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Glatiramoids and multiple sclerosis


The mode of action, pharmacokinetics, and clinical efficacy and safety of glatiramer acetate in the treatment of multiple sclerosis is discussed


Emanuele D’Amico MD Francesco Patti MD Department of Neurology, University of Catania, Italy


Multiple sclerosis (MS) is a neurodegenerative disease, characterised by demyelinisation and axonal degeneration.1


Of importance in the


aetiology of MS is the complex interplay between genetic and environmental factors.1


Furthermore, GA was approved for patients who experienced a single episode of central nervous system (CNS) demyelinisation.3


It is administered subcutaneously at a dose of 20mg daily.


Characteristics and mode of action The average molecular weight of GA is in the range of 5000–9000 daltons. The molecule consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid; L-alanine; L-tyrosine; and L-lysine.2


The immunological effects


of GA were demonstrated in models of experimental autoimmune encephalomyelitis (EAE) the most


The prevalence of MS may vary between different populations with incidences from 2 to 150 per 100,000. There is no curative treatment for MS but since the mid-1990s new drugs have been shown to reduce the number and severity of MS relapses, delaying the progress to a secondary progressive form (SPMS). Interferon (INF) β-1b was the first drug approved for MS patients in 1993. In 1996, glatiramer acetate was approved in the USA for the treatment of relapsing–remitting MS (RRMS), and was subsequently granted approval in Europe in 2001.2


frequently used animal model for MS, and in a study showing the transfer of GA-active T-helper lymphocytes from GA-treated mice ameliorates EAE in untreated mice.4


GA is able to modulate the innate and the adaptive immune system.5


With an


antigen non-specific modulation, GA interacts with dendritic cells (DCs), decreasing the levels of the highly pro-inflammatory cytokines interleukin (IL)-10 and TNF-α.6


GA enhances the


phagocytic activity of microglia both in rat and human monocytes.7


Every branch


of the innate immune system is involved, including natural killer cells, the cytolytic functions of which are enhanced.8 In the immune adaptive system, GA acts as an altered peptide ligand. Emerging therapeutic targets are regulatory T cells (Tregs), involved in the


pathogenesis of autoimmune diseases; studies have shown that GA is able to activate these, inducing transcription factor forkhead box P3 (Foxp3) and, subsequently, suppressing autoimmunity.9


Furthermore, EAE mice treated with GA showed an elevation of Treg cells and a reduction in the Th17 cell population, , which produce the highly pro- inflammatory IL-17.10


GA also enhances


the suppressive ability of CD8 cells, which is impaired in MS patients compared with healthy controls.11


GA could induce anti-GA antibodies, which do not interfere with its mechanism of action.12


The antibodies


belong to the IgG class, predominantly IgG1, and tend to decline six months after initiation of therapy.12


In most MS patients, GA induces a www.hospitalpharmacyeurope.com 17


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