Resumen estructurado de revisiones sistemáticas
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Background: In in patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein α4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an α4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. Methods: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. Results: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). Conclusions: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
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We describe the clinical course of a patient with multiple sclerosis in whom progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the central nervous system, developed during treatment with interferon beta-1a and a selective adhesion-molecule blocker, natalizumab. The first PML lesion apparent on magnetic resonance imaging was indistinguishable from a multiple sclerosis lesion. Despite treatment with corticosteroids, cidofovir, and intravenous immune globulin, PML progressed rapidly, rendering the patient quadriparetic, globally aphasic, and minimally responsive. Three months after natalizumab therapy was discontinued, changes consistent with an immune-reconstitution inflammatory syndrome developed. The patient was treated with systemic cytarabine, and two months later, his condition had improved.
Resumen estructurado de revisiones sistemáticas
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In the early 1990s, attention was drawn to the migration of immune cells into the central nervous system via the blood-brain barrier. The literature showed that lymphocytes binding to the endothelium were successfully inhibited by an antibody against α4β1 integrin. These biological findings resulted in the development of a humanized antibody to α4 integrin - natalizumab (NTZ) - to treat multiple sclerosis (MS). Here, we provide a systematic review and meta-analysis on the efficacy and safety of natalizumab, trying to answer the question whether its use may be recommended both in adult and in pediatric age groups as standard MS treatment. Our results highlight the improvement of clinical and radiological findings in treated patients (p < 0.005), confirming NTZ efficacy. Nevertheless, if NTZ is shown to be efficient, further studies should be performed to evaluate its safety and to target the MS profile that could benefit from this treatment.
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A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies.
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