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2.
Mult Scler ; 10(5): 511-20, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15471366

RESUMEN

In this open-label drug-interaction trial, we studied 38 patients with relapsing-remitting multiple sclerosis (MS) who received 3.0 or 6.0 mg/kg of natalizumab as a single intravenous (i.v.) infusion during stable treatment with intramuscular (i.m.) interferon beta-1a 30 microg (IFNbeta-1a; Avonex). To assess the pharmacokinetic (PK) interaction of natalizumab and IFNbeta-1a, serum concentration-time data for both agents were collected and analysed. Biologic response markers of IFNbeta-1a activity, beta2-microglobulin and neopterin, were also assessed to determine effects of natalizumab on IFNbeta-1a pharmacodynamics (PD). Further, safety and immunogenicity were evaluated. The combination of drug therapies was well tolerated. Although natalizumab serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFNbeta-1a, when compared to the same dose (6.0 mg/kg) administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant. In general, natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFNbeta-1a. The presence of antibodies to IFNbeta-1a and natalizumab was relatively low. Overall, the study provided safety, immunogenicity, PK and PD data to support a combination strategy for the use of natalizumab and IFNbeta-1a in the treatment of patients with relapsing-remitting MS. A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Interferón beta/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/farmacocinética , Adulto , Anticuerpos/sangre , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Interferón beta-1a , Interferón beta/efectos adversos , Interferón beta/farmacocinética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/inmunología , Natalizumab , Resultado del Tratamiento
3.
Neurology ; 57(2): 279-89, 2001 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-11468313

RESUMEN

OBJECTIVE: To provide clinical, electrophysiologic, and ultrastructural findings in three patients with a presynaptic congenital myasthenic syndrome (CMS). BACKGROUND: Familial infantile myasthenia and paucity of synaptic vesicles are the only two fully characterized CMS. We are describing here three patients with another form of presynaptic CMS characterized by deficiency of the action potential-dependent release without reduction of the spontaneous release of neurotransmitter from the nerve terminal. METHODS: The authors performed electromyography and anconeus muscle biopsies that included intracellular recordings and electron microscopy of the neuromuscular junction in three patients with presynaptic CMS. They also sequenced part of the P/Q-calcium alpha(1)-subunit gene (CACNA1A) and the acetylcholine receptor subunit (AChR) genes in these patients. RESULTS: In these patients there were additional neurologic findings including nystagmus and ataxia. In all three patients the end-plate potential quantal content (m) was markedly reduced but neither the amplitudes nor the frequencies of miniature end-plate potentials were diminished. Ultrastructurally, postsynaptic end-plate folds, nerve terminal size, and synaptic vesicle number were normal but double-membrane-bound sacs containing synaptic vesicles were present in the nerve terminal of all three patients. The screening of reported pathogenic mutations in the CACNA1A and a mutational analysis of AChR subunit genes were negative. CONCLUSION: This form of CMS appears to result only from a deficiency of the quantal release of neurotransmitter that may be due to an abnormal calcium mechanism or impaired endocytosis and recycling of synaptic vesicles.


Asunto(s)
Síndromes Miasténicos Congénitos/etiología , Síndromes Miasténicos Congénitos/fisiopatología , Neurotransmisores/deficiencia , Terminales Presinápticos/fisiología , Adolescente , Niño , Electromiografía , Humanos , Masculino , Microscopía Electrónica , Músculos/fisiopatología , Unión Neuromuscular/fisiopatología , Unión Neuromuscular/ultraestructura
5.
Acta Neurol Scand ; 100(3): 139-47, 1999 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10478576

RESUMEN

INTRODUCTION: The presence of T-cell reactivity to alphaB-crystallin in patients with multiple sclerosis (MS) has suggested that this small molecular weight heat shock protein (Hsp) may be an autoantigen in MS. MATERIAL AND METHODS: We have tested the serum of patients with clinically definite MS (n=30), other inflammatory neurological disease (n=22), non-inflammatory neurological disease (n=42) and healthy individuals (n=23) for systemic humoral responses to bovine alphaB-crystallin, to the homologous chaperone protein, alphaA-crystallin, and to another small Hsp, Hsp 27. RESULTS: Sixty-three percent of MS patients exhibited immunoreactivity to alpha-crystallin and this was present in all 4 of 4 non-ambulatory patients with MS. In contrast, serum concentrations in MS patients of antibodies to the small Hsp, Hsp27, and to myelin basic protein were negligible (P<0.001). Serum anti-alpha-crystallin immune responses were detected in significantly lower percentages of patients with other inflammatory neurological diseases (32%, P<0.025), and with non-inflammatory neurological diseases (12%, P<0.001). None of the healthy control individuals showed anti-alpha-crystallin reactivity. The concentration of anti-alpha-crystallin antibodies in patients with MS correlated with severe disease (P<0.05) and with active disease (P<0.025). CONCLUSION: Our observations support the notion that anti-alpha-crystallin autoimmune responses may contribute to pathogenicity in MS and may represent a mechanism of how recurrent attacks of MS develop subsequent to an isolated demyelinating episode.


Asunto(s)
Cristalinas/inmunología , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/inmunología , Adulto , Anciano , Especificidad de Anticuerpos , Autoanticuerpos/sangre , Autoantígenos/inmunología , Ensayo de Inmunoadsorción Enzimática , Epítopos , Femenino , Proteínas de Choque Térmico/inmunología , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad , Proteína Básica de Mielina/inmunología , Fragmentos de Péptidos/inmunología , Recurrencia , Serina Endopeptidasas , Estudios Seroepidemiológicos , Índice de Severidad de la Enfermedad
6.
J Neurol Neurosurg Psychiatry ; 65(6): 857-62, 1998 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9854961

RESUMEN

Morvan's fibrillary chorea is a rare disease characterised by symptoms which include neuromyotonia, cramping, weakness, pruritus, hyperhidrosis, insomnia, and delirium. The first case of Morvan's fibrillary chorea to be associated with clinical manifestations of myasthenia gravis with thymoma, psoriasis, and atopic dermatitis is reported. Muscle histopathology disclosed chronic denervation and myopathic changes and in vitro electrophysiology demonstrated both presynaptic and postsynaptic defects in neuromuscular transmission. Serum antibodies to acetylcholine receptors, titin, N-type calcium channels, and voltage gated potassium channels were detected. Plasmapheresis, thymectomy, and long term immunosuppression induced a dramatic resolution of symptoms. The association of thymoma with other autoimmune disorders and autoantibodies, and prolonged and sustained remission with chronic immunosuppression, place Morvan's fibrillary chorea on the range of neurological diseases arising as a paraneoplastic complication of cortical thymomas.


Asunto(s)
Corea/complicaciones , Síndromes Paraneoplásicos , Timoma/complicaciones , Neoplasias del Timo/complicaciones , Biopsia , Corea/diagnóstico , Progresión de la Enfermedad , Electromiografía/métodos , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Espasticidad Muscular/complicaciones , Músculo Esquelético/inervación , Músculo Esquelético/patología , Rinitis Alérgica Estacional/complicaciones
17.
Arch Neurol ; 54(7): 862-4, 1997 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9236575

RESUMEN

BACKGROUND: When lupus presents with isolated central nervous system findings, the usual serologic markers are often absent and diagnostic difficulty with a delay in treatment is common. OBJECTIVE: To report the usefulness of antiribosomal P protein antibodies in the diagnosis of lupus isolated to the central nervous system when results of tests for anti-double-stranded DNA antibodies are negative. DESIGN: Case report. SETTING: University medical center. PATIENT: The patient was evaluated and treated on referral and follow up for 1 year. RESULTS: We describe a patient with acute onset of psychosis followed by coma and focal clonic movements with undetectable DNA antibodies. Serum antiribosomal P protein antibody levels were elevated. Steroid therapy was followed by marked clinical improvement and a decrease in antibody titer. CONCLUSION: Antiribosomal P protein antibodies provide an important confirmatory test for the diagnosis of lupus isolated to the central nervous system when results of tests for anti-double-stranded DNA antibodies are negative.


Asunto(s)
Autoanticuerpos/inmunología , Enfermedades del Sistema Nervioso Central/diagnóstico , Lupus Eritematoso Sistémico/diagnóstico , Proteínas Protozoarias , Proteínas Ribosómicas/inmunología , Adulto , Femenino , Humanos
19.
Semin Neurol ; 14(2): 106-10, 1994 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-7984824

RESUMEN

Much is known about the pathogenesis of MG. This information has provided a rational basis for treatment of the disease, which is very effective. On the other hand, present treatments are limited by significant adverse effects. Our knowledge of pathogenesis also provides clues for the development of new, effective, but less toxic treatments. In addition, knowledge of the autoimmune mechanisms in MG may be useful in devising better treatments for the many human autoimmune diseases that are less well understood.


Asunto(s)
Miastenia Gravis/inmunología , Unión Neuromuscular/inmunología , Receptores Nicotínicos/inmunología , Animales , Terapia Combinada , Modelos Animales de Enfermedad , Humanos , Inmunización/efectos adversos , Miastenia Gravis/terapia , Transmisión Sináptica/inmunología
20.
Neurol Clin ; 12(2): 273-84, 1994 May.
Artículo en Inglés | MEDLINE | ID: mdl-8041342

RESUMEN

Much of the remarkable advance in our understanding of the immunopathology of MG relates to the availability of two gifts of nature that permit the ready purification of the antigen, AChR. Immunization of experimental animals with AChR has led to the development of the extremely faithful animal model, EAMG. Analysis of both EAMG and MG has revealed that the effector agents in this autoimmune disease are anti-AChR antibodies, whose production is regulated by anti-AChR CD4+ T cells. The pathogenic effects on neuromuscular transmission are mediated by antibody-induced antigenic modulation of end-plate AChR, end-plate membrane destruction through complement fixation and recruitment of inflammatory cells, and antibody-induced blockade of the function of the remaining AChR molecules. The origin of MG remains unknown. One theory proposes that dysregulation of the thymic control of tolerance plays an important role. An alternative hypothesis is that tolerance is broken as the result of a vigorous immune response directed against an invading microorganism that expresses a molecule that is similar to AChR, so-called molecular mimicry. This "normal" response eventually cross-reacts with self-AChR, resulting in the autoimmune damage. Our current knowledge of MG has suggested a number of possible sites of therapeutic intervention that are under active study. Future information concerning the origin of the disease will likely be useful in the design of more effective treatment for this and other related autoimmune diseases.


Asunto(s)
Autoinmunidad , Miastenia Gravis/inmunología , Animales , Humanos
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