Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848771 (neurological disability)
 928 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon-beta decreases the relapse rate, relapse severity, progression of neurological disability, and development of new brain lesions observed with brain magnetic resonance imaging in relapsing-remitting multiple sclerosis patients. The mechanism of action of this effect is presently unknown. This study was based on the hypothesis that immunoregulatory effects of interferon-beta may underlie its demonstrated clinical efficacy. The objective of the study was to determine the effect of interferon-beta-1a on the expression of interleukin-10, a cytokine that strongly inhibits cell-mediated immune responses. Interferon-beta-1a induced accumulation of interleukin-10 messenger RNA and protein secretion by cultured peripheral blood mononuclear cells. The observed in vitro effects were similar for healthy control subjects and multiple sclerosis patients. Intramuscular injections of interferon-beta-1a increased serum levels of interleukin-10 at 12 and 24 hours following the injection. Greater increases were induced with 12 x 10(6)-IU than 6 x 10(6)-IU injections. The effect of interferon-beta-1a was relatively specific for interleukin-10, as treatment with interferon-beta-1a did not result in accumulation of transforming growth factor-beta messenger RNA. Upregulation of interleukin-10 represents a possible mechanism of action of interferon-beta's therapeutic effect in relapsing-remitting multiple sclerosis, and has implications for therapy of other autoimmune diseases.
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PMID:Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis. 887 82

Osteopontin (OPN) is a pleiotropic integrin binding protein with functions in cell-mediated immunity, inflammation, tissue repair, and cell survival. Recent studies have shown that OPN may play an important role in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis (MS). Here, we investigated the plasma levels of OPN in 221 MS patients and 36 healthy controls using an enzyme-linked immunoassay. The MS group comprised of 71 patients with primary and transitional progressive MS (PP/TP-MS), 35 patients with secondary progressive MS (SPMS), and 115 patients with relapsing-remitting MS (RRMS)[46 patients during clinical remission, 26 patients during relapse, and 43 patients treated with interferon-beta (IFNbeta)]. Levels of OPN in plasma were elevated in SPMS patients compared with healthy controls, RRMS patients in remission, and PP/TP-MS patients. Patients with RRMS during relapse presented higher OPN levels than patients with RRMS during clinical remission. When MS patients were classified based on progression of neurological disability, an inverse relation between levels of OPN and disability progression was observed only in patients with relapsing MS. In RRMS patients receiving therapy with IFNbeta, OPN plasma levels were similar to RRMS patients during remission. These findings suggest that OPN is involved in both acute and chronic disease activity, thus expanding the role of OPN in MS pathogenesis suggested by previous studies. Furthermore, the different profiles of OPN levels found in acute relapses and chronic progression and its apparent lack of influence in primary progressive MS phenotypes raise interesting questions on the actual role of OPN in the pathogenesis of MS.
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PMID:Plasma osteopontin levels in multiple sclerosis. 1558 58

The introduction of new immunomodulatory therapies such as, interferon-beta, glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) and mitoxantrone (Ralenova, Wyeth Pharma; Novantrone, Immunex Corp.) has considerably improved the therapeutic options for patients with multiple sclerosis. These agents have been shown to reduce relapse rate, slow down progression of disability and prevent the accumulation of magnetic resonance imaging lesion load in clinically definite multiple sclerosis. Moreover, two formulations of interferon-beta delayed conversion into clinically definite multiple sclerosis in patients with clinically isolated syndromes suggestive of multiple sclerosis. Since axonal damage leading to irreversible neurological disability is already present early at the onset of the disease, immunomodulatory therapy should start as soon as possible. This article reviews the arguments for the early initiation of therapy and provides an overview of clinical studies dealing with the early treatment of multiple sclerosis.
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PMID:Disease-modifying drugs for the early treatment of multiple sclerosis. 1585 42

The presumed but as yet unspecified autoimmune-mediated basis for the pathogenesis of multiple sclerosis has led to attempts to modify the immune system of patients with this disease based on general and selective approaches. The rationale for using interferon-beta for the treatment of multiple sclerosis is based on its antiviral and complex immunoregulatory activities. Interferon-beta-1a (Avonex(R)) is a recombinant molecule which is indistinguishable from natural interferon-beta derived from human fibroblasts. Its precise mechanism of action is unknown, although effects on immune system processes which have been implicated in the pathogenesis of multiple sclerosis have been documented. T cell activation and migration into the CNS is a primary process in the pathogenesis of multiple sclerosis. In vitro and in vivo, interferon-beta-1a, compared with placebo or no treatment, significantly reduced expression of T cell surface activation markers, and significantly increased CNS levels of interleukin-10 - a potent inhibitor of cell-mediated immune responses. Pharmacokinetic studies indicate that intramuscular injection is the optimal route of administration for this formulation of interferon-beta-1a. In patients with relapsing-remitting multiple sclerosis who participated in a randomised double-blind trial, interferon-beta-1a 30mug (6 MIU) administered by intramuscular injection once weekly for 2 years (n = 158), compared with placebo (n = 143), significantly extended the time to onset of sustained neurological disability. Interferon-beta-1a also reduced the rate of disease relapse by approximately one-third compared with placebo, a finding which was supported by cranial magnetic resonance imaging (MRI) data showing significant reductions in lesion number and volume. Interferon-beta-1a was well tolerated, with influenza-like symptoms making up the majority of adverse reactions. The clinical significance of the beneficial effect of interferon-beta-1a on disease progression has been endorsed by the findings of a retrospective statistical analysis of the disability outcomes data obtained in the double-blind trial. In patients with relapsing multiple sclerosis, interferon-beta-1a is the only drug that has been demonstrated to significantly slow disease progression without excessive toxicity, in addition to significantly reducing the rate of relapse - measured clinically and by MRI. Notwithstanding the absence of long term tolerability data, and data from comparative trials with other agents, interferon-beta-1a represents a promising advance in drug therapy for relapsing multiple sclerosis.
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PMID:Interferon-beta-1a: A Review of its Pharmacological Properties and Therapeutic Potential in Multiple Sclerosis. 1802 May 22

Multiple sclerosis (MS) is a common cause of neurological disability in young adults. The disease generally manifests in early to middle adulthood and causes various neurological deficits. Autoreactive T lymphocytes and their associated antigens have long been presumed important features of MS pathogenesis. The Protein tyrosine phosphatase receptor type C gene (PTPRC) encodes the T-cell receptor CD45. Variations within PTPRC have been previously associated with diseases of autoimmune origin such as type 1 diabetes mellitus and Graves' disease. We set out to investigate two variants within the PTPRC gene, C77G and C772T in subjects with MS and matched healthy controls to determine whether significant differences exist in these markers in an Australian population. We employed high resolution melt analysis (HRM) and restriction length polymorphism (RFLP) techniques to determine genotypic and allelic frequencies. Our study found no significant difference between frequencies for PTPRC C77G by either genotype (Chi(2)=0.65, P=0.72) or allele (Chi(2)=0.48, P=0.49). Similarly, we did not find evidence to suggest an association between PTPRC C772T by genotype (Chi(2)=1.06, P=0.59) or allele (Chi(2)=0.20, P=0.66). Linkage disequilibrium (LD) analysis showed strong linkage disequilibrium between the two tested markers (D'=0.9970, SD=0.0385). This study reveals no evidence to suggest that these markers are associated with MS in the tested Australian Caucasian population. Although the PTPRC gene has a significant role in regulating CD4+ and CD8+ autoreactive T-cells, interferon-beta responsiveness, and potentially other important processes, our study does not support a role for the two tested variants of this gene in MS susceptibility in the Australian population.
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PMID:An investigation of the C77G and C772T variations within the human protein tyrosine phosphatase receptor type C gene for association with multiple sclerosis in an Australian population. 1911 28

All biopharmaceutical preparations are potentially immunogenic and need to be evaluated for the risk of development of neutralising antibodies (NAbs). In the case of interferon-beta preparations for the treatment of multiple sclerosis, persistently high-titres of NAbs are detectable in up to one-third of patients depending on the preparation used. In contrast, treatment with glatiramer acetate is not associated with the development of such antibodies, since its mechanism of action does not involve binding and activation of a specific receptor. The development of NAbs to interferon-beta abrogates biological activity in the short term, although the loss of clinical benefit usually only becomes manifest a year or more after antibodies are first detected. This loss of clinical benefit is apparent as a recrudescence of disease activity visible on magnetic resonance imaging, an increase in the frequency of relapses and a progression of neurological disability. Loss of biological activity can be detected very early after the appearance of NAbs using the MxA test, which can be used as a prognostic biological marker for probable future treatment failure. Current European guidelines recommend that all patients treated with an interferon-beta should be monitored systematically for the appearance of NAbs and that patients who develop persistent NAbs should discontinue their interferon-beta treatment. An option for the patients who have experienced less than two relapses in the previous year is to switch to treatment with glatiramer acetate. Such a strategy offers the best guarantee of providing good control of disease activity and optimal allocation of healthcare resources.
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PMID:Implications of neutralising antibodies on therapeutic efficacy. 1920 Aug 62

Multiple sclerosis (MS) is the commonest cause of progressive neurological disability amongst young, Caucasian adults. MS is considered to be an auto-immune disease that results from an attack against myelin, the layer which surrounds axons. The pathophysiology of MS is complex, with both demyelination and axonal degeneration contributing to what is essentially an inflammatory neurodegenerative disease. Axonal loss is increasingly being accepted as the histopathological correlate of neurological disability. Currently, the underpinnings of neurodegeneration in MS, and how to promote neuroprotection are only partly understood. No established treatments that directly reduce nervous system damage or enhance its repair are currently available. Moreover, the ability of currently available immunomodulatory therapies used to treat MS, such as interferon-beta, to prevent long-term disability is uncertain. Results from short-term randomized-controlled trials suggest a partial benefit with regards to disability outcomes, but this is yet to be established in long-term studies. Novel neuroprotective agents have been identified in preclinical studies but their development is being hampered by the absence of appropriate clinical platforms to test them. In this article, we will discuss some of the principal therapeutic candidates that could provide neuroprotection in MS and emerging methodologies by which to test them.
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PMID:Neuroprotection in multiple sclerosis: a therapeutic challenge for the next decade. 2012 60

Neuromyelitis optica (NMO) is a unique inflammatory condition characterized by selective involvement of the optic nerves and spinal cord. The cardinal features of NMO and a tendency of recurrence led to the classification of NMO as a subtype of multiple sclerosis (MS); however, it can be distinguished from MS on the basis of clinicoradiological and serological findings. In particular, NMO is characterized by the presence of spinal cord lesions that are longer than the total length of 3 vertebral segments and presence of anti-aquaporin 4 antibodies. Secondary progression of this condition is usually not observed, and therapy for NMO patients is designed to prevent acute exacerbations and limit irreversible neurological disability. Intravenous administration of a high dose of methylprednisolone is a standard treatment for patients with acute exacerbations of this condition, and patients with refractory cases are often responsive to plasmapheresis. To reduce the frequency of relapses and severity, standard therapies for MS, such as interferon-beta therapy, are not effective; further, a long-term immunosuppressive therapy is required for NMO patients. Immunosuppressive therapies often involve oral administration of prednisolone with or without azathioprine; patients who are refractory to the oral therapy may be treated by parental administration of cyclophosphamide, mitoxantrone, or rituximab. At present, there is no cure for NMO; early and precise diagnosis is critical to initiate immunosuppressive therapy for prevention of relapse.
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PMID:[Treatment and clinical management of patients with neuromyelitis optica and anti-aquaporin 4 antibody]. 2084 5

Basic disease-modifying treatment for relapsing forms of active multiple sclerosis (MS) is now available in many countries with high prevalence rates, for this chronic inflammatory disease of the central nervous system. Several lines of evidence support early immunomodulatory treatment with either recombinant interferon-beta or glatiramer acetate, and positive results from phase III trials encourage start of treatment even in patients with clinically isolated syndromes (CIS). However, currently available drugs for basic therapy are only partially effective and patients may still encounter relapses or disease progression. As treatment-refractory, clinically active MS can quickly lead to irreversible neurological disability there is an urgent need for effective escalating strategies. Patients with suboptimal treatment response to basic therapy have been treated with combination therapies, cytotoxic drugs (such as mitoxantrone and cyclophosphamide) or autologous hematopoietic stem cell transplantation. Recently, the monoclonal antibody, natalizumab, was added to this armamentarium. None of these strategies have been vigorously evaluated in large randomized, controlled phase III trials with patients who failed basic therapy. Therefore, the decision to escalate immunotherapy is still based on limited evidence. This article will review potential candidates for intensified immunosuppression and call for innovative study designs to better evaluate escalating immunotherapy in MS.
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PMID:Escalating immunotherapy of multiple sclerosis. 2118 May 76