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At least 19 recordsLinked to original sources
PubMed2005

Jessner-Kanof lymphocytic infiltration of the skin associated with glatiramer acetate.

Glatiramer acetate (GLAT) is a well tolerated and safe immunomodulatory drug for the treatment of relapsing-remitting multiple sclerosis. The most commonly recognized side effects are localized injection site reactions consisting of pain, pruritus, mild erythema and induration, which sometimes persist for several days. We describe the first case of a biopsy-proven lymphocytic infiltration (T-cell pseudolymphoma) with the clinical appearance of a figured erythema on the ventrolateral thighs in the first four weeks under GLAT treatment, resolving without any evidence of recurrence despite ongoing therapy. A T-cell pseudolymphoma is a very rare side effect of GLAT treatment. For clinical purposes it is important to state that re-exposition after GLAT-induced pseudolymphoma is possible without permanent sequelae.

Adult↗
PubMed2002

Glatiramer acetate.

Glatiramer acetate (GA) is a mixture of synthetic polypeptides composed of four aminoacids. GA is very effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Various mechanisms of action of GA have been proposed, but the most important is probably the induction of antigen-specific suppressor T cells. Class one clinical trials have demonstrated that GA reduces the relapse rate and the accumulation of disability in relapsing-remitting (RR) MS. The positive effects on disease activity and disease progression are explained by the reduction of the number and volume of the active lesions as showed by Magnetic resonance imaging (MRI) studies. Moreover new MRI techniques suggest that GA may also have some neuroprotective effects. The drug is usually well tolerated with modest side effects. In vitro and in vivo animal studies have shown that GA is devoid of teratogenic or mutagenic effects. GA is a good alternative to interferon beta for treatment of RR-MS.

Animals↗
PubMed2003

Induction of apoptosis of CD4+ T cells by immunomodulatory therapy of multiple sclerosis with glatiramer acetate.

Glatiramer acetate (GA), a mixture of synthetic polypeptides, has beneficial effects on the clinical course and the MRI-defined disease activity of patients with multiple sclerosis (MS). In MS, evidence has been provided that the apoptosis of disease-relevant T cells is dysregulated. In this study, we investigated the effect of GA on T cell apoptosis, T cell activation, and cytokine profile of lymphocytes derived from 19 relapsing-remitting MS patients during the first year of GA therapy. Analysis of blood samples obtained every 6 weeks showed an increase in apoptotic T helper cells after 30 weeks of therapy. This effect remained until the end of the study and was accompanied by an increase in activated T cells and interleukin-4-producing lymphocytes. Thus, in addition to the established effect of GA on the cytokine network, GA-mediated immunomodulation might involve the apoptotic elimination of T helper cells.

Adult↗
PubMedDate not supplied

Immunomodulation by the copolymer glatiramer acetate.

Glatiramer acetate (GA; Copaxone, also known as Copolymer 1 or Cop-1), a copolymer of amino acids, is very effective in the suppression of experimental autoimmune encephalitis (EAE), the animal model for multiple sclerosis (MS), in various species including primates. The immunological cross-reaction between the myelin basic protein and GA serves as the basis for the suppressive activity of GA in EAE, by the induction of antigen-specific suppressor cells. The mode of action of GA is by initial strong promiscuous binding to major histocompatibility complex class II molecules and competition with MBP and other myelin proteins for such binding and presentation to T cells. Suppressor T cells induced by GA are of the Th2 type, migrate to the brain and lead to in situ bystander suppression. Clinical trials with GA, both phase II and phase III, were performed in relapsing-remitting MS (RRMS) patients, and demonstrated efficacy in reducing the relapse rate, decreasing MRI-assessed disease activity and burden and slowing progression of disability. GA is generally well tolerated and is not associated with influenza-like symptoms and formation of neutralizing antibodies seen with beta-interferons. It exerts its suppressive effect primarily by immunomodulation, and has recently shown ameliorating effect in a few additional autoimmune disorders as well as in graft rejection. At present GA is considered a valuable first-line treatment option for patients with RRMS.

Animals↗
PubMed2004

Induction of IL-10 in rat peritoneal macrophages and dendritic cells by glatiramer acetate.

Glatiramer acetate (GLAT) is a mixture of basic polypeptides that have been shown to suppress experimental autoimmune encephalomyelitis (EAE). As Copaxone, GLAT is approved for the treatment of relapsing-remitting multiple sclerosis (MS). Different immunomechanisms have been suggested to contribute to the beneficial effects of GLAT which rely on blockade of MHC class II molecules or cross-recognition with myelin basic protein (MBP). Because GLAT could also inhibit experimental autoimmunity not related to myelin proteins, we searched for additional, less-restricted immunomodulatory actions of GLAT. Using freshly isolated resident peritoneal macrophages from naive Lewis rats, it is shown that GLAT profoundly modulates cytokine secretion of the cells. In unseparated macrophages (MPhi) and MPhi of low density, GLAT enhanced constitutive and LPS-induced production of interleukin 10 (IL-10) while LPS-induced synthesis of tumor necrosis factor-alpha (TNF-alpha) was dose-dependently suppressed by GLAT. Although both basic proteins GLAT and MBP facilitated adherence of MPhi, MBP had opposite effects on cytokine production suggesting unique properties of GLAT. In contrast to MPhi, peritoneal mast cells produced only little amounts of cytokines. The inductive effect of GLAT on IL-10 production by antigen-presenting cells was also observed in bone marrow-derived rat dendritic cells (DCs) which, unlike MPhi, were not suppressed in their production of TNF-alpha. Induction of IL-10 in different antigen-presenting cells is a new immunomodulatory mechanism of GLAT. In part, it goes along with the inhibition of TNF-alpha and may be a common basis for the known beneficial effects of GLAT on various cellular autoimmune responses including MS.

Animals↗
PubMedDate not supplied

Glatiramer acetate (Copaxone).

Glatiramer acetate (Copaxone) is a novel preparation of synthetic peptides composed of four amino acids. Laboratory studies have shown that it prevents, or modifies, experimental allergic encephalomyelitis, the animal model for multiple sclerosis (MS), in several mammalian species. Its mode of action has not been fully elucidated but it is known to induce suppresser T-cells, known to be deficient in MS, and competitively inhibits the effect of CNS myelin antigens, thought to be important in the pathogenesis of MS, through MHC blockade. Controlled clinical trials have shown it to improve the natural history of MS by reducing both the relapse rate and the resultant disability. GA shows similar efficacy to interferon-beta (IFN-beta) but with fewer systemic side-effects and appears to be better tolerated by patients. It has thus justified its place in the new era of disease-modifying treatments for MS. While the evidence suggests GA should be considered as first-line therapy in selected patients, its differing mechanism of action also gives patients and doctors the option of an alternative agent when the efficacy of IFN-beta is waning or side-effects predominate.

Adjuvants, Immunologic↗
PubMed2001

European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging--measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group.

Two prior double-blind, placebo-controlled, randomized trials demonstrated that glatiramer acetate (GA) reduces relapse rates in patients with relapsing remitting multiple sclerosis (RRMS). This study was designed to determine the effect, onset, and durability of any effect of GA on disease activity monitored with magnetic resonance imaging (MRI) in patients with RRMS. Two hundred thirty-nine eligible patients were randomized to receive either 20 mg GA (n = 119) or placebo (n = 120) by daily subcutaneous injection. Eligibility required one or more relapses in the 2 years before entry and at least one enhancing lesion on a screening MRI. The study was a randomized, double-blind, placebo-controlled phase during which all patients studied underwent monthly MRI scans and clinical assessments over 9 months. The primary outcome measure was the total number of enhancing lesions on T1-weighted images. Secondary outcome measures included the proportion of patients with enhancing lesions, the number of new enhancing lesions and change in their volume; the number of new lesions detected on T2-weighted images and change in their volume, and the change in volume of hypointense lesions seen on unenhanced T1-weighted images. Clinical measures of disease activity were also evaluated. The active treatment and placebo groups were comparable at entry for all demographic, clinical, and MRI variables. Treatment with GA showed a significant reduction in the total number of enhancing lesions compared with placebo (-10.8, 95% confidence interval -18.0 to -3.7; p = 0.003). Consistent differences favoring treatment with GA were seen for almost all secondary end points examined: number of new enhancing lesions (p < 0.003), monthly change in the volume of enhancing lesions (p = 0.01), and change in volume (p = 0.006) and number of new lesions seen on T2-weighted images (p < 0.003). The relapse rate was also significantly reduced by 33% for GA-treated patients (p = 0.012). All effects increased over time. Glatiramer acetate significantly reduced MRI-measured disease activity and burden.

Adult↗
PubMed2001

Risk-benefit assessment of glatiramer acetate in multiple sclerosis.

Glatiramer acetate, formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids. Glatiramer acetate has been shown to be effective in preventing and suppressing experimental autoimmune encephalitis (EAE), the animal model of multiple sclerosis (MS). Therefore it was tested in several clinical studies, where it was found to slow the progression of disability and to reduce the relapse rate and the magnetic resonance imaging (MRI)-defined disease activity and burden in relapsing-remitting MS. As a daily standard dose, 20mg of glatiramer acetate is injected subcutaneously. After injection, glatiramer acetate undergoes rapid degradation to amino acids and shorter peptides; so it is not possible to measure any systemic plasma concentrations or excretion rates. Two major mechanisms have been proposed to explain the effects of glatiramer acetate in EAE and MS: the induction of glatiramer acetate-reactive T helper 2 (Th2)-like regulatory suppressive cells and the interference with T cell activation as an altered peptide ligand. The most common adverse effects were mild injection site reactions (erythema, inflammation and induration). The most remarkable adverse event is the acute and transient immediate postinjection reaction manifested by flushing, chest tightness, palpitations and dyspnoea. Other reported adverse effects are transient chest pain and lymphadenopathy. Antibodies to glatiramer acetate induced during treatment do not interfere with its clinical effects. In several controlled clinical studies, glatiramer acetate has been shown to provide consistent, reproducible clinical benefits in the target population of patients with relapsing-remitting MS. The safety profile and risk-benefit ratio are excellent. Overall, glatiramer acetate is very well tolerated and has an excellent risk-benefit profile in patients with relapsing-remitting MS.

Clinical Trials as Topic↗
PubMed2005

Glatiramer acetate in multiple sclerosis.

Glatiramer acetate (Copaxone) is a disease-modifying agent approved by several health authorities worldwide for the treatment of relapsing-remitting multiple sclerosis. Although its primary target is the inflammatory component of the disease, there are emerging pieces of evidence suggesting that glatiramer acetate might also have a neuroprotective effect. In this review, the results of glatiramer acetate clinical trials and other relevant studies as well as the place of glatiramer acetate among other approved disease-modifying treatments for relapsing-remitting multiple sclerosis are discussed critically.

Glatiramer Acetate↗
PubMed2003

Spotlight on glatiramer acetate in relapsing-remitting multiple sclerosis.

Glatiramer acetate (Copaxone) is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS). In three randomised, double-blind trials in patients with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more effective than placebo for the primary outcome measure of each trial (mean relapse rate, proportion of relapse-free patients and number of gadolinium-enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse rate was significantly reduced at endpoint (approximately one-third less) in the two larger trials (the US pivotal trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in patients receiving glatiramer acetate compared with those receiving placebo. The rate was 78% less for glatiramer acetate than placebo patients in the pilot trial that investigated a slightly different patient population. Glatiramer acetate significantly decreased disease activity and burden of disease, as assessed in the European/Canadian study using a range of MRI measures. Patients with RRMS treated with glatiramer acetate in the US trial were significantly more likely to experience improved disability (whereas placebo recipients were more likely to experience worsening disability) and their overall disability status was significantly improved compared with placebo recipients. Data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years. Glatiramer acetate was generally well tolerated; the most commonly reported treatment-related adverse events were localised injection-site reactions and transient post-injection systemic reactions. Both reactions were generally mild and self limiting but were responsible for the majority of withdrawals from treatment (up to 6.5% and 3.5%, respectively). Glatiramer acetate is not associated with the influenza-like syndrome or neutralising antibodies that are reported in patients treated with interferon-beta for RRMS. The cost effectiveness of glatiramer acetate has yet to be definitively determined as assessment of available data is confounded by very different models, data sources and assumptions. In conclusion, glatiramer acetate has shown efficacy in well controlled clinical trials in patients with RRMS; it reduces relapse rate and decreases MRI-assessed disease activity and burden. It is generally well tolerated and is not associated with the influenza-like symptoms and formation of neutralising antibodies seen with the interferons-beta. Based on available data and current management guidelines, glatiramer acetate is a valuable first-line treatment option for patients with RRMS.

Adjuvants, Immunologic↗
PubMed2003

[Newer disease--modifying drugs: glatiramer acetate and mitoxantrone].

Glatiramer acetate(GA) is a synthetic molecule composed of four amino acids: glutamine, lysine, alanine, and tyrosine. These four amino acids are represented in myelin basic protein, which is a suspect antigen involved in the induction of autoimmunity in multiple sclerosis (MS). Subcutaneous GA 20 mg/day showed a reduction of the mean relapse rate and a slower decline of Expanded Disability Status Scale(EDSS) in patients with relapsing-remitting MS(RRMS). In addition, GA is effective in reducing magnetic resonance imaging(MRI) measured activity in patients with RRMS. The drug is generally well tolerated and is not associated with the influenza-like symptoms. Mitoxantrone(MX), a cytotoxic drug exhibiting very potent immunosuppressive properties, has been found effective on relapse rate and progression of disability in patients with worsening RRMS or secondary progressive MS. An induction phase with the monthly intravenous administration of 12 mg/m2 followed by a maintenance phase with 12 mg/m2 every 3 months for 2 years seems the most effective and safe treatment regimen, not exceeding the maximum cumulative dose of 140 mg/m2. Cardiotoxicity, the major long-term toxicity, is clearly dose-dependent and is a strict treatment duration limiting factor.

Central Nervous System↗
PubMed2004

Glatiramer acetate for the treatment of multiple sclerosis.

Glatiramer acetate (Copaxone, Teva Pharmaceuticals Ltd) is a collection of immunomodulatory, synthetic polypeptides indicated for the treatment of relapsing-remitting multiple sclerosis (RR MS). Preclinical and clinical studies provide an evolving understanding of the mechanisms by which glatiramer acetate exerts both immunological and potential neuroprotective effects that account for its clinical efficacy. The results of pivotal controlled clinical trials and long-term data, derived from organised extension studies, are evaluated in detail and supportive data from open-label comparison, combination treatment and therapeutic switch studies are considered in order to determine the place of glatiramer acetate among other approved therapies for RR MS. The efficacy of glatiramer acetate is stable or may increase over time and the drug has a favourable side effect profile. Glatiramer acetate is an appropriate first-line immunomodulatory therapy for RR MS.

Adjuvants, Immunologic↗
PubMed2002

Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis.

UNLABELLED: Glatiramer acetate is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS). In three randomised, double-blind trials in patients with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more effective than placebo for the primary outcome measure of each trial (mean relapse rate, proportion of relapse-free patients and number of gadolinium-enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse rate was significantly reduced at endpoint (approximately one-third less) in the two larger trials (the US pivotal trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in patients receiving glatiramer acetate compared with those receiving placebo. The rate was 78% less for glatiramer acetate than placebo patients in the pilot trial that investigated a slightly different patient population. Glatiramer acetate significantly decreased disease activity and burden of disease, as assessed in the European/Canadian study using a range of MRI measures. Patients with RRMS treated with glatiramer acetate in the US trial were significantly more likely to experience improved disability (whereas placebo recipients were more likely to experience worsening disability) and their overall disability status was significantly improved compared with placebo recipients. Data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years. Glatiramer acetate was generally well tolerated; the most commonly reported treatment-related adverse events were localised injection-site reactions and transient post-injection systemic reactions. Both reactions were generally mild and self limiting but were responsible for the majority of withdrawals from treatment (up to 6.5 and 3.5%, respectively). Glatiramer acetate is not associated with the influenza-like syndrome or neutralising antibodies that are reported in patients treated with interferon-beta for RRMS. The cost effectiveness of glatiramer acetate has yet to be definitively determined as assessment of available data is confounded by very different models, data sources and assumptions. CONCLUSION: Glatiramer acetate has shown efficacy in well controlled clinical trials in patients with RRMS; it reduces relapse rate and decreases MRI-assessed disease activity and burden. It is generally well tolerated and is not associated with the influenza-like symptoms and formation of neutralising antibodies seen with the interferons-beta. Based on available data and current management guidelines, glatiramer acetate is a valuable first-line treatment option for patients with RRMS.

Adjuvants, Immunologic↗
PubMed2004

Therapy with glatiramer acetate for multiple sclerosis.

BACKGROUND: Some clinical data have shown that glatiramer acetate (Copaxone), a synthetic amino acid polymer empirically found to suppress experimental allergic encephalomyelitis (EAE), an animal model of MS, might help improve the outcome of patients with multiple sclerosis (MS). OBJECTIVES: We performed a Cochrane review of all randomised, placebo-controlled trials of glatiramer acetate in MS, whatever the disease course. SEARCH STRATEGY: We searched the Cochrane MS Group trials register (June 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE (PubMed) (January 1966 to June 2003), EMBASE (January 1988 to June 2003) and hand searching of symposia reports (1990-2002) from the neurological Associations and MS Societies in both Europe and America. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS, whatever the administration schedule and disease course, were eligible for this review. DATA COLLECTION AND ANALYSIS: Both patients with relapsing-remitting (RR) and chronic progressive (CP) MS were analysed. Study protocols were comparable across trials as to patient entry criteria and outcome definition. No major flaws were found in methodological quality. However, efficacy of blinding should be balanced against well-known side effects, including injection-site reactions in glatiramer acetate-treated patients. MAIN RESULTS: A total of 646 patients contributed to this review, as it is summarised in Table 01. Glatiramer acetate did not show any significant effect on disease progression, measured as a sustained worsening in the Expanded Disability Status Scale (EDSS). On the other hand, a slight decrease in the mean EDSS score, driven by a major study, should be considered in the light of the limited validity of this outcome measure. No benefit was shown in CP MS patients (progression at two years: RR=0.69, 95% CI [0.33 to 1.46]). The frequency of reported adverse events does not support any major toxicity associated with glatiramer acetate administration. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, anxiety (relative risk = 3.40 (95% CI [2.22 to 5.21], p <0.00001]). Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable. REVIEWER'S CONCLUSIONS: Glatiramer acetate did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses. Therefore its routine use in clinical practice is not currently supported. More investigations are needed. Further research should also develop more reliable measures of patient disability over time and include quality of life among primary outcomes.

Glatiramer Acetate↗
PubMed2001

Glatiramer acetate for multiple sclerosis.

Glatiramer acetate (Copaxone-Teva) was first marketed in the UK last year as a treatment for reducing the "frequency of relapses in ambulatory patients with relapsing-remitting multiple sclerosis characterised by at least one clinical relapse over the preceding two-year period". Here, we assess the place of this drug.

Brain↗
PubMed2000

Human and murine CD4 T cell reactivity to a complex antigen: recognition of the synthetic random polypeptide glatiramer acetate.

The capacity of glatiramer acetate (GA), a random copolymer of alanine, lysine, glutamic acid, and tyrosine to stimulate primary in vitro human and murine T cell proliferation was examined. PBMCs isolated from healthy humans and relapsing remitting multiple sclerosis patients and spleen cells from inbred strains of mice, expressing different H-2 haplotypes, were used as sources of non-GA-primed lymphocytes. GA functioned as a universal Ag, inducing dose-dependent proliferation of all non-GA-primed human and murine T cell populations tested. Moreover, GA stimulated PBMCs derived ex vivo from human cord blood, strongly suggesting that GA can activate both naive and memory T cells. The human T cell proliferative responses to GA were HLA class II DR-restricted by virtue of the ability of anti-class II Ab to inhibit T cell proliferation, and the demonstration that individual GA specific human T cell clones were HLA class II DR-restricted by either restriction element but not both. Furthermore, GA-reactive T cells secreted Th0 cytokines and expressed a diverse repertoire of TCR. Limiting dilution analysis indicated that the T cell precursor frequency among the healthy human adults tested ranged from 1:5,000 to 1:125,000. Given that all of the T cell populations tested were isolated from non-GA-primed donors, it appears that virtually all humans and murine strains contain significant numbers of T cell populations cross-reactive with GA. These findings may explain the recent clinical finding that daily s.c. administration of GA ameliorates the progression of multiple sclerosis.

Adult↗
PubMed2005

Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action.

Glatiramer acetate is a synthetic random copolymer approved for the immunomodulatory therapy of relapsing-type multiple sclerosis (MS). Previous work has focused on the effects of this drug on T cells, especially the glatiramer-acetate-induced shift of the cytokine profile towards those characteristic of T-helper-2 (Th2) cells. Glatiramer acetate was thought to bring about this Th2 shift by acting like an altered peptide ligand but more recent work has shown that the drug notably affects the properties of antigen-presenting cells, such as monocytes and dendritic cells. These new observations might offer an explanation for the previously observed Th2 shift. In this review, we focus on these new findings. We address several controversial issues, including the possible neurotrophic effects of glatiramer acetate, the potential role of neutralising antibodies to the drug, and attempts to develop biomarkers of the treatment response. Finally, we will think about how a better understanding of glatiramer acetate might help the development of new immunomodulatory agents for MS.

Antibodies↗
PubMed2002

Cytokine production in T lymphocyte-microglia interaction is attenuated by glatiramer acetate: a mechanism for therapeutic efficacy in multiple sclerosis.

The efficacy of glatiramer acetate in multiple sclerosis (MS) is thought to involve the production of Th2 regulatory lymphocytes that secrete anti-inflammatory cytokines; however, other mechanisms cannot be excluded Given that activated T lymphocytes infiltrate into the CNS and become in dose proximity to microglia, we evaluated whether glatiramer acetate affects the potential interaction between T cells and microglia. We report that the co-culture of activated T lymphocytes with microglia led to the induction of several cytokines, and that these were reduced by glatiramer acetate treatment Morphological transformation of bipolar/ramified microglia into an activated ameboid form was attenuated by glatiramer acetate. These results reveal a novel mechanism for glatiramer acetate: the impairment of activated T cells to effectively interact with microglia to produce cytokines. The net result of a non-inflammatory milieu within the CNS, in spite of T cell infiltration, may help account for the amelioration of disease activity in MS patients on glatiramer acetate therapy.

Adult↗