RESUMO
BACKGROUND: Reperfusion injury is a significant complication of the management of ST-elevation MI (STEMI). INO-1001 is a potent inhibitor of poly(ADP-ribose) polymerase (PARP), a mediator of oxidant-induced myocyte dysfunction during reperfusion. METHODS & RESULTS: We assessed the safety and pharmacokinetics of INO-1001 in a randomized, placebo-controlled, single-blind, dose-escalating trial in 40 patients with STEMI undergoing primary percutaneous coronary intervention within 24 h of onset. INO-1001 was well-tolerated. A trend toward more frequent transaminitis was observed with 800 mg. Plasma from INO1001-treated patients reduced in vitro PARP activity >90% at all doses. Serial C-reactive protein and IL-6 levels showed a trend toward blunting of inflammation with INO-1001. The apparent median terminal half-life (t(1/2)) of INO-1001 was 7.5 (25th, 75th: 5.9, 10.2) h. CONCLUSIONS: The results from this first trial of INO-1001 in STEMI support future investigation of INO-1001 as a novel treatment for reperfusion injury.
Assuntos
Angioplastia Coronária com Balão , Indóis/farmacologia , Indóis/farmacocinética , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/enzimologia , Inibidores de Poli(ADP-Ribose) Polimerases , Angioplastia Coronária com Balão/métodos , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Meia-Vida , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Projetos Piloto , Poli(ADP-Ribose) Polimerases/sangue , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/enzimologiaAssuntos
Autoanticorpos/sangue , Proteínas de Ligação ao GTP/imunologia , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/enzimologia , Lúpus Eritematoso Sistêmico/imunologia , Transglutaminases/imunologia , Adulto , Sequência de Aminoácidos , Apoptose/genética , Apoptose/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , DNA/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Proteína 2 Glutamina gama-Glutamiltransferase , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/imunologia , Transglutaminases/genética , Transglutaminases/metabolismoAssuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Citrulina/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Proteínas de Filamentos Intermediários/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Ensaio de Imunoadsorção Enzimática/normas , Epitopos/genética , Epitopos/imunologia , Proteínas Filagrinas , Antígeno HLA-DR4/genética , Antígeno HLA-DR4/imunologia , Homozigoto , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Valor Preditivo dos Testes , Prognóstico , Precursores de Proteínas/metabolismo , Fator Reumatoide/sangue , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Translocation of intracellular components to the cell surface during the priming or apoptosis of polymorphonuclear leukocytes (PMN) is an important mechanism for interaction of antineutrophil cytoplasmic antibodies (ANCA) with these antigens. To test the capacity of apoptotic PMN to trigger production of ANCA, six groups of mice were immunized with either live or apoptotic lymphocytes, or with live, apoptotic, formalin-fixed, or lysed PMN. Mice immunized with both live and apoptotic neutrophils developed high titers of antibodies which gave a granular cytoplasmic immunofluorescent pattern. These antibodies were specific for lactoferrin and myeloperoxidase. Following a second intravenous infusion of apoptotic PMNs, mice developed anti-PR3 antibodies. Vasculitis lesions were not found in mice which developed ANCA. The ANCA-containing IgG fraction induced superoxide production by human PMNs. These results support the hypothesis that neutrophil-specific antigens presented on the cell membranes of apoptotic PMN may induce ANCA in the proper conditions.