Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Desenho de Fármacos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Sistemas de Liberação de Medicamentos , Humanos , Integrina alfa4/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Esclerose Múltipla Recidivante-Remitente/metabolismo , Natalizumab , Resultado do TratamentoRESUMO
Natalizumab is a humanized monoclonal antibody to alpha 4 beta 1 integrin (VLA-4) currently under development by Elan and Biogen for the treatment of Crohn's disease and multiple sclerosis. Phase II trials in both indications have been completed, and by December 2002 phase III trials in Crohn's disease and multiple sclerosis had been initiated.
Assuntos
Anticorpos Monoclonais , Doença de Crohn/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Meia-Vida , Humanos , Natalizumab , Ensaios Clínicos Controlados Aleatórios como Assunto , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
Berlex and its parent company, Schering AG, are developing BX-471 (also known as ZK-811752), the lead in a series of non-peptide chemokine receptor 1 (CCR1) antagonists, for the potential treatment of autoimmune diseases, in particular multiple sclerosis (MS) [291682], [376290], [411184]. In March 2000, BX-471 was undergoing phase I trials for the potential treatment of autoimmune diseases [362022]; phase I trials in MS were ongoing in March 2002 [441989], [443941]. Positive results from these trials have been reported and Berlex was planning phase II trials in MS patients as of mid-March 2002 [444906]. In July 2001, Schering estimated filing in the US and EU in 2008 [411184], [416493]. WO-09856771 claims piperazinyl derivatives, pharmaceutical compositions comprising them and their use in the treatment of inflammatory conditions.
Assuntos
Esclerose Múltipla/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piperidinas/uso terapêutico , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Doenças Autoimunes/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Avaliação Pré-Clínica de Medicamentos , Rejeição de Enxerto/tratamento farmacológico , Humanos , Compostos de Fenilureia/química , Piperidinas/química , Receptores CCR1 , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
An important event in the pathogenesis of the autoimmune disease multiple sclerosis (MS) is the recruitment of lymphocytes and inflammatory macrophages to the central nervous system (CNS). Recruitment requires adhesive interactions between the leukocytes and the microvascular endothelium, perivascular cells, and astrocytes in the CNS parenchyma. Previous studies using an animal model of MS, experimental allergic encephalomyelitis (EAE), have shown the involvement of the alpha4 integrin VLA-4 (beta4beta1). In the present study, the effect of a modified peptide inhibitor of alpha4 integrins on the clinical course and leukocyte infiltration during EAE is investigated. EAE was either induced actively, by immunizing Lewis rats with whole guinea pig MBP, or passively, by transfer of an MBP-specific T cell line. Treatment with the inhibitor (CS1 ligand mimic) completely prevented both clinical signs and cellular infiltration in passively induced EAE. Peptide treatment of actively induced EAE, which has a more severe disease course than the transfer model, significantly reduced clinical signs although the recruitment of inflammatory cells and induction of MHC class II expression was not prevented. The alpha4 inhibitor did inhibit the adhesion of lymphocytes to primary astrocytes in vitro suggesting a role for astrocyte-leukocyte interactions in the pathogenesis of induced EAE. Astrocytes were found to express an extracellular matrix protein distinct from fibronectin, which shows immune cross-reactivity with the CS1 domain of fibronectin. Our results show that small-molecule inhibitors of alpha4 integrins act therapeutically in EAE possibly by interfering with cell adhesion events involved in this autoimmune disease.
