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1.
Pediatr Cardiol ; 35(7): 1108-15, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24714980

RESUMO

Cardiopulmonary bypass (CPB) reduces coagulation factor levels through hemodilution and consumption. Differences in CPB-induced alterations of factor XIII (FXIII) levels in children with cyanotic and acyanotic congenital heart defects (CHDs) are not well characterized. FXIII activity (determined by Berichrom assay), prothrombin index, activated partial thromboplastin time, and fibrinogen were measured before open heart surgery with CPB and 5 days postoperatively for children older than 3 years with acyanotic (n = 30) and cyanotic (n = 30) CHDs. The preoperative FXIII levels did not differ significantly among the children of the compared groups. The cyanotic patients showed a significantly longer duration of CPB (111.4 ± 45.8 vs 71.5 ± 33.6 min; p = 0.026) and aortic cross-clamp (68.0 ± 27.1 vs 45.4 ± 31.4 min; p = 0.034). The drop in FXIII levels after termination of CPB was more profound for the children with cyanotic CHDs (87.1 ± 13.4 to 49.1 ± 13.2 vs 81.5 ± 12.6 to 58.6 ± 11.1 %, respectively; p = 0.018). The cyanotc patients also were restored to their baseline FXIII levels later than the children with acyanotic CHDs (at 48 vs 24 h). The post-CPB dynamics of the majority of the other coagulation parameters in the compared groups of patients were similar. The cyanotic patients experienced significantly greater postoperative blood loss than the acyanotic patients (12.6 ± 4.9 vs 5.0 ± 2.1 mL/kg; p < 0.001) and were transfused with larger volumes of red blood cells (10.4 ± 6.5 vs 4.2 ± 2.5 mL/kg; p = 0.007). The decrease in FXIII levels after CPB is more profound and lasts longer in children with cyanotic CHDs than in acyanotic patients. The rational strategy of postoperative FXIII replacement therapy for these categories of patients needs to be determined.


Assuntos
Coagulação Sanguínea/fisiologia , Procedimentos Cirúrgicos Cardíacos/métodos , Cianose/sangue , Fator XIII/metabolismo , Cardiopatias Congênitas/cirurgia , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Cianose/etiologia , Cianose/cirurgia , Feminino , Seguimentos , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/complicações , Humanos , Masculino , Período Pós-Operatório , Prognóstico , Estudos Prospectivos
2.
J Burn Care Res ; 35(4): 328-36, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24043240

RESUMO

The authors have previously shown that recombinant factor XIII (rFXIII) eliminates early manifestations of multiple-organ injury caused by experimental superior mesenteric artery occlusion or trauma-hemorrhagic shock. The aim of the present study was to test the hypothesis that rFXIII provides similar protective effect in experimental burn injury. Rats were randomly divided into five groups (eight animals per group): group 1: burn + placebo treatment; group 2: burn + rFXIII pretreatment; group 3: burn + rFXIII treatment; group 4: sham burn + placebo treatment, and group 5: sham burn + rFXIII treatment. Burn (40% of TBSA) was achieved by immersing the back and abdomen of a rat into 97°C water for 10 and 5 seconds, respectively. Infusion of rFXIII (1 mg/kg) or placebo was performed immediately after burn/sham burn in treatment groups or 24 hours before burn and repeated immediately after it in pretreatment group. Endpoint parameters measured 3 hours after burn/sham burn included muscle blood flow and PO2, lung permeability, gut histology, lung and gut myeloperoxidase activity, neutrophil respiratory burst, and FXIII activity. Both treatment and pretreatment with rFXIII partially preserved microvascular blood flow in the muscle. Muscle PO2 in pretreated rats did not differ from that in shams. Pretreatment but not treatment with rFXIII preserved lung permeability. rFXIII did not have any protective effect on other endpoint parameters. In contrast to superior mesenteric artery occlusion and trauma-hemorrhagic shock experimental models, rFXIII at the doses tested has a limited effect on preventing early manifestations of multiple-organ injury after experimental burn.


Assuntos
Queimaduras/complicações , Fator XIII/farmacologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/complicações , Choque Hemorrágico/complicações , Animais , Citometria de Fluxo , Íleo/metabolismo , Íleo/patologia , Pulmão/metabolismo , Masculino , Microcirculação/efeitos dos fármacos , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/metabolismo , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Neutrófilos/metabolismo , Oxigênio/metabolismo , Pressão Parcial , Permeabilidade/efeitos dos fármacos , Peroxidase/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos
3.
Blood ; 121(11): 2108-16, 2013 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-23335368

RESUMO

Frequent infusions of intravenous factor VIII (FVIII) are required to prevent bleeding associated with hemophilia A. To reduce the treatment burden, recombinant FVIII with a longer half-life was developed without changing the protein structure. FVIII-polyethylene glycol (PEG) conjugates were prepared using an enzymatic process coupling PEG (ranging from 10 to 80 kDa) selectively to a unique O-linked glycan in the FVIII B-domain. Binding to von Willebrand factor (VWF) was maintained for all conjugates. Upon cleavage by thrombin, the B-domain and the associated PEG were released, generating activated FVIII (FVIIIa) with the same primary structure and specific activity as native FVIIIa. In both FVIII- and VWF-deficient mice, the half-life was found to increase with the size of PEG. In vivo potency and efficacy of FVIII conjugated with a 40-kDa PEG (N8-GP) and unmodified FVIII were not different. N8-GP had a longer duration of effect in FVIII-deficient mouse models, approximately a twofold prolonged half-life in mice, rabbits, and cynomolgus monkeys; however, the prolongation was less pronounced in rats. Binding capacity of N8-GP on human monocyte-derived dendritic cells was reduced compared with unmodified FVIII, resulting in several-fold reduced cellular uptake. In conclusion, N8-GP has the potential to offer efficacious prevention and treatment of bleeds in hemophilia A at reduced dosing frequency.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Animais , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Modelos Animais de Doenças , Fator VIII/administração & dosagem , Fator VIII/metabolismo , Feminino , Glicosilação , Hemofilia A/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Coelhos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Resultado do Tratamento
4.
Thromb Haemost ; 101(5): 818-26, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19404533

RESUMO

The mechanism for the elimination of factor VII (FVII) from the circulation is unknown, just as it is unclear how activation of FVII to FVIIa and subsequent complex formation with antithrombin III (AT) or alpha2-macroglobulin (alpha2M) affects clearance. The possibility that the clearance mechanism involves activation and inhibitor complex formation as obligatory intermediate reactions is examined in this study. Human and murine sera were spiked with human FVIIa in the absence and presence of heparin and analysed for complex formation. Complex formation in vivo was studied after intravenous injection of (125)I-VIIa in mice; and the pharmacokinetics (PK) of human and murine FVIIa was studied in normal mice. Furthermore, comparative PK studies were performed with FVII, FVIIa, active site blocked FVIIa and a preformed FVIIa-AT complex in normal and alpha2M-deficient mice. The data demonstrated that FVIIa-AT complexes and to a much lesser extent FVIIa-alpha2M-complexes accumulated in vivo after FVIIa administration. FVIIa-AT accounted for about 50% of total FVIIa antigen left in the circulation after 3 hours. All FVII derivatives studied including FVII, FVIIa and FVIIa-AT were cleared with similar rates suggesting an elimination kinetics which is unaffected by FVII activation and subsequent inactivation by plasma inhibitors.


Assuntos
Antitrombina III/metabolismo , Fator VII/farmacocinética , Fator VIIa/farmacocinética , Soroglobulinas/metabolismo , alfa-Macroglobulinas/metabolismo , Animais , Fator VIIa/administração & dosagem , Heparina/sangue , Humanos , Injeções Intravenosas , Radioisótopos do Iodo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Soroglobulinas/deficiência , Soroglobulinas/genética , alfa-Macroglobulinas/deficiência , alfa-Macroglobulinas/genética
5.
Shock ; 31(6): 621-6, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18948851

RESUMO

Plasma factor XIII (FXIII) is responsible for stabilization of fibrin clot at the final stage of blood coagulation. Because FXIII has also been shown to modulate inflammation and endothelial permeability, we hypothesized that FXIII diminishes multiple organ dysfunction caused by gut I/R injury. A model of superior mesenteric artery occlusion (SMAO) was used to induce gut I/R injury. Rats were subjected to 45-min SMAO or sham SMAO and treated with recombinant human FXIII A2 subunit (rFXIII) or placebo at the beginning of the reperfusion period. Lung permeability, lung and gut myeloperoxidase activity, gut histology, neutrophil respiratory burst, and microvascular blood flow in the liver and muscles were measured after a 3-h reperfusion period. The effect of activated rFXIII on transendothelial resistance of human umbilical vein endothelial cells was tested in vitro. Superior mesenteric artery occlusion-induced lung permeability as well as lung and gut myeloperoxidase activity was significantly lower in rFXIII-treated versus untreated animals. Similarly, rFXIII-treated rats had lower neutrophil respiratory burst activity and ileal mucosal injury. Rats treated with rFXIII also had higher liver microvascular blood flow compared with the placebo group. Superior mesenteric artery occlusion did not cause FXIII consumption during the study period. In vitro, activated rFXIII caused a dose-dependent increase in human umbilical vein endothelial cell monolayer resistance to thrombin-induced injury. Thus, administration of rFXIII diminishes SMAO-induced multiple organ dysfunction in rats, presumably by preservation of endothelial barrier function and the limitation of polymorphonuclear leukocyte activation.


Assuntos
Fator XIII/farmacologia , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/etiologia , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/fisiopatologia , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Artéria Mesentérica Superior , Microcirculação/efeitos dos fármacos , Neutrófilos/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Explosão Respiratória/efeitos dos fármacos
6.
Br J Haematol ; 143(4): 559-69, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18950467

RESUMO

The haemostatic effect of recombinant activated factor VII (rFVIIa;NovoSeven) in thrombocytopenic patients has been a matter of controversy. Haemostasis by rFVIIa occurs via FVIIa-mediated thrombin generation in a platelet-dependent manner and may therefore be suboptimal in patients without functional platelets. Under such conditions, a clot-stabilizing agent, such as factor XIII (FXIII), may supplement the effect ofrFVIIa and improve haemostasis. Recombinant factor XIII (rFXIII-A2) is produced as an A2 homodimer of the FXIII A subunit and is equivalent to cellular FXIII normally found in platelets. The combined effects of rFVIIa andrFXIII-A2 were evaluated in clot lysis assays using factor XIII-deficient plasma and by whole blood thrombelastography (TEG) analysis from normal donors and thrombocytopenic stem cell transplantation patients. Clotting time was shortened by rFVIIa (0.6-10 microg/ml). rFVIIa only modestly improved anti-fibrinolysis,whereas rFXIII-A2 (0-20 microg/ml) enhanced anti-fibrinolysis without effect on clotting time. TEG analysis showed rFVIIa shortened the clotting time, and enhanced clot development, maximal mechanical strength and resistance to fibrinolysis, whereas, rFXIII-A2 enhanced clot development,maximal mechanical strength and markedly enhanced resistance to fibrinolysis. These data illustrate that rFVIIa and rFXIII-A2 contribute to clot formation and stability by different mechanisms suggesting enhanced haemostatic efficacy by combining these agents.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fator VIIa/farmacologia , Fator XIIIa/farmacologia , Trombocitopenia/sangue , Contagem de Células Sanguíneas , Relação Dose-Resposta a Droga , Fibrinólise/efeitos dos fármacos , Humanos , Proteínas Recombinantes/farmacologia , Transplante de Células-Tronco , Tromboelastografia/métodos , Trombocitopenia/terapia
7.
Blood ; 102(13): 4393-8, 2003 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-12933577

RESUMO

Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B.


Assuntos
Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Hemorragia/prevenção & controle , Animais , Animais Endogâmicos , Animais Recém-Nascidos , Anticorpos Heterófilos/biossíntese , Anticorpos Heterófilos/imunologia , Modelos Animais de Doenças , Cães , Fator IX/administração & dosagem , Fator IX/imunologia , Hemofilia B/complicações , Hemorragia/etiologia , Humanos , Tolerância Imunológica , Injeções Subcutâneas , Masculino , Projetos Piloto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Reprodutibilidade dos Testes
8.
Blood ; 102(2): 436-41, 2003 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12649145

RESUMO

Recombinant human interleukin-11 (rhIL-11), a glycoprotein 130 (gp130)-signaling cytokine approved for treatment of thrombocytopenia, also raises von Willebrand factor (VWF) and factor VIII (FVIII) by an unknown mechanism. Desmopressin (1-deamino-8-d-arginine vasopressin [DDAVP]) releases stored VWF and FVIII and is used for treatment of VWF and FVIII deficiencies. To compare the effect of these 2 agents, heterozygous von Willebrand disease (VWD) and normal dogs were treated with either rhIL-11 (50 microg/kg/d subcutaneously x 7 days) or DDAVP (5 microg/kg/d intravenously x 7 days). The rhIL-11 produced a gradual and sustained elevation of VWF and FVIII levels in both heterozygous VWD and normal dogs while DDAVP produced a rapid and unsustained increase. Importantly, rhIL-11 treatment produced a 2.5- to 11-fold increase in VWF mRNA in normal canine heart, aorta, and spleen but not in homozygous VWD dogs, thus identifying a mechanism for elevation of plasma VWF in vivo. Moreover, dogs pretreated with rhIL-11 retain a DDAVP-releasable pool of VWF and FVIII, suggesting that rhIL-11 does not significantly alter trafficking of these proteins to or from storage pools. The half-life of infused VWF is unchanged by rhIL-11 in homozygous VWD dogs. These results show that rhIL-11 and DDAVP raise plasma VWF by different mechanisms. Treatment with rhIL-11 with or without DDAVP may provide an alternative to plasma-derived products for some VWD and hemophilia A patients if it is shown safe in clinical trials.


Assuntos
Desamino Arginina Vasopressina/uso terapêutico , Interleucina-11/uso terapêutico , RNA Mensageiro/biossíntese , Corpos de Weibel-Palade/metabolismo , Doenças de von Willebrand/fisiopatologia , Fator de von Willebrand/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Desamino Arginina Vasopressina/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , Fator VIII/metabolismo , Meia-Vida , Coração/efeitos dos fármacos , Heterozigoto , Interleucina-11/farmacologia , Miocárdio/metabolismo , RNA Mensageiro/genética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Baço/efeitos dos fármacos , Baço/metabolismo , Corpos de Weibel-Palade/efeitos dos fármacos , Doenças de von Willebrand/tratamento farmacológico , Doenças de von Willebrand/genética , Fator de von Willebrand/biossíntese , Fator de von Willebrand/genética
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