RESUMEN
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.
Asunto(s)
Factor VIIa/uso terapéutico , Factor X/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Humanos , Masculino , Adulto JovenRESUMEN
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.
Asunto(s)
Inhibidores de Factor de Coagulación Sanguínea/sangre , Coagulantes/uso terapéutico , Factor VIIa/uso terapéutico , Factor X/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Adolescente , Adulto , Coagulantes/farmacocinética , Esquema de Medicación , Quimioterapia Combinada , Factor VIIa/farmacocinética , Factor X/farmacocinética , Semivida , Hemorragia/prevención & control , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Adulto JovenRESUMEN
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.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Factor VIIa/farmacología , Factor X/farmacología , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Adolescente , Adulto , Inhibidores de Factor de Coagulación Sanguínea/sangre , Pruebas de Coagulación Sanguínea/métodos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Hemofilia A/sangre , Hemofilia B/sangre , Humanos , Japón , Masculino , Trombina/metabolismo , Adulto JovenRESUMEN
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).
Asunto(s)
Factor VIIa/farmacología , Factor X/farmacología , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Área Bajo la Curva , Coagulación Sanguínea/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada/métodos , Factor VIIa/farmacocinética , Factor X/farmacocinética , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Adulto JovenRESUMEN
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.
Asunto(s)
Coagulantes/inmunología , Factor IX/inmunología , Factor VIII/inmunología , Hemofilia A/inmunología , Hemofilia B/inmunología , Isoanticuerpos/inmunología , Adolescente , Adulto , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Niño , Preescolar , Coagulantes/uso terapéutico , Factor IX/uso terapéutico , Factor VIII/uso terapéutico , Femenino , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Humanos , Japón , Masculino , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological regulator of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) activity. A number of studies have shown that elevated levels of PAI-1 are related to pathological states such as an increased risk of arterial thrombotic events and a poor prognosis for cancer patients; however, there are few reports about PAI-1 deficiency in humans because the disorder is very rare. OBJECTIVE: To understand the in vivo impact of a complete PAI-1 deficiency, Serpine1(-/-) mice were generated; a number of in vivo studies have been conducted to elucidate the function of PAI-1 using Serpine1(-/-) mice. The phenotypes demonstrated in Serpine1(-/-) mice, however, were quite different from those in humans. Therefore, it is necessary to find out and analyze SERPINE1 deficiency in humans. PATIENT AND METHODS: The patient is a 47-year-old woman who has had multiple episodes of major bleeding. Although most of the patient's blood coagulation factors were functionally normal, her PAI-1 antigen levels were undetectable. Therefore, DNA sequencing of the SERPINE1 gene were analyzed. RESULTS: The proband had a homozygous 1-bp duplication (C) at exon 3 (c.356dupC; p.Ile120AspfsX42). Both wild-type PAI-1 (42.7 kDa) and mutated (Mut) PAI-1 (14.7kDa) were expressed in COS-1 cells, although the level of Mut PAI-1 expressed in the cell lysates was much lower. Wild-type PAI-1 was observed in the culture supernatant, whereas no Mut PAI-1 was detected in the supernatant. CONCLUSIONS: Considering the results of the present study, the translation of mouse studies to humans must be performed with great care.
Asunto(s)
Hemorragia/etiología , Inhibidor 1 de Activador Plasminogénico/deficiencia , Serpina E2/deficiencia , Cicatrización de Heridas , Animales , Enfermedad Crítica , Femenino , Homocigoto , Humanos , Ratones , Ratones Noqueados , Persona de Mediana Edad , Mutación , Fenotipo , Inhibidor 1 de Activador Plasminogénico/genética , Análisis de Secuencia de ADN , Serpina E2/genética , TransfecciónRESUMEN
BACKGROUND AND OBJECTIVES: Morbidity and mortality from ABO-incompatible transfusion persist as consequences of human error. Even so, insufficient attention has been given to improving transfusion safety within the hospital. MATERIALS AND METHODS: National surveys of ABO-incompatible blood transfusions were conducted by the Japanese Society of Blood Transfusion, with support from the Ministry of Health, Labor and Welfare. Surveys concluded in 2000 and 2005 analysed ABO-incompatible transfusion data from the previous 5 years (January 1995 to December 1999 and January 2000 to December 2004, respectively). The first survey targeted 777 hospitals and the second, 1355 hospitals. Data were collected through anonymous questionnaires. RESULTS: The first survey achieved a 77.4% response rate (578 of 777 hospitals). The second survey collected data from 251 more hospitals, but with a lower response rate (61.2%, or 829 of 1355 hospitals). The first survey analysed 166 incidents from 578 hospitals, vs. 60 incidents from 829 hospitals in the second survey. The main cause of ABO-incompatible transfusion was identification error between patient and blood product: 55% (91 of 166) in the first survey and 45% (27 of 60) in the second. Patient outcomes included nine preventable deaths from 1995 to 1999, and eight preventable deaths from 2000 to 2004. CONCLUSION: Misidentification at the bedside persists as the main cause of ABO-incompatible transfusion.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/análisis , Incompatibilidad de Grupos Sanguíneos/epidemiología , Errores Médicos/estadística & datos numéricos , Reacción a la Transfusión , Acreditación , Bancos de Sangre/organización & administración , Bancos de Sangre/normas , Bancos de Sangre/estadística & datos numéricos , Incompatibilidad de Grupos Sanguíneos/etiología , Tipificación y Pruebas Cruzadas Sanguíneas , Transfusión Sanguínea/estadística & datos numéricos , Urgencias Médicas , Encuestas Epidemiológicas , Capacidad de Camas en Hospitales , Hospitales/normas , Hospitales/estadística & datos numéricos , Humanos , Japón/epidemiología , Laboratorios de Hospital/organización & administración , Laboratorios de Hospital/normas , Laboratorios de Hospital/estadística & datos numéricos , Errores Médicos/prevención & control , Sistemas de Entrada de Órdenes Médicas , Sistemas de Medicación en Hospital , Sistemas de Identificación de PacientesRESUMEN
1. Inter-breed morphological comparisons were made among 11 breeds of Japanese native chickens (Gifujidori, Hinaidori, Shokoku, Totenko, Tomaru, Satsumadori, Shamo, Koshamo, Koeyoshi, Chabo and Nagoya), White Leghorn, broiler chickens (Chunky) and red junglefowl collected in the Philippines, based on results of direct measurements and analysis by computer vision techniques of the skull. 2. Analysis of direct measurements identified two groups of chicken: a small type that included the Chabo, Koshamo, red junglefowl, Gifujidori and Shokoku and a large type that included the remaining breeds studied. These groupings were made based on size determined both in the first (PC1) and second principal component (PC2). The greatest length of the cranium and condylobasal length greatly contributed to the morphological differences between these two groups. 3. Analysis by computer vision techniques, however, identified three groups: the Bantam group (which includes red junglefowl), Shokoku group and Shamo group. White Leghorn clustered within the Shokoku group while the broiler chicken belonged to the Shamo group. The region around the junction of the neural cranium and the visceral cranium contributed greatly to the morphological differences among breeds, both in the PC1 and PC2.
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Pollos/anatomía & histología , Pollos/genética , Cráneo/anatomía & histología , Animales , Pollos/clasificación , Gráficos por Computador , Simulación por Computador , Femenino , Variación Genética , Japón , Masculino , Filogenia , Especificidad de la EspecieRESUMEN
Type 2A von Willebrand disease (VWD) is characterized by decreased platelet-dependent function of von Willebrand factor (VWF); this in turn is associated with an absence of high-molecular-weight multimers. Sequence analysis of the VWF gene from two unrelated type 2A VWD patients showed an identical, novel, heterozygous T-->G transversion at nucleotide 4508, resulting in the substitution of L1503R in the VWF A2 domain. This substitution, which was not found in 60 unrelated normal individuals, was introduced into a full-length VWF cDNA and subsequently expressed in 293T cells. Only trace amount of the mutant VWF protein was secreted but most of the same was retained in 293T cells. Co-transfection experiment of both wild-type and mutant plasmids indicated the dominant-negative mechanism of disease development; as more of mutant DNA was transfected, VWF secretion was impaired in the media, whereas more of VWF was stored in the cell lysates. Molecular dynamic simulations of structural changes induced by L1503R indicated that the mean value of all-atom root-mean-squared-deviation was shifted from those with wild type or another mutation L1503Q that has been reported to be a group II mutation, which is susceptible to ADAMTS13 proteolysis. Protein instability of L1503R may be responsible for its intracellular retention and perhaps the larger VWF multimers, containing more mutant VWF subunits, are likely to be mal-processed and retained within the cell.
Asunto(s)
Biología Molecular , Mutación/genética , Enfermedades de von Willebrand/genética , Factor de von Willebrand/genética , Adolescente , Sustitución de Aminoácidos/genética , Análisis Mutacional de ADN , Desamino Arginina Vasopresina/uso terapéutico , Epistaxis/tratamiento farmacológico , Exones/genética , Femenino , Expresión Génica , Hemostasis/efectos de los fármacos , Hemostasis/genética , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Adhesividad Plaquetaria/fisiología , Reacción en Cadena de la Polimerasa , Proteínas Recombinantes , Relación Estructura-Actividad , Transfección , Enfermedades de von Willebrand/fisiopatología , Factor de von Willebrand/biosíntesisRESUMEN
OBJECTIVE: To elucidate the molecular consequences of hereditary protein S (PS) deficiency, we investigated the in vitro synthesis of the PS missense mutants in COS-1 cells and their activated protein C (APC) cofactor activities. PATIENTS: Four patients with quantitative PS deficiency suffering from venous thrombosis were examined. RESULTS: We identified three distinct novel missense mutations, R275C, P375Q and D455Y, and two previously reported missense mutations, C80Y and R314H. The P375Q and D455Y mutations were found in one patient and observed to be in linkage on the same allele. The R314H mutant showed the lowest level of expression (32.7%), and the C80Y, P375Q + D455Y, and R275C mutants exhibited a moderate impairment of expression, that is, 43.8%, 49.5%, and 72.3% of the wild type, respectively. Furthermore, pulse-chase experiments demonstrated that all mutants showed impaired secretion and longer half-lives in the cells than the wild type PS. In the APC cofactor assays, the C80Y mutant showed no cofactor activity, and the R275C mutant showed reduced activity, 62.3% of the wild type PS, whereas the R314H and P375Q + D455Y mutants exhibited normal cofactor activity. CONCLUSION: These data indicate that the C80Y and R275C mutations affect the secretion and function of the PS molecule, and that the R314H and P375Q + D455Y mutations are responsible for only secretion defects, causing the phenotype of quantitative PS deficiency observed in the patients.
Asunto(s)
Mutación Missense , Deficiencia de Proteína S/genética , Proteína S/genética , Adulto , Análisis Mutacional de ADN , Femenino , Regulación de la Expresión Génica , Ligamiento Genético , Semivida , Humanos , Masculino , Persona de Mediana Edad , Proteína S/metabolismoRESUMEN
The safety and efficacy of Kogenate, a recombinant factor VIII (rFVIII) preparation for the treatment of bleeding episodes, were studied in a 123-patient meta-analysis population of previously treated patients (PTPs), including 15 enrolled in the registration Phase III trial (PTP-I group), 93 from the post-marketing special investigation (PTP-II group), and 15 from short-term special investigations in surgery or tooth extraction (SI group). These patients (82 severe, 31 moderate, 9 mild, and 1 unknown), aged 11 months to 72 years, were enrolled in 28 centers in Japan. Blood samples taken at the baseline and at 3, 6, 9, 12, 18, and 24 months after the introduction of Kogenate were evaluated for FVIII inhibitor antibodies, antibodies formed against trace proteins derived from the rFVIII production process, and for general changes in laboratory test results. Mean exposure to Kogenate was 1103 days in PTP-I, 86 days in PTP-II, 27 days in patients in surgery, and 2 days in patients with tooth extraction. Assessment of FVIII inhibitor activity was conducted in 115 of the 123 patients by means of the Bethesda assay. Twelve patients were found to have a low titer of FVIII inhibitor (0.5-3.0 BU/mL) prior to any administration of Kogenate, and 103 were inhibitor-negative at the baseline. Among this latter group, 3 patients (2.9%) tested inhibitor-positive, with titers ranging from 1.2 to 2.1 BU/mL, with 4 patients below 1.0 BU/mL. One patient in the 11 PTPs investigated (PTP-I) developed antibodies against baby hamster kidney protein and mouse immunoglobulin G, but these findings were transient and asymptomatic. Hemostasis was achieved (markedly effective or effective) in 3666 of the 3855 bleeding episodes (95.1%) observed in 108 patients. Only 1 infusion was necessary in 3790 (98.3%) of these episodes. These data indicate that Kogenate is safe and very effective for the treatment of bleeding in PTPs with hemophilia A.
Asunto(s)
Contaminación de Medicamentos , Factor VIII/efectos adversos , Hemofilia A/sangre , Hemorragia/sangre , Adolescente , Adulto , Anciano , Animales , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Inhibidores de Factor de Coagulación Sanguínea/sangre , Inhibidores de Factor de Coagulación Sanguínea/inmunología , Niño , Preescolar , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Cricetinae , Perros , Factor VIII/administración & dosificación , Factor VIII/inmunología , Estudios de Seguimiento , Hemofilia A/tratamiento farmacológico , Hemofilia A/inmunología , Hemorragia/tratamiento farmacológico , Hemorragia/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Lactante , Persona de Mediana Edad , Factores de TiempoRESUMEN
The close relationship between iodine intake and the effects of anti-thyroid drugs (ATD) for Graves' disease (GD) has been well established. However, it remains unknown whether restriction of dietary iodine improves the effect of ATD. This study aimed to clarify this issue in Japanese patients with GD who routinely ingest large amounts of dietary iodine. We performed a prospective clinical study in 81 patients with newly diagnosed GD who were divided into an iodine restricted group and a control group. Urinary iodine, thyroid hormones and TSH receptor antibody were measured during the first 8 weeks of ATD therapy. Urinary iodine concentrations in the iodine restricted group were significantly lower than in the control group (p=0.043). However, there were no significant differences in the decrease of thyroid hormones and TSH receptor antibody between the two groups. Restriction of dietary iodine does not ameliorate the effect of ATD therapy for GD in an area of excessive iodine intake.
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Antitiroideos/uso terapéutico , Dieta , Enfermedad de Graves/tratamiento farmacológico , Yodo/administración & dosificación , Metimazol/uso terapéutico , Adulto , Femenino , Humanos , Yodo/orina , Masculino , Persona de Mediana Edad , Receptores de Tirotropina/inmunología , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
We investigated the molecular basis of a severe factor V (FV) deficiency in a Japanese female, and identified two distinct mutations in the FV gene, a novel cytosine insertion (1943insC) and a previously reported point mutation (A5279G). We expected the patient to be a compound heterozygote for those mutations, as a 1943insC, but not an A5279G, was found in the mother and a sibling. The 1943insC will cause a frame-shift after 590Gln, resulting in amino acid substitutions with two abnormal residues followed by a stop codon in the FV A2 domain (FS592X). The A5279G will cause an amino acid alteration in the FV A3 domain (Y1702C), which has been observed in several ethnic groups. We found that both mutant mRNAs were detected by reverse transcriptase polymerase chain reaction (RT-PCR) in the patient's platelets, whereas no FV antigen and activity were detected in plasma. On the one hand, the RT-PCR signal from the FS592X-FV mutant mRNA was markedly reduced, suggesting that the RNA surveillance system would eliminate most of the abnormal FS592X-FV transcripts with a premature termination. On the other hand, expression analyses revealed that only small amounts of Y1702C-FV with a low specific activity were secreted, and that the FS592X-FV was not detected in cultured media. These data indicated that both mutant FV molecules would be impaired, at least in part, during the post-transcriptional process of protein synthesis and/or in secretion. Taken together, it seems to suggest that each gene mutation could be separately responsible for severe FV deficiency, while this phenotype is due to the in-trans combination of the two defects.
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Deficiencia del Factor V/genética , Factor V/genética , Mutación , Adulto , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células COS , Chlorocebus aethiops , Análisis Mutacional de ADN/métodos , Femenino , Heterocigoto , Humanos , Datos de Secuencia Molecular , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosAsunto(s)
Antivirales/farmacología , Factor VII/metabolismo , Hemofilia A/sangre , Hemofilia A/tratamiento farmacológico , Hemofilia B/sangre , Hemofilia B/tratamiento farmacológico , Hepatitis C Crónica/sangre , Hepatitis C Crónica/tratamiento farmacológico , Ribavirina/farmacología , Adulto , Células Cultivadas , Factor VII/genética , Expresión Génica/efectos de los fármacos , Hemofilia A/complicaciones , Hemofilia B/complicaciones , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/complicaciones , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaAsunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/virología , Infecciones por Flaviviridae/complicaciones , Infecciones por Flaviviridae/virología , Virus GB-C , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hemofilia A/complicaciones , Hepatitis Viral Humana/complicaciones , Hepatitis Viral Humana/virología , Adolescente , Adulto , Terapia Antirretroviral Altamente Activa , Infecciones por Flaviviridae/tratamiento farmacológico , Virus GB-C/genética , Virus GB-C/aislamiento & purificación , Hepatitis Viral Humana/tratamiento farmacológico , Humanos , Masculino , ARN Viral/sangre , ARN Viral/genética , Viremia/complicaciones , Viremia/tratamiento farmacológico , Viremia/virologíaRESUMEN
BACKGROUND AND OBJECTIVES: Cardiovascular/thrombotic diseases are frequently induced by a variety of stressors. Obese patients are susceptible to thrombotic diseases associated with stress, but the underlying mechanism is still unknown. We have begun to investigate the expression of a primary inhibitor of fibrinolysis, plasminogen activator inhibitor-1 (PAI-1), in association with tissue thrombosis, using restraint-stressed obese mice. METHODS AND RESULTS: We analyzed the expression of PAI-1 after restraint (immobilization) stress in genetically obese mice in comparison with their lean counterparts. Dramatic increases in PAI-1 antigen in plasma and in tissue extracts were observed in the obese mice exposed to restraint stress. The induction of PAI-1 mRNA by stress in the tissues was also pronounced in the stressed obese mice as compared with the lean mice, especially in the hearts and adipose tissues. In situ hybridization analysis revealed that strong signals for PAI-1 mRNA were localized in the adipocytes, cardiovascular endothelial cells, and renal glomerular cells of the stressed obese mice. Histological examination revealed that renal glomerular fibrin deposition was detected only in the obese mice after 2 h of restraint stress. CONCLUSIONS: Obesity enhances the stress-mediated PAI-1 induction in the blood and tissues. This phenomenon may be associated with the increased risk of stress-induced renal fibrin deposition in obese subjects.
Asunto(s)
Riñón/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Adipocitos/citología , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Animales , Índice de Masa Corporal , Endotelio Vascular/metabolismo , Fibrina/metabolismo , Fibrinólisis , Inmovilización , Inmunohistoquímica , Hibridación in Situ , Glomérulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Miocardio/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
The safety and efficacy of a recombinant factor VIII (rFVIII) preparation (Kogenate) for the treatment of bleeding episodes was studied in previously untreated patients (PUPs) with severe, moderate, and mild hemophilia A. Patient peripheral blood samples taken at baseline and at 3, 6, 9, 12, 18, and 24 months after the first infusion were evaluated for FVIII inhibitor antibodies by the Bethesda assay, for antibodies formed against trace proteins derived from the rFVIII production process, and for general changes in laboratory test results. Samples for general laboratory testing were also drawn every 6 months after the first 24 months. Hemostatic efficacy was assessed by physicians, and adverse events were recorded throughout the study period. Forty-three PUPs (30 with FVIII:C <1%; 10 with FVIII:C 1%-5%; and 3 with FVIII:C >5%) aged 3 months to 32 years were enrolled at 33 centers in Japan. Patients were studied for a mean of 51 months (range, 11-80 months), and the mean exposure time was 83 days (range, 2-571 days). The incidence of occurrence of FVIII inhibitors was 34.9% (high responders [> or = 10 Bethesda U/mL], 11.6%; low responders [0.5-<10 Bethesda U/mL], 23.3%). The median cumulative exposure time of inhibitor detection was 12 days, indicating inhibitor development at an early stage after the start of infusion of this preparation. Hemostasis was achieved with a single dose of Kogenate in 94.8% of the 951 bleeding episodes recorded in the study. Transient increases in antibodies against baby hamster kidney proteins and antimouse immunoglobulin G were observed in 14.0% and 18.6% of patients, respectively. Anti-rFVIII seroconversion was observed in 18.6% of patients and only in patients with inhibitor antibodies. Antibody responses to trace proteins were not correlated with drug-related adverse events with the exception of FVIII activity inhibition in PUPs with anti-rFVIII seroconversion. These data indicate that Kogenate is safe and effective for the treatment of bleeding in PUPs with hemophilia A.
Asunto(s)
Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Factor VIII/antagonistas & inhibidores , Factor VIII/inmunología , Hemorragia/etiología , Hemorragia/prevención & control , Hemostasis/efectos de los fármacos , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Lactante , Isoanticuerpos/biosíntesis , Isoanticuerpos/sangre , Japón , Masculino , Vigilancia de Productos Comercializados , Resultado del TratamientoAsunto(s)
Enfermedad de Alzheimer/enzimología , Antioxidantes/metabolismo , Regulación Enzimológica de la Expresión Génica , Hemo Oxigenasa (Desciclizante)/genética , Linfocitos/enzimología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Cartilla de ADN , Femenino , Hemo-Oxigenasa 1 , Humanos , Masculino , Proteínas de la Membrana , Reacción en Cadena de la Polimerasa/métodos , Escalas de Valoración Psiquiátrica , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: TT virus (TTV), a novel DNA virus, was originally thought to be transmitted by transfusion. However, nonparenteral transmission is recently suspected to be a major mode of transmission. To investigate the possibility of reinfection with TTV in multiply transfused patients and to evaluate the significance of transfusion transmission of TTV in patients with hemophilia, serial changes in TTV genotype were investigated in three groups. STUDY DESIGN AND METHODS: Serial changes in TTV genotype were investigated in 16 multiply transfused patients with hemophilia, 16 age-matched patients with chronic hepatitis C, and 16 age-matched healthy subjects. RESULTS: Mixed infection with multiple TTV genotypes was common in all groups. However, changes in TTV genotype were frequent in patients with hemophilia (15/16; 93.8%) but rare in patients with chronic hepatitis C and in healthy subjects (each group: 1/16; 6.3%). CONCLUSION: Changes in TTV genotype were frequently observed in multiply transfused patients with hemophilia but not in patients with chronic hepatitis or in healthy subjects without risk of transfusion transmission. This difference may suggest that exposure to TTV or even reinfection occurs frequently in patients with hemophilia, which could be evidence of transfusion transmission of TTV in this population.