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1.
PLoS One ; 13(3): e0195122, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29590221

RESUMO

INTRODUCTION: Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. OBJECTIVE: To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. MATERIALS AND METHODS: In vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury. RESULTS: Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035). CONCLUSION: These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.


Assuntos
Anticoagulantes/farmacologia , Antídotos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Fator Xa/farmacologia , Hemorragia/tratamento farmacológico , Piridinas/farmacologia , Proteínas Recombinantes/farmacologia , Tiazóis/farmacologia , Animais , Modelos Animais de Doenças , Hemorragia/induzido quimicamente , Masculino , Coelhos
2.
Biochem J ; 385(Pt 2): 399-408, 2005 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-15456405

RESUMO

We developed a high-throughput HTRF (homogeneous time-resolved fluorescence) assay for Akt kinase activity and screened approx. 270000 compounds for their ability to inhibit the three isoforms of Akt. Two Akt inhibitors were identified that exhibited isoenzyme specificity. The first compound (Akt-I-1) inhibited only Akt1 (IC50 4.6 microM) while the second compound (Akt-I-1,2) inhibited both Akt1 and Akt2 with IC50 values of 2.7 and 21 microM respectively. Neither compound inhibited Akt3 nor mutants lacking the PH (pleckstrin homology) domain at concentrations up to 250 microM. These compounds were reversible inhibitors, and exhibited a linear mixed-type inhibition against ATP and peptide substrate. In addition to inhibiting kinase activity of individual Akt isoforms, both inhibitors blocked the phosphorylation and activation of the corresponding Akt isoforms by PDK1 (phosphoinositide-dependent kinase 1). A model is proposed in which these inhibitors bind to a site formed only in the presence of the PH domain. Binding of the inhibitor is postulated to promote the formation of an inactive conformation. In support of this model, antibodies to the Akt PH domain or hinge region blocked the inhibition of Akt by Akt-I-1 and Akt-I-1,2. These inhibitors were found to be cell-active and to block phosphorylation of Akt at Thr308 and Ser473, reduce the levels of active Akt in cells, block the phosphorylation of known Akt substrates and promote TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand)-induced apoptosis in LNCap prostate cancer cells.


Assuntos
Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , Peptídeos/química , Peptídeos/genética , Fosfoproteínas/química , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Homologia de Sequência de Aminoácidos , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Trifosfato de Adenosina/metabolismo , Proteínas Reguladoras de Apoptose , Benzilaminas/farmacologia , Ligação Competitiva , Proteínas Sanguíneas/imunologia , Carcinoma/química , Carcinoma/metabolismo , Carcinoma/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Clonagem Molecular , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Masculino , Glicoproteínas de Membrana/farmacologia , Estrutura Molecular , Peptídeos/imunologia , Peptídeos/metabolismo , Fosfoproteínas/imunologia , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Quinoxalinas/farmacologia , Transdução de Sinais/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF , Fator de Necrose Tumoral alfa/farmacologia , Neoplasias do Colo do Útero/química , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
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