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Métodos Terapêuticos e Terapias MTCI
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1.
Ann Rheum Dis ; 75(1): 253-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25165034

RESUMO

OBJECTIVE: Biological disease-modifying antirheumatic drugs (DMARDs) that inhibit aberrant immune reactions in rheumatoid arthritis (RA) cannot induce complete remission in all patients. Combination therapies using two biological DMARDs have failed to exert additive effects and increased serious infections. We have found that cell cycle inhibition of synovial fibroblasts with cyclin-dependent kinase (CDK) inhibitors ameliorated the disease in animal models of RA without attenuating acquired immunity. The objective of this study was to determine whether a clinically well-tolerated selective CDK 4/6 inhibitor (CDKI), palbociclib, is effective and whether combination with cytokine blockers acts additively without enhancing immune suppression. METHODS: The effects of CDKI on haematopoiesis and physical and behavioural findings in mice were evaluated. Mice with collagen-induced arthritis (CIA) were treated with CDKI, etanercept or anti-interleukin (IL)-6 receptor antibody (MR16-1) alone or with a combination of CDKI with etanercept or MR16-1. Their clinical, histological and radiographic scores, serum anti-(type II collagen (CII)) antibody levels and proliferative responses of lymph node cells to CII were determined. RESULTS: Although CDKI induced marginal myelosuppression, it was well tolerated and ameliorated CIA dose-dependently. The combinations of low-dose CDKI and either tumour necrosis factor-α or IL-6 blocker enhanced the antiarthritic effects additively. The addition of CDKI to either cytokine blocker did not affect the levels of anti-CII antibodies and proliferative responses of lymphocytes to CII. CONCLUSIONS: A clinically well-tolerated CDK4/6 inhibitor exerted antiarthritic effects in this mouse model. By combining therapeutic agents targeting immune reaction and synovial proliferation, we have demonstrated for the first time that two molecular targeting treatments act additively and may not increase immune suppression.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/toxicidade , Formação de Anticorpos/efeitos dos fármacos , Antirreumáticos/administração & dosagem , Antirreumáticos/toxicidade , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Etanercepte/administração & dosagem , Etanercepte/uso terapêutico , Etanercepte/toxicidade , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Terapia de Alvo Molecular/métodos , Piperazinas/administração & dosagem , Piperazinas/toxicidade , Piridinas/administração & dosagem , Piridinas/toxicidade , Receptores de Interleucina-6/antagonistas & inibidores
2.
Sci Rep ; 4: 6406, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25230773

RESUMO

Small-vessel vasculitis is a life-threatening autoimmune disease that is frequently associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Conventional immunotherapy including steroids and cyclophosphamide can cause serious adverse events, limiting the efficacy and safety of treatment. Eicosapentaenoic acid (EPA), a key component of fish oil, is an omega-3 polyunsaturated fatty acid widely known to be cardioprotective and beneficial for vascular function. We report two elderly patients with systemic ANCA-associated vasculitis (AAV) in whom the administration of EPA in concert with steroids safely induced and maintained remission, without the use of additioal immunosuppressants. To explore the mechanisms by which EPA enhances the treatment of AAV, we employed SCG/Kj mice as a spontaneous murine model of AAV. Dietary enrichment with EPA significantly delayed the onset of crescentic glomerulonephritis and prolonged the overall survival. EPA-derived anti-inflammatory lipid mediators and their precursors were present in the kidney, plasma, spleen, and lungs in the EPA-treated mice. Furthermore, a decrease in ANCA production and CD4/CD8-double negative T cells, and an increase in Foxp3(+) regulatory T cells in the lymph nodes of the kidney were observed in the EPA-treated mice. These clinical and experimental observations suggest that EPA can safely support and augment conventional therapy for treating autoimmune small-vessel vasculitis.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Modelos Animais de Doenças , Ácido Eicosapentaenoico/uso terapêutico , Imunomodulação/efeitos dos fármacos , Idoso , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Western Blotting , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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