[Basic mechanisms of action of fingolimod in relation to multiple sclerosis]

ArticleinRevista de neurologia 55(1):31-7 · July 2012with3 Reads
Source: PubMed
Fingolimod has recently been approved for the therapy of relapsing multiple sclerosis. This drug binds to different sphingosine-1-phosphate receptors. To analyze basic mechanisms of action that can account for the efficacy of this drug in multiple sclerosis. Fingolimod acts as an inverse agonist on sphingosine-1-phosphate receptors, inducing degradation of receptors. On lymphoid circulation, this effect causes retention in lymph nodes of naive and central memory T cells, including Th17 T lymphocytes, bearing CCR7 and CD62L receptors. As a result, the level of circulating T cells is markedly decreased. B ell circulation is impaired and complex effects on other immune cells are also induced. Fingolimod enters the central nervous system and binds to receptors on glial cells and neurons. In experimental autoimmune encephalomyelitis, the therapeutic efficacy of fingolimod is not only associated with a reduced entry of inflammatory cells into the nervous system, but also with a direct effect mostly on astroglial cells. In multiple sclerosis patients, the available evidence indicates that fingolimod efficacy is directly associated with impairment of circulation of several T cell subsets and possibly B cells. Animal studies raise the possibility that an additional effect on glial cells might also contribute to the clinical efficacy.
  • [Show abstract] [Hide abstract] ABSTRACT: The scientific advances regarding the ethiopathogenesis and physiopathology of multiple sclerosis are so fast that periodic update of concepts is awaited. Moreover, new epidemiological data and criteria improving differential diagnosis have been described. The objective of this review is to update concepts about epidemiology, ethiopathogenesis, physiopathology and differential diagnosis of multiple sclerosis. Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system more frequent in young ages and in the female sex, the incidence of which increases with latitude. Recent studies indicate an increase in the incidence and earlier onset in women. Although the cause of the disease is unknown, genetic and environmental risk factors have been identified. The HLA allele HLA-DRB1*15 is the genetic factor more strongly associated with the risk of developing multiple sclerosis; the better established environmental factors are the exposition to the Epstein-Barr virus, smoking and vitamin D levels. The combination of environmental factors with a certain individual genetic predisposition, discloses an immunological dysregulation. Multiple sclerosis is considered to be mediated by T cells and its physiopathology is complex, intervening various immunological factors. From adaptive immunity, it must be emphasized the role of Th17 populations, with secretion of proinflammatory cytokines, cytotoxic T CD8+ and B lymphocytes. The innate immunity also participates in multiple sclerosis immunopathogenesis, mainly through microglia activation. The action of humoral and cellular changes induces focal inflammation with demyelination and axonal damage pointing to a dual face - inflammatory and degenerative - of the disease. Despite the natural repair mechanisms leading to remyelination and axonal recovery, in later stages this ability becomes exhausted and disease progresses. The absence of specific diagnostic biomarkers for multiple sclerosis imposes the exclusion of other inflammatory diseases with neurological involvement, especially when a first demyelinating event occurs - clinically isolated syndrome. The main neurological manifestations appearing in that condition that allow to support or reject the diagnosis of multiple sclerosis are described. The characteristic clinical and paraclinical data of other idiopathic demyelinating (neuromyelitis optica, acute disseminated encephalomyelitis, acute transverse myelitis, optic neuritis) and systemic inflammatory disorders with neurological involvement (systemic erythematous lupus, Behçet's disease, Sjögren'disease) are presented. In conclusion, the knowledge of the factors that contribute to the development of multiple sclerosis and the pathological processes taking place in the nervous system favours a better understanding of the disease and the discovery of new immunotherapeutic targets. The precise diagnosis of multiple sclerosis requires a rigorous systematization of differential diagnoses.
    Full-text · Article · Jan 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Background Fingolimod, a selective immunosupressor, was recently approved by the European Medicines Agency for the treatment of highly active forms of recurrent-remitting multiple sclerosis. Clinical studies have evaluated the safety and the tolerability of fingolimod. Till date, there is data available for 10,000 patients and 16,500 patient-years of exposure. Aims Review of safety data on fingolimod and proposal of monitoring guidelines for patients treated with this medication. Review The most frequent adverse events of fingolimod are lymphopenia, liver toxicity and cardiovascular effects. Lymphopenia is explained by pharmacodynamic mechanisms and values <200/μL are frequent, prompting transitory treatment suspension. Change in liver tests occur at the beginning of treatment and require vigilance, mostly resolving spontaneously without intervention. Cardiovascular effects include transitory bradycardia usually asymptomatic, a small increase of 1/3 mmHg in arterial blood pressure and a modest but persistent QT prolongation. Electrocardiographic abnormalities, such as AV blocks, may occur after the first dose, but are usually transient. Macular edema had an incidence of 0.4% at 3-4 months of treatment, and was usually reversible after treatment interruption. There was a higher incidence of respiratory and severe herpetic infections. The incidence of malignancies was not superior to the expected in general population, but the mutagenic risk is not established as it may be a late effect of medication. Teratogenicity, which was found in animal models, enforces the need for adequate contraception during treatment. There is a low risk for pharmacokinetic interactions, but pharmacodynamic interactions, mainly with antiarrythmics, are potencially dangerous. Conclusions Fingolimod is a relatively safe medication. It requires specific care in clinical monitoring in order to minimize known risks and needs pharmacosurveillance plans focused in uncertain risks that will be clarified only after longterm exposure of a non-selected population.
    Article · Jan 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Fingolimod is the first approved drug with oral availability for the treatment of relapsing multiple sclerosis. To review the mechanism of action of fingolimod and its relationship with the development of infections. To propose preventive measures for those patients who are receiving the drug or will initiate a new treatment. In addition, the role of fingolimod in the development of progressive multifocal leukoencephalopathy on the basis of recent knowledge of its pathophysiology will be discussed. The mechanism of action of fingolimod is based on an antagonic effect on the sphingosine 1-phospate receptors that will generate an inhibition of the egress of naive and central memory lymphocytes into the bloodstream, allowing the free recirculation of memory effectors T lymphocytes. This effect will produce lymphopenia. Fingolimod-associated lymphopenia is a consequence of lymphocyte redistribution, and it is selective and reversible. There is no evidence of higher number of opportunistic and non-opportunistic infections in comparison to placebo or interferon beta-1a in patients receiving fingolimod. However, two patients developed severe herpetic infections under fingolimod. Fingolimod induce a selective and reversible lymphopenia that, taking into account the most recent available data, does not seem to be associated with higher risk of opportunistic infections due to a preservation of immuno-surveillance. The risk of herpesvirus infection should be taken into consideration and more studies are warranted to confirm if an association of these infections with the use of fingolimod exists.
    Article · Aug 2012
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