mrna-in-oln-93-oligodendroglial-cells
#7
Ismael Segura-Ulate, Barbara Yang, Javier Vargas-Medrano, Ruth G Perez
Multiple system atrophy (MSA) is a demyelinating neurodegenerative disorder characterized by accumulation of aggregated α-synuclein (aSyn) inside oligodendrocyte precursors, mature oligodendroglia, and neurons. MSA dysfunction is associated with loss of trophic factor production by glial and neuronal cells. Here, we report that recombinant wild type human aSyn uptake by OLN-93, an oligodendroglia cell-line, reduced brain-derived neurotrophic factor (BDNF) expression. Furthermore, OLN-93 cells stably transfected with human wild type or an MSA-associated mutant aSyn, A53E that produces neuronal and glial inclusions, reduced BDNF mRNA to nearly unmeasurable qPCR levels...
May 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28003234/fingolimod-gilenya-and-melanoma
#8
Christopher Lee Robinson, Mary Guo
The Food and Drug Administration (FDA) had approved fingolimod usage for multiple sclerosis in 2010. Melanoma after the usage of fingolimod immunomodulation was reported rarely in clinical trials, and only two case reports exist in the published literature, both occurring in Europe. Most of the incidences reported in clinical trials were in-situ, whereas both case reports were of malignant melanoma. Fingolimod has been found to inhibit metastatic melanoma growth in a mouse model that depends on vascular endothelial growth factor (VEGF)-induced angiogenesis for metastasis...
December 21, 2016: BMJ Case Reports
https://www.readbyqxmd.com/read/27890706/the-sphingosine-1-phosphate-receptor-a-novel-therapeutic-target-for-multiple-sclerosis-and-other-autoimmune-diseases
#9
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...
February 2017: 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
#10
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 expression of S1P1 receptors...
January 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27699272/effects-of-sphingosine-1-phosphate-receptor-1-phosphorylation-in-response-to-fty720-during-neuroinflammation
#11
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
#12
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
#13
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
#14
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
#15
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
#16
MULTICENTER STUDY
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
#17
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...
May 2017: 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
#18
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
#19
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
#20
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
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