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Alice Laroni, Davide Brogi, Vincenzo Brescia Morra, Leonello Guidi, Carlo Pozzilli, Giancarlo Comi, Alessandra Lugaresi, Renato Turrini, Debora Raimondi, Antonio Uccelli, Giovanni Luigi Mancardi
: The safety profile of fingolimod is well established in clinical trials and post-marketing studies. This study aimed to evaluate the safety and tolerability of fingolimod in a cohort of Italian patients with relapsing-remitting multiple sclerosis (RRMS). This is a non-comparative, open-label, multicentre, interventional study conducted in patients with RRMS with no suitable alternative treatment option. Safety and tolerability of fingolimod 0.5 mg were assessed by recording adverse events (AEs) and serious AEs (SAEs)...
October 18, 2016: Neurological Sciences
Chihiro Fujii, Takayuki Kondo, Hirofumi Ochi, Yoichiro Okada, Yuichiro Hashi, Tetsuya Adachi, Masaharu Shin-Ya, Sadayuki Matsumoto, Ryosuke Takahashi, Masanori Nakagawa, Toshiki Mizuno
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease. Fingolimod, a highly effective disease-modifying drug for MS, retains CCR7(+) central memory T cells in which autoaggressive T cells putatively exist, in secondary lymphoid organs, although relapse may still occur in some patients. Here, we analyzed the T cell phenotypes of fingolimod-treated, fingolimod-untreated patients, and healthy subjects. The frequency of CD56(+) T cells and granzyme B-, perforin-, and Fas ligand-positive T cells significantly increased during fingolimod treatment...
October 18, 2016: Scientific Reports
Jennifer N Hahn, Deepak K Kaushik, Manoj K Mishra, Jianxiong Wang, Claudia Silva, V Wee Yong
Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial...
October 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Robert J Fox, Andrew Chan, Annie Zhang, James Xiao, Dane Levison, James B Lewin, Michael R Edwards, Jing L Marantz
Objective Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) and fingolimod are approved oral disease-modifying treatments for relapsing-remitting multiple sclerosis. In phase 3 trials, DMF (DEFINE/CONFIRM) and fingolimod (FREEDOMS/FREEDOMS II) resulted in significant reductions in clinical and magnetic resonance imaging activity, with acceptable safety profiles. Direct comparisons of these treatments are not possible due to a lack of head-to-head trials. We compared 2-year efficacy of DMF versus fingolimod at the approved dosage using a matching-adjusted indirect approach...
October 13, 2016: Current Medical Research and Opinion
Michael A Mancano
The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: Your report will be published anonymously unless otherwise requested...
November 2015: Hospital Pharmacy
Hai-Yun Xiao, Scott H Watterson, Charles M Langevine, Anurag S Srivastava, Soo S Ko, Yanlei Zhang, Robert Joseph Cherney, Weiwei Guo, John L Gilmore, James E Sheppeck, Dauh-Rurng Wu, Peng Li, Duraisamy Ramasamy, Pirama Nayagam Arunachalam, Arvind Mathur, Tracy L Taylor, David J Shuster, Kim W McIntyre, Ding Ren Shen, Melissa Yarde, Mary Ellen Cvijic, Anthony M Marino, Praveen V Balimane, Zheng Yang, Dana M Banas, Georgia Cornelius, Celia J D Arienzo, Bethanne M Warrack, Lois D Lehman-McKeeman, Luisa M Salter-Cid, Jenny H Xie, Joel C Barrish, Percy H Carter, Alaric J Dyckman, T G Murali Dhar
Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a non-selective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes...
October 11, 2016: Journal of Medicinal Chemistry
Chiara Fenoglio, Milena De Riz, Anna M Pietroboni, Alberto Calvi, Maria Serpente, Sara M G Cioffi, Marina Arcaro, Emanuela Oldoni, Elio Scarpini, Daniela Galimberti
MicroRNAs (miRNAs) have recently found to be dysregulated in serum from multiple sclerosis (MS) patients. Cell free circulating miR-15b, -23a and 223 levels were analyzed by Real Time PCR in a cohort consisting of 30 serum samples from Relapsing Remitting MS patients at baseline (T0) and after three, six, nine and twelve months (T1, T2, T3, T4) after starting the treatment. A down-regulation of miRNA levels in patients at T0 compared with controls was present (p<0.001). MiRNA levels slightly increased at T1 and this trend reached the statistical significance at T2 vs T0 and remains stable at T3 and T4...
October 15, 2016: Journal of Neuroimmunology
Chiara Cordiglieri, Fulvio Baggi, Pia Bernasconi, Dimos Kapetis, Elisa Faggiani, Alessandra Consonni, Francesca Andreetta, Rita Frangiamore, Paolo Confalonieri, Carlo Antozzi, Renato Mantegazza
Multiple Sclerosis (MS) is an inflammatory disease with neurodegenerative alterations, ultimately progressing to neurological handicap. Therapies are effective in counteracting inflammation but not neurodegeneration. Biomarkers predicting disease course or treatment response are lacking. We investigated whether altered gene and protein expression profiles were detectable in the peripheral blood of 78 relapsing remitting MS (RR-MS) patients treated by disease-modifying therapies. A discovery/validation study on RR-MS responsive to glatiramer acetate identified 8 differentially expressed genes: ITGA2B, ITGB3, CD177, IGJ, IL5RA, MMP8, P2RY12, and S100β...
October 5, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
K Sugahara, Y Maeda, K Shimano, A Mogami, H Kataoka, K Ogawa, K Hikida, H Kumagai, M Asayama, T Yamamoto, T Harada, P Ni, S Inoue, A Kawaguchi
BACKGROUND AND PURPOSE: We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT-1303), a second-generation sphingosine 1-phosphate (S1P) receptor modulator, designed to reduce the bradycardia effects associated with fingolimod and other S1P receptor modulators. EXPERIMENTAL APPROACH: The selectivity of the active metabolite amiselimod phosphate (amiselimod-P) for human S1P receptors and activation of the G-protein-coupled inwardly rectifying potassium (GIRK) channel in human atrial myocytes were assessed...
October 7, 2016: British Journal of Pharmacology
Alessandra Bua, Melania Ruggeri, Stefania Zanetti, Paola Molicotti
Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by damage to myelin and axons, over time leading to progressive neuronal degeneration and microglial activation. There is still no curative treatment, but during the last 20 years eight different therapies have become available including interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab, fingolimod, alemtuzumab, mitoxantrone and teriflunomide. Teriflunomide is an immunomodulatory drug that exerts an inhibitory effect on T cell activation in central nervous system of the patients with multiple sclerosis...
October 4, 2016: Medical Microbiology and Immunology
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
Emanuele D'Amico, Aurora Zanghì, Carmela Leone, Hayrettin Tumani, Francesco Patti
Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by the John Cunningham virus (JCV) that has been associated with therapeutic immunosuppression in patients with multiple sclerosis (MS). So far, more than 600 cases of PML have been reported in association with natalizumab administration. There have also been confirmed cases of PML in individuals who received fingolimod and dimethyl fumarate without previous natalizumab treatment. The new licensed disease-modifying therapies for MS carry the risk of immunosuppressant and so of JCV reactivation...
September 30, 2016: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Saskia M Leibowitz, Jun Yan
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways are involved in cell immune responses, apoptosis and infections. In multiple sclerosis (MS), NF-κB pathways are changed, leading to increased levels of NF-κB activation in cells. This may indicate a key role for NF-κB in MS pathogenesis. NF-κB signaling is complex, with many elements involved in its activation and regulation. Interestingly, current MS treatments are found to be directly or indirectly linked to NF-κB pathways and act to adjust the innate and adaptive immune system in patients...
2016: Frontiers in Molecular Neuroscience
Georgios Tsivgoulis, Aristeidis H Katsanos, Dimitris Mavridis, Nikolaos Grigoriadis, Efthymios Dardiotis, Ioannis Heliopoulos, Panagiotis Papathanasopoulos, Theodoros Karapanayiotides, Constantinos Kilidireas, Georgios M Hadjigeorgiou, Konstantinos Voumvourakis
BACKGROUND: Although Fingolimod (FGD) and Natalizumab (NTZ) appear to be effective in relapsing-remitting multiple sclerosis (RRMS), they have never been directly compared in a randomized clinical trial (RCT). METHODS AND FINDINGS: We evaluated the comparative efficacy of FGD vs. NTZ using a meta-analytical approach. Data from placebo-controlled RCTs was used for indirect comparisons and observational data was utilized for head-to-head comparisons. We identified 3 RCTs (2498 patients) and 5 observational studies (2576 patients)...
2016: PloS One
Tara Nazareth, Howard S Friedman, Prakash Navaratnam, Denise A Herriott, John J Ko, Peri Barr, Rahul Sasane
BACKGROUND: In the US, the approved multiple sclerosis (MS) oral disease-modifying therapies (ODMTs) are fingolimod (FTY), teriflunomide (TFN), and dimethyl fumarate (DMF). FTY and TFN are recommended with once-daily doses with no up-titration, whereas DMF treatment is recommended twice-daily (BID) and is initiated with a 7-day starter dose of 120 mg BID before up-titration to the maintenance dose of 240 mg BID. Limited information exists regarding real-world ODMT prescribing patterns to aid physician/patient decision-making...
September 29, 2016: BMC Neurology
Jaesuk Yun, So Young Kim, Kyung Sik Yoon, Heejung Shin, Ho-Sang Jeong, Hyejoo Chung, Young-Hoon Kim, Jisoon Shin, Hye Jin Cha, Kyoung Moon Han, Seungha Hyeon, Tac-Hyung Lee, Hye-Kyung Park, Hyung Soo Kim
Astemizole, a non-sedating histamine H1 receptor blocker, is widely known to cause cardiac arrhythmia, which prolongs the QT interval. However, the precise molecular mechanism involved in antihistamine-induced cardiovascular adverse effects other than hERG channel inhibition is still unclear. In this study, we used DNA microarray analysis to detect the mechanisms involved in life-threatening adverse effects caused by astemizole. Rat primary cardiomyocytes were treated with various concentrations of astemizole for 24 h and the corresponding cell lysates were analyzed using a DNA microarray...
September 28, 2016: Archives of Pharmacal Research
Peng Zhao, Xiaoxia Yang, Liu Yang, Minshu Li, Kristofer Wood, Qiang Liu, Xiaodong Zhu
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons with limited treatment options. Emerging evidence shows that FTY720 protects against neural injury via modulation of the S1P1 receptor. However, it remains unclear whether FTY720 could influence neurodegeneration in PD. Therefore, the present study was designed to determine the impact of fingolimod (FTY720), a sphingosine-1-phosphate receptor (S1PR) agonist, on 2 mouse models of PD. We found that FTY720 significantly reduced the deficit of motor function, diminished the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and attenuated the decrease of striatal dopamine and metabolite levels in mice receiving 6-hydroxydopamine (6-OHDA) or rotenone to simulate PD...
September 26, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Stacy Ellen Hatcher, Emmanuelle Waubant, Jennifer S Graves
No abstract text is available yet for this article.
September 26, 2016: JAMA Neurology
Chittaranjan Andrade
No abstract text is available yet for this article.
September 26, 2016: JAMA Neurology
Martin Merschhemke, Davorka Tomic, Norman Putzki
No abstract text is available yet for this article.
September 26, 2016: JAMA Neurology
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