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https://www.readbyqxmd.com/read/28453541/the-real-world-effectiveness-and-safety-of-fingolimod-in-relapsing-remitting-multiple-sclerosis-patients-an-observational-study
#1
Guillermo Izquierdo, Fátima Damas, Maria Dolores Páramo, Juan Luis Ruiz-Peña, Guillermo Navarro
Fingolimod approval was based mainly on two clinical trials, FREEDOMS and TRANSFORMS, which demonstrated the efficacy and safety of fingolimod in patients with multiple sclerosis (MS). We present an observational study that validates these trials findings in a real-world setting, whereby the effectiveness and safety of fingolimod was assessed in Seville's' (Spain) clinical practice. This retrospective study in MS patients assessed effectiveness (relapses, EDSS, gadolinium-enhancing T1 and new/enlarged T2-weighted lesions): total cohort (n = 249) and stratified according to prior treatment (glatiramer acetate/interferon beta-1 [immunomodulator], natalizumab, naïve), gender, basal EDSS score, basal Gd+ lesions, ARR prior to treatment, age at treatment initiation and number of prior treatments...
2017: PloS One
https://www.readbyqxmd.com/read/28446186/fingolimod-attenuates-experimental-autoimmune-neuritis-and-contributes-to-schwann-cell-mediated-axonal-protection
#2
Björn Ambrosius, Kalliopi Pitarokoili, Lisa Schrewe, Xiomara Pedreiturria, Jeremias Motte, Ralf Gold
BACKGROUND: Fingolimod, a sphingosine-1-phosphate receptor modulator with well-described immunomodulatory properties involving peripheral immune cell trafficking, was the first oral agent approved for the treatment of relapsing remitting multiple sclerosis. Analogous immunomodulatory treatment options for chronic peripheral autoimmune neuropathies are lacking. METHODS: We tested fingolimod in the animal model of experimental autoimmune neuritis in Lewis rat. Six to eight-week-old female rats were immunized with P2 peptide and from this day on treated with fingolimod...
April 26, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28440858/treatment-with-disease-modifying-drugs-for-people-with-a-first-clinical-attack-suggestive-of-multiple-sclerosis
#3
REVIEW
Graziella Filippini, Cinzia Del Giovane, Marinella Clerico, Omid Beiki, Miriam Mattoscio, Federico Piazza, Sten Fredrikson, Irene Tramacere, Antonio Scalfari, Georgia Salanti
BACKGROUND: The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions...
April 25, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28428119/timing-of-high-efficacy-therapy-in-relapsing-remitting-multiple-sclerosis-a-systematic-review
#4
REVIEW
Bernd Merkel, Helmut Butzkueven, Anthony L Traboulsee, Eva Havrdova, Tomas Kalincik
BACKGROUND: Immunotherapy initiated early after first presentation of relapsing-remitting multiple sclerosis is associated with improved long-term outcomes. One can therefore speculate that early initiation of highly effective immunotherapies, with an average efficacy that is superior to the typical first-line therapies, could further improve relapse and disability outcomes. However, the most common treatment strategy is to commence first-line therapies, followed by treatment escalation in patients who continue to experience on-treatment disease activity...
April 17, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/28413713/catastrophic-outcome-of-patients-with-a-rebound-after-natalizumab-treatment-discontinuation
#5
Inés González-Suarez, Luis Rodríguez de Antonio, Aida Orviz, Sara Moreno-García, María D Valle-Arcos, Jordi A Matias-Guiu, Cristina Valencia, Manuela Jorquera Moya, Celia Oreja-Guevara
INTRODUCTION: Natalizumab (NTZ) is an effective drug for the treatment of relapsing-remitting multiple sclerosis. In some patients discontinuation is mandatory due to the risk of progressive multifocal leukoencephalopathy. However, severe clinical and radiological worsening has been described after drug cessation. Our aim was to describe the clinical and radiological features of the rebound phenomenon. MATERIAL AND METHODS: Patients switched from NTZ to Fingolimod (FTY) who had presented a rebound after discontinuation were selected...
April 2017: Brain and Behavior
https://www.readbyqxmd.com/read/28396093/what-s-new-about-oral-treatments-in-multiple-sclerosis-immunogenetics-still-under-question
#6
REVIEW
Cristiana Pistono, Cecilia Osera, Chiara Boiocchi, Giulia Mallucci, Mariaclara Cuccia, Roberto Bergamaschi, Alessia Pascale
Multiple Sclerosis (MS) is a chronic pathology affecting the Central Nervous System characterized by inflammatory processes that lead to demyelination and neurodegeneration. In MS treatment, disease modifying therapies (DMTs) are essential to reduce disease progression by suppressing the inflammatory response responsible for promoting lesion formation. Recently, in addition to the classical injectable DMTs like Interferons and Glatiramer acetate, new orally administered drugs have been approved for MS therapy: dimethyl fumarate, teriflunomide and fingolimod...
April 8, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28391741/unexpected-exacerbations-following-initiation-of-disease-modifying-drugs-in-neuromyelitis-optica-spectrum-disorder-which-factor-is-responsible-anti-aquaporin-4-antibodies-b-cells-th1-cells-th2-cells-th17-cells-or-others
#7
Jun-Ichi Kira
Some disease-modifying drugs for multiple sclerosis, which mainly act on T cells, are ineffective for neuromyelitis optica spectrum disorder and induce unexpected relapses. These include interferon beta, glatiramer acetate, fingolimod, natalizumab, and alemtuzumab. The cases reported here suggest that dimethyl fumarate, which reduces the number of Th1 and Th17 cells and induces IL-4-producing Th2 cells, is also unsuitable for neuromyelitis optica spectrum disorder, irrespective of anti-aquaporin 4 IgG serostatus...
April 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/28373076/fty720-fingolimod-regulates-key-target-genes-essential-for-inflammation-in-microglial-cells-as-defined-by-high-resolution-mrna-sequencing
#8
Amitabh Das, Sarder Arifuzzaman, Sun Hwa Kim, Young Seek Lee, Kyoung Hwa Jung, Young Gyu Chai
Although microglial cells have an essential role in the host defense of the brain, the abnormal activation of microglia can lead to devastating outcomes, such as neuroinflammation and neurodegeneration. Emerging evidence indicates that FTY720 (fingolimod), an FDA-approved drug, has beneficial effects on brain cells in the central nervous system (CNS) and, more recently, immunosuppressive activities in microglia via modulation of the sphingosine 1 phosphate (S1P) 1 receptor. However, the exact molecular aspects of FTY720 contribution in microglia remain largely unaddressed...
March 31, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28362522/multiple-sclerosis-update-use-of-mri-for-early-diagnosis-disease-monitoring-and-assessment-of-treatment-related-complications
#9
Mark S Igra, David Paling, Mike P Wattjes, Daniel J A Connolly, Nigel Hoggard
MRI has long been established as the most sensitive in vivo technique for detecting multiple sclerosis (MS) lesions. The 2010 revisions of the McDonald Criteria have simplified imaging criteria, such that a diagnosis of MS can be made on a single contrast-enhanced MRI scan in the appropriate clinical context. New disease-modifying therapies have proven effective in reducing relapse rate and severity. Several of these therapies, most particularly natalizumab, but also dimethyl fumarate and fingolimod, have been associated with progressive multifocal leukoencephalopathy (PML)...
April 26, 2017: British Journal of Radiology
https://www.readbyqxmd.com/read/28361437/effect-of-preventive-and-curative-fingolimod-treatment-regimens-on-microglia-activation-and-disease-progression-in-a-rat-model-of-multiple-sclerosis
#10
David Vállez García, Janine Doorduin, Daniele de Paula Faria, Rudi A J O Dierckx, Erik F J de Vries
Fingolimod was the first oral drug approved for multiple sclerosis treatment. Its principal mechanism of action is blocking of lymphocyte trafficking. In addition, recent studies have shown its capability to diminish microglia activation. The effect of preventive and curative fingolimod treatment on the time-course of neuroinflammation was investigated in the experimental autoimmune encephalomyelitis rat model for multiple sclerosis. Neuroinflammatory progression was followed in Dark Agouti female rats after immunization...
March 30, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28356890/evaluation-and-optimization-of-in-silico-designed-sphingosine-1-phosphate-s1p-receptor-subtype-1-modulators-for-the-management-of-multiple-sclerosis
#11
Daphne H Gusman, Claire Shoemake
Multiple Sclerosis (MS) is a chronic autoimmune disorder affecting the Central Nervous System (CNS) through inflammation, demyelination and neurodegeneration. Sphingosine-1-phosphate receptor (S1PR1) modulators have been approved for the management of MS. Phosphorylated fingolimod mimics endogenous sphingosine-1-phosphate (S1P), a bioactive lipid that regulates remyelination and cell injury. Amiselimod was developed as a successor of fingolimod, with more specificity for S1PR1, and showed promising results until phase 2 clinical trials...
March 2017: Yale Journal of Biology and Medicine
https://www.readbyqxmd.com/read/28336784/evaluation-of-the-effect-of-fingolimod-treatment-on-microglial-activation-using-serial-pet-imaging-in-multiple-sclerosis
#12
Marcus Sucksdorff, Eero Rissanen, Jouni Tuisku, Salla Nuutinen, Teemu Paavilainen, Johanna Rokka, Juha Rinne, Laura Airas
Traditionally, multiple sclerosis (MS) has been considered a white matter (WM) disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, i.e. in areas of normal appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using an 18 kDa translocator protein (TSPO) binding radioligands and positron emission tomography (PET). It is unknown whether fingolimod affects microglial activation in MS...
March 23, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28334528/why-prodrugs-and-propesticides-succeed
#13
John E Casida
What are the advantages of bioactivation in optimizing drugs and pesticides? Why are there so many prodrugs and propesticides? These questions are examined here by considering compounds selected on the basis of economic value or market success in 2015. The 100 major drugs and 90 major pesticides are divided into ones acting directly and those definitely or possibly requiring bioactivation. Established or candidate prodrugs accounted for 19% of the total drug sales, with corresponding values of 20, 37, and 17% for proinsecticides, proherbicides, and profungicides...
April 7, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28302022/glial-cell-a-potential-target-for-cellular-and-drug-based-therapy-in-various-cns-diseases
#14
Shakeeb Ahmed, Azka Gull, Tahir Khuroo, Mohd Aqil, Yasmin Sultana
Glial cells are integrated part of neurovascular unit of blood brain barrier (BBB). They undergo mitosis and mainly classified as astrocytes, oligodendrocytes, microglia, ependymal cells and nerve glial antigen 2 cells. Being a most versatile glial cell, astrocytes provide structural support to neurons, maintain brain homeostasis, take part in neuronal communication, and perform some housekeeping functions. Oligodendrocytes myelinate the neuronal axons for proper transmission of nerve impulse and microglia are brain immune cells...
March 16, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28300418/incurred-sample-reanalysis-of-fingolimod-and-fingolimod-phosphate-in-blood-stability-evaluation-and-application-to-a-rat-pharmacokinetic-study
#15
Ramakrishna Nirogi, Nagasurya Prakash Padala, Devender Reddy Ajjala, Rajesh Kumar Boggavarapu, Praveen Kunduru
BACKGROUND: Incurred sample reanalysis (ISR) is an in-study validation parameter, which reinforces that the validated bioanalytical methods are reproducible. ISR of whole blood samples is complex when the test compounds can interconvert, ex vivo. Fingolimod and fingolimod phosphate are highly distributed in the blood cellular components and undergo rapid interconversion, both in vivo and ex vivo. An LC-MS/MS method capable of simultaneous quantification of fingolimod and fingolimod phosphate with the controlled sample preparation procedure is essential...
March 16, 2017: Bioanalysis
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
#16
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. The present study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels; 1) in vitro, 2) ex vivo and 3) in vivo. 1) Patch-clamp experiments in whole cell configuration were performed on Cav 1...
March 16, 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28294696/cerebrospinal-fluid-mtdna-concentration-is-elevated-in-multiple-sclerosis-disease-and-responds-to-treatment
#17
Cyra E Leurs, Petar Podlesniy, Ramon Trullas, Lisanne Balk, Martijn D Steenwijk, Arjan Malekzadeh, Fredrik Piehl, Bernard Mj Uitdehaag, Joep Killestein, Jack van Horssen, C E Teunissen
BACKGROUND: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. OBJECTIVES: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes...
March 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/28283486/systematic-literature-review-and-network-meta-analysis-in-highly-active-relapsing-remitting-multiple-sclerosis-and-rapidly-evolving-severe-multiple-sclerosis
#18
Eline Huisman, Katerina Papadimitropoulou, James Jarrett, Matthew Bending, Zoe Firth, Felicity Allen, Nick Adlard
OBJECTIVE: Multiple sclerosis (MS) is a chronic, neurodegenerative autoimmune disorder affecting the central nervous system. Relapsing-remitting MS (RRMS) is the most common clinical form of MS and affects ∼85% of cases at onset. Highly active (HA) and rapidly evolving severe (RES) RRMS are 2 forms of RRMS amenable to disease-modifying therapies (DMT). This study explored the efficacy of fingolimod relative to other DMTs for the treatment of HA and RES RRMS. METHODS: A systematic literature review (SLR) was conducted to identify published randomised controlled trials in HA and RES RRMS...
March 10, 2017: BMJ Open
https://www.readbyqxmd.com/read/28283109/classifying-pml-risk-with-disease-modifying-therapies
#19
REVIEW
Joseph R Berger
OBJECTIVE: To catalogue the risk of PML with the currently available disease modifying therapies (DMTs) for multiple sclerosis (MS). BACKGROUND: All DMTs perturb the immune system in some fashion. Natalizumab, a highly effective DMT, has been associated with a significant risk of PML. Fingolimod and dimethyl fumarate have also been unquestionably associated with a risk of PML in the MS population. Concerns about PML risk with other DMTs have arisen due to their mechanism of action and pharmacological parallel to other agents with known PML risk...
February 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/28279838/modulation-of-sphingosine-1-phosphate-in-inflammatory-bowel-disease
#20
REVIEW
Laurent Peyrin-Biroulet, Ronald Christopher, Dominic Behan, Cheryl Lassen
Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, involve an inappropriate immune reaction in the digestive tract, causing a variety of disabling symptoms. The advent of monoclonal antibodies (anti-tumor necrosis factor, anti-integrin, anti-interleukin -23) has revolutionized IBD management. Nevertheless, these agents, with potential for immunogenicity, are associated with high rates of response loss and disease relapse over time. They are also associated with high production costs...
March 7, 2017: Autoimmunity Reviews
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