Clinical Neuroscience

[Clinical significance of the cardiovascular effects of fingolimod treatment in multiple sclerosis]


NOVEMBER 20, 2012

Clinical Neuroscience - 2012;65(11-12)

[Fingolimod is a sphingosine-1 phosphate receptor modulator, which is effective in the treatment of severe relapsingremitting form of multiple sclerosis. Once daily oral use of fingolimod decreased the annualized relapse rate, inflammatory brain lesion activity and the rate of brain atrophy compared both to placebo and intramuscular administered interferon beta-1a. The drug targets the cardiovascular system as well via sphingosine- 1 phosphate receptors. After initiation of fingolimod therapy transient sinus bradycardia and slowing of the atrioventricular conduction develops. The onset of the effect is as early as 1 hour post administration, while heart rate and conduction normalized in 24 hours in most of the cases. According to the clinical trials symptomatic bradycardia developed in 0.5% of the cases, responding to the appropriate therapy. The incidence of Mobitz I type II atrioventricular blocks and blocks with 2:1 atrioventricular conduction was 0.2% and 0.1%, respectively. All of these cardiovascular events showed regression during observation and no higher degree atrioventricular blocks were detected at the approved therapeutic dose. Following the first dose effect, fingolimod had a moderate hypertensive effect on long-term. For the safety of fingolimod treatment detailed cardiovascular risk stratification of all patients, adequate patient monitoring after the first dose and competency in treating the possible side effects is necessary. In patients with increased cardiovascular risks, treatment should be considered only if anticipated benefits outweigh potential risks and extended monitoring is required.]



Further articles in this publication

Clinical Neuroscience

[Vinpocetin in neurological diseases]

SZAPÁRY László, KÉSMÁRKY Gábor, TÓTH Kálmán, MISNYOVSZKY Melinda, TÓTH Tímea, BALOGH Ágnes, NAGY Krisztián, NÉMETH György, FEHÉR Gergely

[Introduction - Stroke is the third leading cause of death worldwide (following cardiovascular and cancer mortality) and associated with serious disability for the vast majority of patients. There is no salvage therapy for irreversibly damaged brain areas, improving the circulation of the surrounding hypoperfused territories may be associated with benefitial clinical states. Cerebral hypoperfusion may play a role in the pathogenesis of other kind of neurological diseases, improvement of global circulation may have a preventive effect on these conditions. Aims - The aim of our study was to review the experimental and clinical articles focusing on the role of vinpocetin in different neurological conditions. Results - Vinpocetin appears to have several different mechanisms of action that allow for its antiinflammatory, antioxidant, vasodilating, antiepileptic and neuroprotective activities in experimental conditions. On the other hand, several meta-analysis of the existing studies in acute stroke examining short and long term fatality rates with vinpocetin was unable to assess efficacy. In chronic cerebrovascular patients, vinpocetin improves impaired hemorheological variables, has significant vasodilating properties, improves endothelial dysfunction, neuroimaging studies showed selective increase in cerebral blood flow and cerebral metabolic rate, all of which are potentially beneficial in cerebrovascular disease and may improve cognitive functions. Summary - Based on the above mentioned results vinpocetin plays an important role both in basic research and in clinical management of different neurological diseases.]

Clinical Neuroscience

[Meeting of the management of Hungarian Epilepsy League]


Clinical Neuroscience

[Clinical experiences with Creutzfeldt-Jakob disease: three case studies]

SZŰCS Anna, VÁRALLYAY Péter, OSZTIE Éva, PAPP Erzsébet, SÓLYOM András, FINTA Lehel, VARGA Dániel, BARCS Gábor, HOLLÓ András, KAMONDI Anita

[The clinical picture, electroencephalographic, imaging and cerebrospinal fluid parameters as well as the molecular background of Creutzfeldt-Jakob disease have been well explored. The diagnostic criteria, offering clinicians a fair chance to identify these patients in vivo, have recently been updated. However, the diagnosis is still a challenge in everyday neurological routine. We report on three of our Creutzfeldt-Jakob patients for calling attention to the classical and the recently defined features of the disease. We conclude that based on the rapidly progressing neuropsychiatric syndrome Creutzfeldt-Jakob disease may be suspected; follow-up EEG may reveal the typical (pseudo)-periodic pattern with progressive deterioration of the background activity. In addition, diffusion-weighted brain MRI imaging (DWI) has high diagnostic value. Detection of 14-3-3 protein in the cerebrospinal fluid supports the in vivo diagnosis.]

Clinical Neuroscience

[Account on the scientific meeting of Környey Society in 2012]

KOPA János

Clinical Neuroscience

[New, effective immunomodulatory drug in treatment of multiple sclerosis: the fingolimode]


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[Change of therapeutic algorithm in sclerosis multiplex based on two case reports]

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[The aim of our case reports is to demonstrate the therapeutic use and possibilities one has with alemtuzumab, should it be used either as a first or second line therapy. Our first patient's disease in the beginning seemed to be benign. It was not the case however, over several years the diesase showed high activity both radiologically and clinically, she was treated with alemtuzumab as part of an esclationbased therapeutic strategy. The second patient's disease on the other hand showed formidable activity since the very beginning both radiologically and clinically. Therefore we were facing a very disastrous prognosis on the long run, accordingly he received alemtuzumab treatment very early into his illness.]

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[Current treatment of multiple sclerosis]


[Multiple sclerosis (MS) is an autoimmune and degenerative disorder. In the past decades, the introduction of parenteral immunomodulatory therapies brought significant progress. These agents increase the number of relapses (shubs) by about 30%, and some of them has been shown to halter the accumulation of neurological symptoms and the development of disability. As first-line agents, interferon beta and glatiramer acetate (consisting of amino acids) can be used. Some new therapeutic strategies have been developed as a result of biotechnological development. The advantage of humanised monoclonal antibodies is that they affect the autoimmune inflammatory process more selectively. Among monoclonal antibodies, natalizumab, which binds to alpha-4-beta-1 integrin receptors and inhibits the migration of T-lymphocytes into the central nervous system, is available from February 2010 in Hungary, recommended as second-line treatment. The efficacy of natalizumab in decreasing relapse rate is >60 %. However, its use is associated with progressive multifocal leukoencephalopathy (PML) in one out of 1000 treated patient. Currently it is recommended as second-line treatment, if the patient has active disease despite immunomodulatory therapy. Among orally administered agents, a preparation containing fingolimod is expected to become available next year, and another pill, cladribin has been also found to be efficient in randomised, controlled phase III trials. Fingolimod acts on sphingosine 1-phosphate receptors- 1 (S1P1). Cladribine is a purine nucleotide analogue, and its efficacy is based on long-term reduction of CD4+ and CD8+ lymphocytes. Further promising oral immunomodulatory agents are laquinimod and BG000012 (dimethylfumarate), which are currently being tested in phase III clinical trials in relapsing-remitting MS. The most efficient treatment should be chosed on the basis of the activity, aetiology and the posited pathomechanism of the disease. With the increasing number of therapeutic options, choosing the treatment that is optimal for the patient while also considering side effects might be challenging for both the patients and physicians.]

Clinical Neuroscience

[Selective ultrastructural vulnerability in the cuprizone-induced experimental demyelination]

ÁCS Péter, KOMOLY Sámuel

[Background and purpose - It has been reported that multiple sclerosis has four different neuropathological subtypes, and two of them (type III and IV) are characterized by primary oligodendrocyte loss. However, the exact pathomechanism that lead to oligodendrocyte apoptosis in human demyelinating diseases is still elusive. The copper chelator cuprizone induces primary oligodendrocyte apoptosis and consequent demyelination in well defined areas of the mouse brain. Nevertheless, the precise subcellular events that result in oligodendrocyte cell death in the cuprizone model are still unknown. We aimed to study the ultrastructural alterations that might induce oligodendrocyte apoptosis in the cuprizone experimental demyelination model. Methods - C57BL/6 mice were given cuprizone for two, 21 and 35 days to induce demyelination to investigate early pathological events, and different stages of demyelination. In addition, mice were given cuprizone for 35 days and were allowed to recover for two or 14 days to study early and late remyelination. After the cuprizone treatment, mice were sacrificed and the corpus callosum, the superior cerebellar peduncle, the optic nerve and the sciatic nerve were studied by electron microscopy. Results - The ultrastructural analysis revealed that cuprizone induced oligodendrocyte apoptosis is accompanied by the formation of giant mitochondria in the affected cells in the corpus callosum and in the superior cerebellar peduncle. Apoptosis of the myelin producing cells was present through the whole cuprizone challenge. Severe demyelination occurred after three weeks of cuprizone administration associated with massive macrophage infiltration and astrocytosis of the demyelinated areas. Axons and neurons remained unaffected. Conclusion - The formation of giant mitochondria in myelin producing oligodendrocytes is the first pathological sign in the cuprizone experimental demyelination. Mitochondrium pathology in the cuprizone challenge might serve as a useful model to study the pathomechanism of multiple sclerosis subtypes (III and IV) characterized by primary oligodendrocyte degeneration.]

Lege Artis Medicinae



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[Fingolimod therapy in multiple sclerosis - the issue of the pathomechanism]

TAR Lilla, VÉCSEI László

[Multiple sclerosis is an autoimmune inflammatory disease of the central nervous system with neurodegenerative chararacteristics. The newly discovered per os administrable drug fingolimod (FTY720) has a different mechanism of action than the current disease-modifying therapies. In vivo the drug binds to four out of the five sphingosine-1-phosphate receptors after phosphorylation. Fingolimod-phosphate (FTY720-P) causes internalization and degradation of the sphingosine-1-phosphate receptors in the membrane of lymphocytes thus in contrast to sphingosine-1-phosphate it acts like a functional antagonist. In experimental autoimmune encephalomyelitis - an animal model of multiple sclerosis - fingolimod blocks the sphingosine-1-phosphate gradient controlled lymphocyte egress from the lymph nodes and therefore reduces the peripheral lymphocyte count especially the encephalitogenic Th17 subset is reduced. Modulation of the sinus lining and blood-brainbarrier constructing endothelial cells also contributes to the complex mechanism of action. Additionally due to its liphohilic nature fingolimod is able to penetrate the blood brain barrier thus, beside its peripheral effects the drug can probably modulate the cells of the central nervous system directly. Presumably it can reduce neurodegeneration caused by astrogliosis through modification of astrocyte and oligodendrocyte activity. The results of current clinical studies are holding out with bright prospective in the aspect of either the favourable effects or the well tolerated side effects.]