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1.
J Invest Dermatol ; 131(9): 1838-44, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21677670

RESUMO

JAKs are required for signaling initiated by several cytokines (e.g., IL-4, IL-12, IL-23, thymic stromal lymphopoietin (TSLP), and IFNγ) implicated in the pathogenesis of inflammatory skin diseases such as psoriasis and atopic dermatitis (AD). Direct antagonism of cytokines, such as IL-12 and IL-23 using ustekinumab, has proven effective in randomized studies in psoriasis patients. We hypothesized that local inhibition of cytokine signaling using topical administration of INCB018424, a small molecule inhibitor of JAK1 and JAK2, would provide benefit similar to systemic cytokine neutralization. In cellular assays, INCB018424 inhibits cytokine-induced JAK/signal transducers and activators of transcription (STAT) signaling and the resultant production of inflammatory proteins (e.g., IL-17, monocyte chemotactic protein-1, and IL-22) in lymphocytes and monocytes, with half-maximal inhibitory concentration values <100 nM. In vivo, topical application of INCB018424 resulted in suppression of STAT3 phosphorylation, edema, lymphocyte infiltration, and keratinocyte proliferation in a murine contact hypersensitivity model and inhibited tissue inflammation induced by either intradermal IL-23 or TSLP. Topical INCB018424 was also well tolerated in a 28-day safety study in Gottingen minipigs. These results suggest that localized JAK1/JAK2 inhibition may be therapeutic in a range of inflammatory skin disorders such as psoriasis and AD. Clinical evaluation of topical INCB018424 is ongoing.


Assuntos
Dermatite Atópica/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Pirazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Quimiocinas/metabolismo , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Células Epidérmicas , Humanos , Hipersensibilidade Tardia/tratamento farmacológico , Hipersensibilidade Tardia/metabolismo , Hipersensibilidade Tardia/patologia , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Nitrilas , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Psoríase/patologia , Pirazóis/química , Pirimidinas , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Suínos , Porco Miniatura , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
2.
J Immunol ; 184(9): 5298-307, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20363976

RESUMO

Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis. Kinase inhibitors have shown promising oral disease-modifying antirheumatic drug potential with efficacy similar to anti-TNF biologics. Direct and indirect inhibition of the JAKs, with small molecule inhibitors like CP-690,550 and INCB018424 or neutralizing Abs, such as the anti-IL6 receptor Ab tocilizumab, have demonstrated rapid and sustained improvement in clinical measures of disease, consistent with their respective preclinical experiments. Therefore, it is of interest to identify optimized JAK inhibitors with unique profiles to maximize therapeutic opportunities. INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including IL-6 and IL-23 at concentrations <50 nM. Significant efficacy, as assessed by improvements in clinical, histologic and radiographic signs of disease, was achieved in the rat adjuvant arthritis model with doses of INCB028050 providing partial and/or periodic inhibition of JAK1/JAK2 and no inhibition of JAK3. Diminution of inflammatory Th1 and Th17 associated cytokine mRNA levels was observed in the draining lymph nodes of treated rats. INCB028050 was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse hematologic effects. These data suggest that fractional inhibition of JAK1 and JAK2 is sufficient for significant activity in autoimmune disease models. Clinical evaluation of INCB028050 in RA is ongoing.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/enzimologia , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Artrite Experimental/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/fisiologia , Janus Quinase 1/fisiologia , Janus Quinase 2/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
3.
Blood ; 115(15): 3109-17, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20130243

RESUMO

Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC(50)] = 281nM), and proliferation of JAK2V617F(+) Ba/F3 cells (IC(50) = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F(+) polycythemia vera patients (IC(50) = 67nM) versus healthy donors (IC(50) > 400nM). In a mouse model of JAK2V617F(+) MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.


Assuntos
Janus Quinases/antagonistas & inibidores , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/uso terapêutico , Substituição de Aminoácidos/genética , Animais , Apoptose/efeitos dos fármacos , Contagem de Células Sanguíneas , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Citocinas/sangue , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/genética , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Camundongos , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/patologia , Nitrilas , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirimidinas , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia , Resultado do Tratamento
4.
Clin Cancer Res ; 15(22): 6891-900, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19887489

RESUMO

PURPOSE: Deregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is a hallmark for the Philadelphia chromosome-negative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy. EXPERIMENTAL DESIGN: A novel inhibitor of JAK1/2 was characterized using kinase assays. Cellular effects of this compound were measured in cell lines bearing the JAK2V617F or JAK1V658F mutation, and its antiproliferative activity against primary polycythemiavera patient cells was determined using clonogenic assays. Antineoplastic activity in vivo was determined using a JAK2V617F-driven xenograft model, and effects of the compound on survival, organomegaly, body weight, and disease-associated inflammatory markers were measured. RESULTS: INCB16562 potently inhibited proliferation of cell lines and primary cells from PV patients carrying the JAK2V617F or JAK1V658F mutation by blocking JAK-STAT signaling and inducing apoptosis. In vivo, INCB16562 reduced malignant cell burden, reversed splenomegaly and normalized splenic architecture, improved body weight gains, and extended survival in a model of JAK2V617F-driven hematologic malignancy. Moreover, these mice suffered from markedly elevated levels of inflammatory cytokines, similar to advanced myeloproliferative disease patients, which was reversed upon treatment. CONCLUSIONS: These data showed that administration of the dual JAK1/2 inhibitor INCB16562 reduces malignant cell burden, normalizes spleen size and architecture, suppresses inflammatory cytokines, improves weight gain, and extends survival in a rodent model of JAK2V617F-driven hematologic malignancy. Thus, selective inhibitors of JAK1 and JAK2 represent a novel therapy for the patients with myeloproliferative diseases and other neoplasms associated with JAK dysregulation.


Assuntos
Inibidores Enzimáticos/farmacologia , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mutação , Animais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Transplante de Neoplasias , Policitemia Vera/tratamento farmacológico
5.
Nurs Outlook ; 55(4): 169-175, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17678681

RESUMO

As the foundation of evaluating content for nursing leadership and administration courses, leadership and management competencies were identified from a literature review of 140 articles published between 2000-2004. Similarities and differences among the competencies were assessed. A large intersection of common competencies was discovered, indicating a lack of discrimination between leadership and management competencies. Arguably, this fusion ignores the different purposes served by leadership and management. Alternately, the convergence of leadership and management competencies might reflect that traditional distinctions have narrowed. Nevertheless, ambiguity persists regarding essential leadership and management competencies and the way they are reflected in nursing curricula. If concerns about the work environment are to be remedied for patients and staff, nurse educators are urged to act quickly to identify requisite competencies and better align course content with them. This will better prepare nurse administrators to succeed in their arduous work.


Assuntos
Liderança , Enfermeiros Administradores/educação , Enfermeiros Administradores/organização & administração , Papel do Profissional de Enfermagem , Supervisão de Enfermagem/organização & administração , Gestão de Recursos Humanos/normas , Competência Profissional/normas , Atitude do Pessoal de Saúde , Comunicação , Currículo , Bacharelado em Enfermagem , Educação de Pós-Graduação em Enfermagem , Guias como Assunto , Conhecimentos, Atitudes e Prática em Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Relações Interprofissionais , Enfermeiros Administradores/psicologia , Papel do Profissional de Enfermagem/psicologia , Pesquisa em Educação em Enfermagem , Sociedades de Enfermagem/organização & administração , Pensamento , Estados Unidos
6.
Prog Med Chem ; 40: 63-105, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12516523

RESUMO

An intensive research effort to identify potent, viable drugs for the management of acquired immunodeficiency syndrome (AIDS) resulted in the development of SUSTIVA (efavirenz), the first non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the FDA as a preferred first-line therapy. The search for NNRTIs that possess a broader activity spectrum against mutant viral forms of human immunodeficiency syndrome type-I reverse transcriptase culminated in the discovery that trifluoromethyl-containing quinazolin-2(1H)-ones possess potent activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs). This chapter reviews the discovery and structure activity relationships that resulted in the identification and subsequent preclinical and clinical development of four quinazolinone NNRTIs at the DuPont Pharmaceuticals Company.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Quinazolinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Humanos , Quinazolinas/química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
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