RESUMO
INTRODUCTION: Patients with acquired haemophilia A (AHA) have autoantibodies against factor VIII (FVIII), and may develop spontaneous bleeding that requires treatment with FVIII inhibitor bypassing agents such as recombinant activated FVII (rFVIIa, NovoSeven® ). However, data regarding the use of rFVIIa are limited. AIM: To investigate the use, efficacy and safety of rFVIIa for the treatment of AHA by analysis of 10-year multicentre Japanese postmarketing surveillance data. METHODS: Treatment regimens, haemostatic efficacy and adverse events were recorded for rFVIIa therapy of AHA patients with bleeding episodes. Treatment was evaluated as markedly effective, effective, moderate or ineffective. RESULTS: Data were collected for 371 bleeding episodes in 132 patients. Bleeding improved after rFVIIa therapy in 92% of episodes (markedly effective in 41%, effective in 10%, moderate in 41%). The response rate was significantly better in patients who received an initial dose of ≥90 µg kg-1 than in those who received an initial dose of <90 µg kg-1 . The response rate was also significantly better when rFVIIa was administered earlier after the onset of bleeding. Twelve serious adverse events were recorded in six patients, including five serious thromboembolic events in three patients who were all elderly with significant comorbidities. CONCLUSION: This is the largest, single-country study of rFVIIa therapy in AHA patients reported to date. The Japanese surveillance data show comparable efficacy and safety to prior multinational studies. Doses of 90-120 µg kg-1 and prompt initiation of treatment may be important to achieve good bleeding control.
Assuntos
Fator VIIa/uso terapêutico , Hemofilia A/complicações , Hemorragia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Monitoramento Epidemiológico , Fator VIIa/efeitos adversos , Feminino , Hemofilia A/tratamento farmacológico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Adulto JovemRESUMO
INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 µg kg-1 MC710 (as FVIIa) once or twice (to a maximum of 180 µg kg-1 ) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale (VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion (ROM) for improvement of joint mobility. RESULTS: In 21 treatments for bleeding episodes, 19 were rated "excellent" or "effective" 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation (DIC). CONCLUSION: These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors.
Assuntos
Fator VIIa/uso terapêutico , Fator X/uso terapêutico , Hemofilia A/tratamento farmacológico , Adolescente , Adulto , Humanos , Masculino , Adulto JovemRESUMO
MC710, a mixture of plasma-derived activated factor VII and factor X at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In a Phase II trial, we evaluated the haemostatic efficacy and safety of single doses of MC710, and investigated pharmacokinetic and pharmacodynamic parameters in nine joint bleeding episodes in six male haemophilia patients with inhibitors. This trial was a multi-centre, open-label, non-randomized study of two doses (60 and 120 µg kg(-1) as FVIIa dose), allowing the re-administration of different MC710 dosages to the same subjects. Haemostatic efficacy was assessed by evaluating reduction in pain and swelling, as well as increase in range of motion in a bleeding joint. The results of the study showed that in nine bleeding episodes, seven treatments were rated as 'excellent' or 'effective' according to investigator's rating system of efficacy at 8 h after administration. No serious or severe adverse events were observed after administration; furthermore, measurement of several diagnostic markers revealed no signs or symptoms of disseminated intravascular coagulation (DIC). The haemostatic potential of MC710 was confirmed at doses of 60 and 120 µg kg(-1) in this trial. MC710 is thus expected to be a safe and efficacious novel bypassing agent for controlling bleeding in haemophilia patients with inhibitors.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/sangue , Coagulantes/uso terapêutico , Fator VIIa/uso terapêutico , Fator X/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Adolescente , Adulto , Coagulantes/farmacocinética , Esquema de Medicação , Quimioterapia Combinada , Fator VIIa/farmacocinética , Fator X/farmacocinética , Meia-Vida , Hemorragia/prevenção & controle , Humanos , Masculino , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Adulto JovemRESUMO
We reported the results of a clinical pharmacological study of MC710 (a mixture of plasma-derived FVIIa and FX) in haemophilia patients with inhibitors during a non-haemorrhagic state. This report provides the results of a clot waveform analysis (CWA) and thrombin generation test (TGT) using blood samples obtained in this study. CWA and TGT were conducted using blood samples obtained from a pharmacokinetic and pharmacodynamic study in which MC710 (five dose rates: 20, 40, 80, 100 and 120 µg kg(-1)) was compared with NovoSeven (120 µg kg(-1)) and FEIBA (two dose rates: 50 and 75 U kg(-1)) as control drugs in 11 haemophilia patients with inhibitors without haemorrhagic symptoms. CWA showed that MC710 provided significantly greater improvement than the control drugs in activated partial thromboplastin time (APTT) at 80 µg kg(-1); maximum clot velocity and maximum clot acceleration were more enhanced by MC710 than by control drugs. TGT revealed that MC710 significantly shortened the initiation time of thrombin generation in comparison to FEIBA and induced greater thrombin generation potency than NovoSeven. It was not clear whether or not MC710 caused significant dose-dependent changes in the two measurements; however, differences between MC710 and the control drugs were clarified. MC710 was confirmed to have superior coagulation activity and thrombin productivity and is expected to have superior bypassing activity.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fator VIIa/farmacologia , Fator X/farmacologia , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Adolescente , Adulto , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Testes de Coagulação Sanguínea/métodos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Hemofilia A/sangue , Hemofilia B/sangue , Humanos , Japão , Masculino , Trombina/metabolismo , Adulto JovemRESUMO
MC710, a combined product of plasma-derived activated factor VII (FVIIa) and factor X (FX) at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In this study, pharmacokinetic (PK), pharmacodynamic (PD) parameters and safety of single doses of MC710 were investigated in 11 male haemophilia patients with inhibitors in a non-bleeding state. This was a multi-centre, open-labelled, non-randomized, active controlled crossover, dose-escalation study of five doses (20-120 µg kg(-1) of FVIIa) with re-administration of different MC710 dosages to the same subjects. The active controls were NovoSeven (120 µg kg(-1)) and/or FEIBA (50 and 75 U kg(-1)) which were used to compare PD parameters. The area under the curve (AUC) and maximum plasma concentration (C(max)) of MC710 active ingredients increased dose-dependently within the range of 20 and 120 µg kg(-1). After administration of MC710, activated partial thromboplastin time (APTT) was dose-dependently improved and prothrombin time (PT) was shortened to approximately 6 s at 10 min, and APTT improvement and PT shortening effects were maintained until 12 h after administration of MC710 at all doses. No serious or severe adverse event was observed after administration of MC710; furthermore, several diagnostic marker values and those changes did not indicate any signs of disseminated intravascular coagulation (DIC). These results suggest that MC710 would have haemostatic potential equal to or greater than NovoSeven and FEIBA and was be tolerable when given at doses up to 120 µg kg(-1).
Assuntos
Fator VIIa/farmacologia , Fator X/farmacologia , Hemofilia A/tratamento farmacológico , Adolescente , Adulto , Área Sob a Curva , Coagulação Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Fator VIIa/farmacocinética , Fator X/farmacocinética , Humanos , Masculino , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Adulto JovemRESUMO
Studies conducted in European and North American countries have demonstrated that various factors including races affect the frequency of inhibitor formation in haemophilia patients. The present study was undertaken to analyse factors affecting the incidence of inhibitor formation in Japanese haemophilia A and B patients. Analytical data were retrospectively collected from haemophilia A and B patients born after 1988, the year when monoclonal antibody-purified factor VIII products were first marketed in Japan. Various data were collected from 184 patients (153 cases of haemophilia A; 31 cases of haemophilia B). The sample size of haemophilia B cases was too small to reveal any significant differences between the inhibitor formation group and the inhibitor-free group in any of background variables. For patients with haemophilia A, on the other hand, univariate analysis identified the severity of haemophilia and a positive family history of inhibitor development as risk factors for the formation of inhibitors. In analyses of the clotting factor products used, the incidence of inhibitor formation did not differ significantly between the group treated with plasma-derived products (29.7%) and the group treated with recombinant products (25.0%). When background variables were compared, age was higher in the group treated with plasma-derived products but none of the other background variables differed between the two groups. These results suggest that in Japanese haemophilia patients, the type of clotting factor preparations used for therapy has not influenced the incidence of inhibitor formation.
Assuntos
Coagulantes/imunologia , Fator IX/imunologia , Fator VIII/imunologia , Hemofilia A/imunologia , Hemofilia B/imunologia , Isoanticorpos/imunologia , Adolescente , Adulto , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Criança , Pré-Escolar , Coagulantes/uso terapêutico , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Feminino , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Humanos , Japão , Masculino , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
Cyclosporine A (CsA) may increase the incidence of thrombotic events, but whether tacrolimus (Tc) has such effects is still unclear. The serotonergic system has been linked to the thrombotic effects of CsA, but a direct effect of CsA on serotonin-induced platelet aggregation has not been demonstrated because of methodological difficulties. We measured the effects of CsA and Tc on serotonin-induced platelet aggregate formation by particle counting using light scattering. CsA and Tc both enhanced serotonin-induced formation of small platelet aggregates, however, neither CsA nor Tc affected aggregation induced by high or low concentrations of ADP, with or without addition of a serotonin receptor antagonist. Both CsA and Tc enhance platelet aggregation induced via the serotonin pathway.
Assuntos
Ciclosporina/farmacologia , Imunossupressores/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Serotonina/fisiologia , Tacrolimo/farmacologia , Difosfato de Adenosina/farmacologia , Transplante de Medula Óssea/efeitos adversos , Sinergismo Farmacológico , Humanos , Técnicas In Vitro , Luz , Espalhamento de Radiação , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Trombofilia/induzido quimicamenteRESUMO
To establish a rapid and automatic gene analysis method, we used capillary electrophoresis (CE) for the analysis of the intron 13 microsatellite repeat polymorphism (MRP) of the coagulation factor VIII gene for the diagnosis of hemophilia A. In the analysis of a 20-bp DNA ladder marker, the reproducibility evaluated using the relative standard deviation (RSD) of the relative migration time for one fragment of each fragment were less than 0.01%, whereas the RSDs of the actual migration time of each fragment were 0.1-0.3%. Thus, the appropriate internal standard should be mixed with the sample when CE resolves polymerase chain reaction (PCR) products. We next analyzed the intron 13 MRP evaluated with (CA)n repeats of the factor VIII gene using a 200-bp DNA fragment as the internal standard. The results showed that the PCR products from the intron 13 MRP could be resolved using CE, even with the repeat numbers of 20 and 21, which differ by only 2 bp. These results suggest that CE is a suitable method for analyzing PCR products for gene diagnosis.
Assuntos
Análise Mutacional de DNA/métodos , Fator VIII/genética , Íntrons/genética , Repetições de Microssatélites , Reação em Cadeia da Polimerase , Adulto , Eletroforese Capilar , Hemofilia A/diagnóstico , Hemofilia A/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
The platelet aggregating activity of plasma obtained from five patients with thrombotic thrombocytopenic purpura (TTP) was evaluated by a particle counting method using light scattering. When normal platelets were suspended in the plasma obtained from TTP patients, small aggregate formation was observed after stirring at 1000 rpm without the addition of platelet aggregating agents; no aggregate was observed, however, in the plasma obtained from healthy donors. Since the inhibitory effect of the addition of normal plasma to TTP plasma on this reaction was dose-dependent and not additive, the efficacy of plasma therapy was not confirmed. Small aggregates were formed in the high molecular weight fraction (HMWF) of TTP plasma but not in the low molecular weight fraction (LMWF), suggesting that the platelet aggregating activity existed in HMWF. Among the antiplatelet agents usually used for TTP, dipyridamole was more effective for the inhibition of this reaction than aspirin. This spontaneous platelet aggregation reaction by a particle counting method using light scattering could be useful for evaluating the platelet aggregating activity in patients with TTP.
Assuntos
Agregação Plaquetária/fisiologia , Púrpura Trombocitopênica/sangue , Adolescente , Adulto , Aspirina/farmacologia , Dipiridamol/farmacologia , Feminino , Humanos , Luz , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
We measured the serum levels of macrophage colony-stimulating factor (M-CSF) in 37 patients with an old cerebral infarction who had been surmised to have a damaged vessel wall and who had been in a stable condition for over three months after stroke onset, and those of 41 healthy control subjects. The M-CSF levels in the patients were significantly higher (P < 0.01) than those of the controls at 1320.4 +/- 410.6 unit/ml and 853.9 +/- 180.3 unit/ml, respectively. The plasma levels of von Willebrand factor (vWF) antigen (P < 0.01) and thrombomodulin (TM) (P < 0.05), as well as those of thrombin-antithrombin III (TAT) complex (P < 0.05), prothrombin fragment 1+2 (F1+2) (P < 0.02), D-dimer products of crosslinked fibrin degradation products (D-dimer) (P < 0.01), and plasmin-antiplasmin (PAP) complex (P < 0.05) in the patients were also significantly higher than those in the controls. Significant positive correlations (P < 0.01) were found between these parameters and the M-CSF level, but there was no significant correlation between the M-CSF level and the white blood cell count, serum lipids, or blood pressure. Based on these results, we suggest that an increased M-CSF level indicates vascular damage or a thrombotic state in patients with an old cerebral infarction.
Assuntos
Artérias Cerebrais/patologia , Infarto Cerebral/sangue , Fator Estimulador de Colônias de Macrófagos/sangue , Idoso , Biomarcadores , Contagem de Células Sanguíneas , Infarto Cerebral/etiologia , Infarto Cerebral/patologia , Circulação Cerebrovascular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para CimaAssuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/epidemiologia , Inibidores da Protease de HIV/uso terapêutico , Humanos , Japão/epidemiologia , Resultado do Tratamento , Carga Viral/tendênciasRESUMO
Isosorbide dinitrate (ISDN) has an inhibitory effect on platelet aggregation through the generation of nitric oxide (NO). We examined the effect of ISDN on whole blood aggregation using an impedance aggregometer. Blood samples were obtained from 16 patients with acute myocardial infarction and 4 patients with angina pectoris before and after an intravenous administration of ISDN during coronary arteriography. Whole blood obtained from normal healthy donors was used for an in vitro study. Whole blood aggregation after administration of ISDN was significantly inhibited compared to that before administration (36.1 +/- 8.3 vs 43.7 +/- 8.4 omega, p < 0.001), and cyclic guanine monophosphate (c-GMP) concentration increased (5.56 +/- 2.0 vs 5.14 +/- 1.86 p mol/ml, p < 0.05). The inhibitory effect of ISDN was also observed in the in vitro study, in which the effective concentration of ISDN corresponded to the blood level of ISDN (> or = 10(-7) mol) in the clinical setting. The inhibitory effect of ISDN was diminished by the addition of methylene blue or NG-monomethyl-L-arginine monoacetate in the exo vivo and in vitro studies. The concentration of c-GMP was increased by the addition of ISDN to platelets and white blood cell suspended plasma compared to the control (1.93 +/- 0.50 vs 1.77 +/- 0.42 p mol/ml, p < 0.05), but there was no significant difference when ISDN was added to platelet-rich plasma. These results suggest that ISDN inhibits whole blood aggregation through NO generation and white blood cells are important in the mechanism of ISDN action.
Assuntos
Sangue/efeitos dos fármacos , Dinitrato de Isossorbida/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Vasodilatadores/farmacologia , Angina Pectoris/sangue , Agregação Celular/efeitos dos fármacos , GMP Cíclico/sangue , Feminino , Humanos , Técnicas In Vitro , Dinitrato de Isossorbida/sangue , Leucócitos/fisiologia , Masculino , Azul de Metileno/farmacologia , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Vasodilatadores/sangue , ômega-N-Metilarginina/farmacologiaRESUMO
Plasma soluble P-selectin is thought to be a useful marker for thrombotic diseases. To evaluate the thrombotic state and risk of stroke in aged healthy subjects, we investigated plasma P-selectin levels in healthy subjects and ischemic stroke patients. Plasma P-selectin was measured in 67 healthy subjects and 35 aged (>or= 65 years of age) patients with chronic ischemic stroke using a sandwich enzyme-linked immunosorbent assay (ELISA). Plasma P-selectin was significantly higher in aged (>or= 65 years of age) healthy subjects than in young (< 65 years of age) healthy subjects. Significant difference did not exist between aged healthy subjects and aged stroke patients who were not receiving anti-platelet agents. Anti-platelet agent had no significant effect on plasma P-selectin levels in aged stroke patients. The amounts of P-selectin released from platelets into the plasma after stimulation with adenosin diphosphate in young and aged healthy subjects were not significantly different. Elevated levels of P-selectin in aged healthy subjects suggests the existence of a subclinical thrombotic state which can result in a stroke. Elevated P-selectin levels are not thought to be due to platelet hyperfunction.
RESUMO
The effects of platelets on clot lysis and plasminogen activation by staphylokinase (SAK) were investigated. At concentrations ranging from 2 x 10(-7) to 1 x 10(-5)g/ml of SAK, the lysis time of platelet-rich plasma clots (PRP-clots) was shorter than that of platelet-poor plasma clots (PPP-clots). This reduction of clot lysis time was observed in a dose-dependent manner on platelet count in PRP. The activation rate of plasminogen by SAK measured by the amidolytic method using S-2251 was enhanced by the addition of washed platelets. These enhancing effects of platelets on clot lysis and plasminogen activation were not altered by pretreatment of platelets with indomethacin and theophylline, but were diminished by platelet disruption. Thus, we concluded that platelets enhance fibrinolytic activity of SAK, and this effect is not due to the release reaction or intracellular contents of platelets, but to the existence of platelet surface in the intact shape as a catalytic site for fibrinolysis.