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1.
Azathioprine and its active metabolites can be detected in the cerebrospinal fluid (after i.v. injection). At a single dose of azathioprine maximum immunosuppressive activity occurs in the serum after 1 h and in the cerebrospinal fluid after about 4 h. Maximum immunosuppressive activity in human cerebrospinal fluid is about 12.5% of the equivalent serum level. A certain amount of time is needed for azathioprine and its metabolites to reach the cerebrospinal fluid where they remain for some time before passing into the serum, from where they are broken down. The findings are clinically important for the treatment of inflammatory nervous diseases, for example, multiple sclerosis, which are assumed to be of immunopathological origin.  相似文献   

2.
Cladribine is a purine nucleoside analog developed to treat lymphoid malignancies. Reported therapeutic benefits for the autoimmune disease multiple sclerosis indicate additional immunomodulatory effects beyond the well-characterized cytotoxic activity causing lymphopenia. Here, we demonstrate that cladribine reduces the secretion of inflammatory cytokines and chemokines by murine and human dendritic cells, the most potent antigen-presenting cells. This compound also modulates the expression of the activation markers CD86 and MHC II. Furthermore, cladribine affects the T cell priming capacity of dendritic cells, resulting in reduced induction of interferon-γ- and tumor necrosis factor-α-producing T cells and increased induction of interleukin-10-producing T cells. These effects, observed at cladribine concentrations in the therapeutically relevant range of serum steady-state concentrations for leukemia and multiple sclerosis, confirm the immunomodulatory activity of cladribine.  相似文献   

3.
The development of neutralizing antibodies to the protein drug interferon-?? is a significant impediment to its use in the treatment of multiple sclerosis. Neutralizing antibodies to interferon-?? arise from aggregation of the peptide during manufacturing and storage. We tested the ability of dodecylmaltoside, a nontoxic alkylsaccharide surfactant, to reduce aggregation of interferon-?? in vitro and to reduce its immunogenicity in vivo. Interferon-??, in solution with and without dodecylmaltoside, was periodically evaluated for aggregation by light scatter for 1?month. Interferon-??, with and without dodecylmaltoside, was given 3?days/week for 1?month to mice; the sera of these mice were analyzed for anti-interferon-?? antibodies by ELISA. Dodecylmaltoside reduces the aggregation of interferon-?? in vitro and its immunogenicity in vivo. Our positive findings warrant additional tests of dodecylmaltoside as a therapeutic adjuvant in rodent models of multiple sclerosis.  相似文献   

4.
Muir VJ  Plosker GL 《CNS drugs》2011,25(3):239-249
Cladribine, an immunosuppressant that selectively reduces peripheral lymphocyte levels, has potential as an oral therapy for relapsing-remitting multiple sclerosis. An oral (tablet) formulation is being investigated in clinical trials. In the large, well designed, phase III CLARITY trial, short-course treatment with oral cladribine (cumulative dose of 3.5 or 5.25 mg/kg) resulted in a significantly greater reduction in annualized relapse rates at 96 weeks compared with placebo in patients with relapsing-remitting multiple sclerosis. Improvements in the annualized relapse rate with oral cladribine were independent of key baseline patient characteristics which included age, sex, previous treatment with disease-modifying drugs and the number of relapses in the previous 12 months. In addition, a significantly higher proportion of patients were relapse-free at 96 weeks and there were significant reductions in the risk of 3-month sustained progression of disability in cladribine recipients compared with placebo recipients. The mean numbers of brain lesions on magnetic resonance imaging were also significantly reduced with cladribine compared with placebo in the CLARITY trial. Lymphocytopenia, herpes zoster infections and neoplasms (including malignancies) were more common in cladribine than placebo recipients.  相似文献   

5.
Several lines of evidence suggest that gender affects the susceptibility and course of multiple sclerosis. A higher disease prevalence, as well as an overall better prognosis, in women than men is observed. This sex dimorphism may be explained by the effect of sex hormones on brain damage and repair mechanisms. Experimental, clinical and MRI evidence confirms a pathogenetic link between sex hormones and multiple sclerosis, also suggesting sex-specific effects of hormones in multiple sclerosis pathology and therapy. A gender-based approach to multiple sclerosis could provide further benefits for its treatment and management.  相似文献   

6.
Tumor necrosis factor alpha, a proinflammatory cytokine, plays an important role in the clinical activity of relapsing?Cremitting multiple sclerosis and the development of progression. Dysregulation in the expression of tumor necrosis factor gene had been suggested in the pathogenesis of multiple sclerosis. Our aim was to investigate the relationship between tumor necrosis factor ???376 polymorphism with disease susceptibility and course of multiple sclerosis in Egyptian patients. Polymerase chain reaction and restriction fragment length polymorphism were carried out on 36 primary progressive multiple sclerosis patients, 36 age- and sex-matched remitting relapsing multiple sclerosis patients (diagnosed according to McDonald??s Diagnostic criteria) and 30 age- and sex-matched healthy controls. The GG genotype and the guanine allele (G) were detected significantly more often in the primary progressive (p?=?0.02; p?=?0.004, respectively) and remitting relapsing (p?=?0.015; p?=?0.024, respectively) multiple sclerosis groups as compared with the healthy control group. The G allele in the examined position in tumor necrosis factor alpha might have a role as regards susceptibility in both remitting relapsing and primary progressive multiple sclerosis.  相似文献   

7.
Multiple sclerosis is an autoimmune neurodegenerative disease, which usually caused by inflammation, demyelination, and axonal injury. The currently available medications for multiple sclerosis do not directly promote myelin sheath repair. Therefore, many researches have attempted to achieve better therapeutic effects through promoting remyelination. Natural products not only alleviate clinical symptoms, but also have the unique advantages of protecting and repairing effects on nervous system. We here present a systematic review on published papers about treating multiple sclerosis by natural products, aiming to provide comprehensive information on natural products in the treatment of multiple sclerosis.  相似文献   

8.
The first sign of developing multiple sclerosis is a clinically isolated syndrome that resembles a multiple sclerosis relapse. Objective/methods: The objective was to review the clinical trials of two medicines in clinically isolated syndromes (interferon β and glatiramer acetate) to determine whether they prevent progression to definite multiple sclerosis. In the BENEFIT trial, after 2 years, 45% of subjects in the placebo group developed clinically definite multiple sclerosis; the rate was lower in the interferon β-1b group. All subjects were then offered interferon β-1b, and the original interferon β-1b group became the early-treatment group and the placebo group became the delayed-treatment group. After 5 years, the number of subjects with clinical definite multiple sclerosis remained lower in the early-treatment than in the late-treatment group. In the PreCISe trial, after 2 years, the time for 25% of the subjects to convert to definite multiple sclerosis was prolonged in the glatiramer group. Interferon β-1b and glatiramer acetate slow the progression of clinically isolated syndromes to definite multiple sclerosis. However, it is not known whether this early treatment slows the progression to the physical disabilities experienced in multiple sclerosis.  相似文献   

9.
An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of multiple sclerosis, including spasticity and pain. Endogenous molecules with cannabinoid-like activity, such as the "endocannabinoids", have been shown to mimic the anti-inflammatory properties of cannabinoids through the cannabinoid receptors. Several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis. Indeed, they can down regulate the production of pathogenic T helper 1-associated cytokines enhancing the production of T helper 2-associated protective cytokines. A shift towards T helper 2 has been associated with therapeutic benefit in multiple sclerosis. In addition, cannabinoids exert a neuromodulatory effect on neurotransmitters and hormones involved in the neurodegenerative phase of the disease. In vivo studies using mice with experimental allergic encephalomyelitis, an animal model of multiple sclerosis, suggest that the increase of the circulating levels of endocannabinoids might have a therapeutic effect, and that agonists of endocannabinoids with low psychoactive effects could open new strategies for the treatment of multiple sclerosis.  相似文献   

10.
The evidence suggesting a role of extensive cortical demyelization and atrophy in progressive multiple sclerosis is rapidly increasing. Although conventional magnetic resonance imaging has had a huge impact on multiple sclerosis by enabling an earlier diagnosis, and by providing surrogate markers for monitoring disease response to anti-inflammatory/immunomodulatory treatments, it is limited by the low pathological specificity and the low sensitivity to both diffuse damage in normal-appearing white matter and focal and diffuse damage in gray matter. Advanced magnetic resonance imaging techniques can partially overcome these limitations by providing markers more specific to the underlying pathologic substrates and more sensitive to the structural and functional "occult" brain tissue damage in patients with multiple sclerosis. This review describes brain and spinal cord imaging studies of multiple sclerosis with particular emphasis on gray matter imaging in both secondary progressive and primary progressive multiple sclerosis, discusses the clinical implications of gray matter damage, and outlines current magnetic resonance imaging developments at high and ultrahigh magnetic field strength.  相似文献   

11.
The past decade has seen a surge of research interest in multiple sclerosis and an accelerated expansion of investigative efforts into multiple sclerosis therapeutics. Investigators have continued dissecting the complex immunological perturbations that may contribute to the disease and made major advances in understanding the genetics of multiple sclerosis. This article addresses current investigative issues and offers predictions about where the understanding and treatment of multiple sclerosis may stand at the end of the 21st century's second decade.  相似文献   

12.
Multiple sclerosis is a common human demyelinating disease of the central nervous system (CNS), and it is thought to involve autoimmune responses to CNS myelin antigens. Current symptomatic therapies for multiple sclerosis are in some cases ineffective and may have a high risk of serious side effects. This has led some multiple sclerosis patients to self-medicate with cannabis, which anecdotal evidence suggests may be beneficial in controlling symptoms such as spasticity, pain, tremor and bladder dysfunction. In support of these claims, results from experimental studies have suggested that cannabinoid-based treatments may be beneficial in a wide number of diseases. Furthermore, recent research in animal models of multiple sclerosis has demonstrated the efficacy of cannabinoids in controlling disease-induced symptoms such as spasticity and tremor, as well as in ameliorating the severity of clinical disease. However, these initially promising results have not yet been fully translated into the clinic. Although cannabinoid treatment of multiple sclerosis symptoms has been shown to be both well tolerated and effective in a number of subjective tests in several small-scale clinical trials, objective measures demonstrating the efficacy of cannabinoids are still lacking. Currently, a number of large-scale phase III clinical trials are under way to further elucidate the use of cannabinoids in the symptomatic treatment of multiple sclerosis. This review highlights the recent advances in our understanding of the endocannabinoid system, discusses both the experimental and clinical evidence for the use of cannabinoids to treat multiple sclerosis and explores possible future strategies of cannabinoid therapy in multiple sclerosis.  相似文献   

13.
多发性硬化症是炎性CD4+T细胞介导的中枢神经系统自身免疫脱髓鞘疾病,病程反复且不可逆,已成为除创伤外中国青壮年残疾的主要原因,且在幼儿中发病率逐年上升,给家庭和社会带来了沉重的经济负担。现有药物主要通过抑制免疫系统活性来缓解疾病,但仍无法治愈多发性硬化症。现已开展多项药物临床试验以寻找更为有效的多发性硬化症治疗策略,本文综述了多发性硬化症药物临床试验现状,质量影响因素及临床疗法,并试图阐明多发性硬化症药物临床试验潜在的改进领域和发展前景。  相似文献   

14.
Therapeutic strategies for multiple sclerosis have radically changed in the past 15 years. Five regulatory-approved immunomodulatory agents are reasonably effective in the treatment of relapsing-remitting multiple sclerosis, and appear to delay the time to progression to disabling stages. Inhibiting disease progression remains the central challenge for the development of improved therapies. As understanding of the immunopathogenesis of multiple sclerosis has advanced, a number of novel potential therapeutics have been identified, and are discussed here. It has also become apparent that traditional views of multiple sclerosis simply as a CD4+ T-cell-mediated disease of the central nervous system are incomplete. The pathogenic role of other immune components such as the innate immune system, regulatory T cells, T helper 17 cells and B cells is reaching centre stage, opening up exciting avenues and novel potential targets to affect the natural course of multiple sclerosis.  相似文献   

15.
Around 2.5 million people worldwide have multiple sclerosis, of whom about 85,000 are in the UK.1Natalizumab (pronounced na-ta-liz-you-mab; Tysabri - Biogen Idec), the first in a new class known as selective adhesion-molecule inhibitors, is licensed in the UK as monotherapy for "highly active" relapsing/remitting multiple sclerosis.2 Here we review natalizumab and assess its place for patients with multiple sclerosis.  相似文献   

16.
BACKGROUND: Multiple sclerosis is a debilitating autoimmune disorder that causes disability in young adults. OBJECTIVE: To review the efficacy and safety of IFN-beta1b in the management of relapsing-remitting and secondary progressive multiple scleroses and clinical isolated syndrome. METHODS: A MEDLINE (1966-May 2007) search of clinical trials using the terms 'multiple sclerosis' and 'interferon' was performed. Manual bibliographic search was conducted. English-language articles were evaluated. RESULTS: IFN-beta1b is more efficacious than placebo and at least as efficacious as IFN-beta1a or glatiramer for the management of relapsing-remitting multiple sclerosis. IFN-beta1b also delayed the time to diagnosis of definite multiple sclerosis and reduced brain lesion burden in patients with clinical isolated syndrome. More long-term, large scale clinical data are warranted to ascertain its relative efficacy compared to other treatments. CONCLUSION: IFN-beta1b is an effective treatment for multiple sclerosis. Common side effects are lymphopenia, injection site reactions, asthenia, flu-like symptoms and headache.  相似文献   

17.
Multiple sclerosis is common among women of childbearing age. Neuraxial blocks have been administered to them with reluctance because of the hypothetical risk that local anesthetics might be more histotoxic to neural tissue already compromised by multiple sclerosis. In spite of the lack of uniform guidelines on disorders in pregnancy like multiple sclerosis, and of the published data that sometimes contrast each other, experience gained in recent years has indicated that regional anesthesia is safe even in these patients, but there aren't many published cases. We describe the case of a pregnant woman affected by multiple sclerosis in which we administered spinal anesthesia for a cesarean section, and we analyzed the aspects that literature defines as critical points in this group of patients. The results were favorable with regard to the level, intensity and duration of anesthesia. No neurological exacerbations were recognized during the hospital stay, nor during the follow-up that lasted 12 months.  相似文献   

18.
多发性硬化是一种免疫介导的中枢神经系统炎症性脱髓鞘性疾病,目前尚无治愈方法。近年来利用甲状腺激素对多发性硬化的动物模型进行治疗,发现甲状腺激素可促进髓鞘再生,对轴索和神经元有保护作用,这就对治疗多发性硬化症开辟了一条新思路。综述了利用甲状腺激素在实验性自身免疫性脑脊髓炎(EAE)模型,双环己铜草酰二腙(CPZ)诱导脱髓鞘模型等动物模型中的研究进展,以期为临床应用以及新药研发提供参考。  相似文献   

19.
In the past few years there has been significant progress in the development of therapy for the treatment of relapsing remitting and secondary progressive multiple sclerosis. Research interest in multiple sclerosis (MS) therapeutics has remained high and clinical investigation into potential new therapies continues. This review summarises the advances with currently available therapies and briefly outlines the results from studies with other drugs being developed for the treatment of multiple sclerosis.  相似文献   

20.
Fingolimod     
《Prescrire international》2011,20(118):173-4, 176-7
In the absence of a better alternative, subcutaneous interferon beta is the standard first-line treatment for relapsing-remitting multiple sclerosis. Fingolimod, an oral immunosuppressant that reduces the circulating lymphocyte count, is in the process of receiving marketing authorisation for this use in the European Union. Initial clinical evaluation is based on 2 trials. In a 12-month, comparative, double-blind, randomised trial including 1292 patients daily treatment with oral fingolimod (0.5 mg or 1.25 mg) modestly prolonged the interval between exacerbations compared to weekly intramuscular injections of interferon beta-1a: about one exacerbation prevented every 6 years. No tangible impact on progression of disability was observed. A double-blind placebo-controlled trial that lasted 2 years also showed a statistically significant reduction in the annual frequency of exacerbations. There was no firm evidence that fingolimod had a tangible effect on progression of disability. An indirect comparison suggests that the impact of fingolimod on exacerbations is roughly similar to that of cladribine, another oral immunosuppressant that received a negative opinion in this indication from the European Medicines Agency. Several short-term adverse effects consistent with the pharmacological action of fingolimod and the results of animal pharmacology studies were observed in clinical trials, including infections (especially herpetic), pulmonary disorders, cardiac conduction disorders and macular oedema. A risk of lymphoma and heart failure is possible in the longer term. Given the modest gain in efficacy compared with interferon beta (based on weak supporting evidence) and the major adverse effects of fingolimod, it is better to continue to use interferon beta for initial treatment of relapsing-remitting multiple sclerosis, and to reserve fingolimod for use in clinical trials in which patients are closely monitored.  相似文献   

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