RESUMO
Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC50 1-2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC50 0.27 and 0.28 µM, respectively) and Fcε receptor 1-mediated basophil degranulation (IC50 0.15 µM). Similar levels of ex vivo inhibition were measured after dosing in mice (Syk signaling IC50 0.32 µM). Syk-independent signaling and activation were unaffected at much higher concentrations, demonstrating the specificity of kinase inhibition in cellular systems. Oral administration of P505-15 produced dose-dependent anti-inflammatory activity in two rodent models of rheumatoid arthritis. Statistically significant efficacy was observed at concentrations that specifically suppressed Syk activity by â¼67%. Thus specific Syk inhibition can mimic Syk genetic deficiency to modulate immune function, providing a therapeutic strategy in P505-15 for the treatment of human diseases.
Assuntos
Artrite Experimental/prevenção & controle , Cicloexilaminas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Sinovite/prevenção & controle , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Artrite Experimental/complicações , Artrite Experimental/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Basófilos/efeitos dos fármacos , Basófilos/imunologia , Biocatálise/efeitos dos fármacos , Sangue/efeitos dos fármacos , Sangue/imunologia , Sangue/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cicloexilaminas/administração & dosagem , Cicloexilaminas/farmacocinética , Cicloexilaminas/uso terapêutico , Modelos Animais de Doenças , Edema/complicações , Edema/patologia , Edema/prevenção & controle , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Pé/patologia , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucócitos/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Ratos Endogâmicos LewRESUMO
Ceramic bearing surfaces have been introduced to prevent bone loss after osteolysis seen with conventional polyethylene bearing surfaces. One hundred three ceramic-on-ceramic total hip arthroplasties in 97 patients were retrospectively reviewed. Average follow-up was 50.4 months. Preoperative Harris Hip Score was 49.5 points, which improved to 87.2 postoperatively (P < .05). Pain score improved from 13.7 points preoperatively to 40.6 points postoperatively (P < .05). Functional score improved from 30 points preoperatively to 41 points postoperatively (P < .05). No fractures, dislocations, infections, or osteolysis was observed on radiographs. Five patients (4.9%), at 11, 16, 30, 38, and 60 months postoperatively, presented with "squeaky" hips that continue to perform well. Long-term studies will be required to determine the true efficacy of these hard bearing surfaces.