RESUMEN
INTRODUCTION: The Phase 3 A-LONG study demonstrated the safety and efficacy of rFVIIIFc for the control and prevention of bleeding episodes in severe haemophilia A. AIM: To describe the treatment of bleeding episodes with rFVIIIFc in the A-LONG study. METHODS: A-LONG subjects (<1 IU dL-1 endogenous FVIII) were treated with individualized prophylaxis (Arm 1), weekly prophylaxis (Arm 2) or episodic treatment (Arm 3). Information recorded for each bleeding episode included type, location and dose to treat the episode. RESULTS: During A-LONG, 757 bleeding episodes occurred during the efficacy period; the majority [456 (60%)] occurred in Arm 3 (episodic treatment). Of 93 subjects in the prophylaxis arms who entered the study with target joints, 43 (60%) in Arm 1 and 11 (52%) in Arm 2 did not experience a target joint bleed. Overall, 98% of bleeding episodes (and 98% of bleeds involving a target joint) resolved with one or two infusions; the median dose per infusion to treat a bleed was 27 IU kg-1 (27 IU kg-1 for target joints). Using population pharmacokinetic simulations, FVIII activity levels were predicted to be below the upper limit of normal (150 IU dL-1 ) in most patients in the event that rFVIIIFc is used to treat a bleeding episode in close proximity to a prophylactic dose. CONCLUSIONS: These findings demonstrate the efficacy of rFVIIIFc for the treatment of acute bleeding episodes in subjects with severe haemophilia A, regardless of treatment regimen.
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Factor VIII/uso terapéutico , Hemofilia A/complicaciones , Hemorragia/complicaciones , Hemorragia/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/genética , Proteínas Recombinantes de Fusión/uso terapéutico , Factor VIII/efectos adversos , Factor VIII/farmacocinética , Femenino , Hemofilia A/prevención & control , Humanos , Masculino , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Seguridad , Resultado del TratamientoRESUMEN
BACKGROUND: Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development. METHODS: We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch). RESULTS: We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5-135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases. CONCLUSIONS: By studying the largest cohort of inhibitor development in PTPs assembled to date, we showed that inhibitor development in PTPs, is on average, a milder event than in PUPs.
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Historia Natural/métodos , Adulto , Hemofilia A/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Children with von Willebrand disease (VWD) in whom DDAVP is ineffective or contraindicated require treatment with a coagulation factor concentrate containing von Willebrand factor (VWF) and factor VIII (FVIII). The aim of this study was to monitor the safety, efficacy and tolerability of Wilate(®) (a VWF:FVIII concentrate with a 1:1 ratio) used across the North London Paediatric Haemophilia Network since May 2010. In total, 47 children (aged 0.0-17.0 years) with type 1 (n = 28), type 2 (n = 7), type 3 (n = 10) and acquired VWS (n = 2) have been treated for bleeds, surgery and/or prophylaxis using 260 000 IU Wilate(®). Analysis of dose and frequency of treatment show expected responses to treatment with mean doses of 55, 50 and 50 IU kg(-1) for bleeds, surgery and prophylaxis respectively. Most bleeds responded to a single treatment. Surgical procedures were covered with clinician approved dosing schedules with 95% (39/41) reported as having excellent or good efficacy. There was no accumulation of FVIII or VWF and no thromboembolic events. This case series confirms the efficacy, safety and tolerability of Wilate(®) in neonates, children and adolescents when used on-demand, prophylactically and in the surgical setting.
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Factor VIII/farmacología , Hospitales Universitarios/estadística & datos numéricos , Centros de Atención Terciaria/estadística & datos numéricos , Enfermedades de von Willebrand/tratamiento farmacológico , Factor de von Willebrand/farmacología , Adolescente , Niño , Preescolar , Técnicas de Laboratorio Clínico , Combinación de Medicamentos , Factor VIII/uso terapéutico , Femenino , Hemorragia/complicaciones , Hemostasis/efectos de los fármacos , Humanos , Lactante , Recién Nacido , Londres , Masculino , Derivación y Consulta , Estudios Retrospectivos , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/fisiopatología , Enfermedades de von Willebrand/cirugía , Factor de von Willebrand/uso terapéuticoRESUMEN
BACKGROUND: Disc degeneration (DD) is a common condition that progresses with aging. Although the events leading to DD are not well understood, a significant genetic influence has been found. This study was undertaken to assess the association between relevant candidate gene polymorphisms and moderate DD in a well-defined and characterized cohort of young adults. Focusing on young age can be valuable in determining genetic predisposition to DD. METHODS: We investigated the associations of existing candidate genes for DD among 538 young adults with a mean age of 19 belonging to the 1986 Northern Finland Birth Cohort. Nineteen single nucleotide polymorphisms (SNP) in 16 genes were genotyped. We evaluated lumbar DD using the modified Pfirrmann classification and a 1.5-T magnetic resonance scanner for imaging. RESULTS: Of the 538 individuals studied, 46% had no degeneration, while 54% had DD and 51% of these had moderate DD. The risk of DD was significantly higher in subjects with an allele G of IL6 SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96) and rs1800797 (OR 1.37, 95% CI 1.02-1.85) in the additive inheritance model. The role of IL6 was further supported by the haplotype analysis, which resulted in an association between the GGG haplotype (SNPs rs1800797, rs1800796 and rs1800795) and DD with an OR of 1.51 (95% CI 1.11-2.04). In addition, we observed an association between DD and two other polymorphisms, SKT rs16924573 (OR 0.27 95% CI 0.07-0.96) and CILP rs2073711 in women (OR 2.04, 95% CI 1.07-3.89). CONCLUSION: Our results indicate that IL6, SKT and CILP are involved in the etiology of DD among young adults.
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Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad/genética , Interleucina-6/genética , Degeneración del Disco Intervertebral/epidemiología , Degeneración del Disco Intervertebral/genética , Proteínas/genética , Pirofosfatasas/genética , Adolescente , Estudios de Cohortes , Finlandia/epidemiología , Estudios de Asociación Genética , Genotipo , Haplotipos/genética , Humanos , Patrón de Herencia , Degeneración del Disco Intervertebral/patología , Modelos Logísticos , Imagen por Resonancia Magnética , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
Venous thromboembolism (VTE) is a common complication in patients with malignant disease. First recognised by Bouillard in 1823 and later described by Trousseau in 1844, multiple studies have since provided considerable evidence for a clinical association between VTE and cancer. Across all cancers, the risk for VTE is elevated 7-fold; in certain malignancies, the risk for VTE may be increased up to 28-fold. Venous thromboembolism is the second leading cause of death in patients with cancer; among survivors, complications commonly include recurrent VTE and post-thrombotic syndrome, and (more rarely) chronic thromboembolic pulmonary hypertension, which are costly, and have a profound impact on the patient's quality of life. Tumour cells can activate blood coagulation through multiple mechanisms, including production of procoagulant, fibrinolytic, and proaggregating activities, release of proinflammatory and proangiogenic cytokines, and interacting directly with host vascular and blood cells (e.g., endothelial cells, leukocytes, and platelets) through adhesion molecules. Increasing evidence suggests that elements of the haemostatic system also have a direct role in eliciting or enhancing angiogenesis, cell survival, and metastasis. Despite the problem posed by VTE in the setting of cancer, it is evident that a significant number of oncologists do not recognise the link between cancer, its treatment, and thrombogenesis. On 22 May 2009, a group of UK-based physicians met in London, UK, to evaluate recent data on cancer thrombosis. This article (1 of 4) briefly reviews key data on the epidemiology and pathophysiology of VTE as a context for a discussion and consensus statement developed by meeting attendees, on the implications of this information for UK clinical practice.
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Neoplasias/complicaciones , Tromboembolia Venosa/etiología , Inhibidores de la Angiogénesis/uso terapéutico , Hemostasis , Humanos , Neoplasias/terapia , Embolia Pulmonar/etiología , Recurrencia , Factores de Riesgo , Tamoxifeno/efectos adversos , Tromboembolia Venosa/epidemiologíaRESUMEN
In patients with severe haemophilia and inhibitors, regular factor VIII inhibitor bypassing activity (FEIBA) prophylaxis has been shown to reduce the frequency of bleeding by up to 85% and to improve patient quality of life. FEIBA is well tolerated; the incidence of thrombotic events and of allergic reactions is extremely low. The concept of prophylaxis in haemophilia patients with inhibitors is relatively new and some clinicians may be unsure of how to use FEIBA in this context. These treatment recommendations, based on published evidence plus the collective experience of a group of haematologists (with practical knowledge of managing inhibitor patients with FEIBA prophylaxis), are intended to provide guidance to clinicians considering initiating and maintaining patients on FEIBA prophylaxis with specific focus on practical aspects of patient selection, dosing, monitoring and stop criteria.
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Factores de Coagulación Sanguínea/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Hemorragia/prevención & control , Adolescente , Adulto , Inhibidores de Factor de Coagulación Sanguínea/sangre , Factores de Coagulación Sanguínea/efectos adversos , Niño , Preescolar , Hemofilia A/complicaciones , Hemofilia B/complicaciones , Humanos , Tolerancia Inmunológica , Lactante , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Adulto JovenRESUMEN
AIMS: To examine the development of self-assessed and parent proxy-assessed health related quality of life (HRQL) in pre-adolescent schoolchildren. METHODS: The population (n = 1,346) consisted of the total cohort of children starting 4th grade (age 10) in 2004 in primary schools in a Finnish city of 175,000 inhabitants. HRQL was assessed using the Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0). The baseline study was conducted in 2004 (child age 10) and follow-up in a panel setting in 2006 (child age 12). The response rate for the children was 80% (n = 1,094) in 2004 and 85% (n = 1,139) in 2006. The response rate for children having responded both in 2004 and 2006 was 73% (n = 986). For parents of the children, one parent participated in the parents' survey (n = 999 in 2004, n = 888 in 2006). RESULTS: HRQL scores increased significantly in the two-year follow up (child t = 10.16-5.95, p < 0.0001, parent-proxy t = 6.35-2.76, p < 0.0001-0.006). Correlation between baseline and follow-up assessments was significant (child r = 0.4-0.5, p < 0.0001, parent r = 0.47-0.57, p < 0.0001). The correlation between baseline HRQL and change was negative (child r =-0.67 to -0.56, p < 0.0001, parent r =-0.62 to -0.46, p < 0.0001). Correlation between child and parent assessments increased from baseline (r = 0.20-0.39, p < 0.0001) to follow up (r = 0.3-0.42, p < 0.0001). CONCLUSIONS: Child-assessed and parent proxy-assessed HRQL scores increase, suggesting HRQL improves, when children grow from age 10 to age 12. Baseline HRQL may not strongly predict future HRQL in early adolescence. The correlation between child self-assessment and parent proxy-assessment is fragile.
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Estado de Salud , Calidad de Vida , Adolescente , Factores de Edad , Niño , Estudios de Cohortes , Femenino , Finlandia/epidemiología , Estudios de Seguimiento , Humanos , Masculino , Padres/psicología , Apoderado , Psicometría/métodos , Autoevaluación (Psicología) , Factores SexualesRESUMEN
BACKGROUND: Presence of bleeding symptoms, inheritance and reduced von Willebrand factor (VWF) contribute to the diagnosis of type 1 von Willebrand disease (VWD). However, quantitative analysis of the importance of VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) levels in the diagnosis is lacking. OBJECTIVES: To evaluate the relative contribution of VWF measurement to the diagnosis of VWD. PATIENTS AND METHODS: From the MCMDM-1VWD study cohort, 204 subjects (considered as affected by VWD based on the enrolling Center diagnoses and the presence of linkage with the VWF locus) were compared with 1155 normal individuals. Sensitivity, specificity and diagnostic positive likelihood ratios (LR) of VWF:Ag and VWF:RCo were computed. RESULTS: ABO blood group was the variable most influencing VWF levels, but adjustment of the lower reference limit for the ABO group did not improve sensitivity and specificity of VWF:Ag or VWF:RCo. The lower reference limit (2.5th percentile) was 47 IU dL(-1) for both VWF:Ag and VWF:RCo and showed similar diagnostic performance [receiver-operator curve area: 0.962 and 0.961 for VWF:Ag and VWF:RCo, respectively; P = 0.81]. The probability of VWD was markedly increased only for values below 40 IU dL(-1) (positive LR: 95.1 for VWF:Ag), whereas intermediate values (40 to 60 IU dL(-1)) of VWF only marginally indicated the probability of VWD. CONCLUSIONS: Although the conventional 2.5 lower percentile has good sensitivity and specificity, only VWF:Ag or VWF:RCo values below 40 IU dL(-1) appear to significantly indicate the likelihood of type 1 VWD. The LR profile of VWF level could be used in a diagnostic algorithm.
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Enfermedades de von Willebrand/sangre , Enfermedades de von Willebrand/diagnóstico , Factor de von Willebrand/biosíntesis , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Europa (Continente) , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
OBJECTIVES: To investigate whether height at the age of 31 is associated with the incidence of knee and hip osteoarthritis (OA) in the following 15 years. METHODS: Participants in The Northern Finland Birth Cohort 1966 (NFBC1966) diagnosed with knee or hip OA between the ages of 31 and 46 were used as OA cases. Study subjects without knee and hip OA were used as the controls. Height and weight were measured in a clinical examination at the age of 31 (baseline). Mean heights for the OA cases and the controls were compared by an independent samples t-test. Cox regression analysis was performed to calculate the risk for OA for different height quartiles. The results were adjusted for body mass index/weight, education, smoking and leisure-time physical activity at baseline. Additionally, a Kaplan-Meier analysis was performed. RESULTS: Men with knee OA were 2.6 cm taller (P < 0.001) and women with knee OA 1.2 cm taller (P = 0.048) than the controls. Hip OA cases were found to be slightly shorter than the controls, but no statistically significant differences were observed. The adjusted hazard ratios (HRs) for knee OA and hip OA in the highest quartile were 2.5 (95% CI 1.4-4.5) and 1.0 (95% CI 0.3-3.4) for men and 1.8 (95% CI 1.0-3.1) and 0.7 (95% CI 0.2-2.3) for women. CONCLUSIONS: Height at the age of 31 was associated with incidence of early knee OA, diagnosed prior to age 46. However, the low incidence of hip OA made our results for hip OA inconclusive.
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Estatura , Osteoartritis de la Cadera/epidemiología , Osteoartritis de la Cadera/fisiopatología , Osteoartritis de la Rodilla/epidemiología , Osteoartritis de la Rodilla/fisiopatología , Adulto , Factores de Edad , Peso Corporal , Estudios de Casos y Controles , Femenino , Finlandia/epidemiología , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Osteoartritis de la Cadera/diagnóstico , Osteoartritis de la Rodilla/diagnóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de Riesgo , Factores Sexuales , Factores de TiempoRESUMEN
OBJECTIVE: Although several studies have shown that adolescent musculoskeletal pain is associated with psychological problems in a cross-sectional setting, the associations of long-term musculoskeletal pain with psychological distress and anxiety are not known. METHODS: The study included 1773 adolescents belonging to the Northern Finland Birth Cohort 1986. They received a postal questionnaire at the age of 16years and a follow-up questionnaire two years later. The first inquiry contained questions about the sites of musculoskeletal pain; the second had the same pain questions, along with measures of distress and anxiety. Risk ratios (RR) were assessed by log-linear regression analysis. RESULTS: Multi-site musculoskeletal pain (in ≥2 body locations) at both 16 and 18years was common, reported by 53% of girls and 30% of boys. Multi-site pain at both ages, compared to those with multi-site pain neither at 16 nor 18years, was associated with psychological distress at the age of 18 among both girls (RR 1.8 95% CI 1.2-2.7) and boys (RR 3.5 95% CI 2.1-5.9). For anxiety, the corresponding relative risks were 1.5 (95% CI 1.0-2.2) and 1.8 (95% CI 1.4-2.3), respectively. For short-term multi-site pain (prevalent only at the age of 16 or 18), these relative risks were between 0.8 and 2.3. CONCLUSIONS: Adolescents with long-term multi-site pain have higher levels of distress and anxiety than those without or with only short-term multi-site pain. Associations were found in both genders, but the relationship between pain and distress was more pronounced among boys. The associations had modest effect strength.
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Ansiedad/complicaciones , Ansiedad/psicología , Dolor Crónico/psicología , Dolor Musculoesquelético/psicología , Estrés Psicológico/complicaciones , Adolescente , Ansiedad/diagnóstico , Dolor Crónico/diagnóstico , Femenino , Finlandia , Humanos , Masculino , Dolor Musculoesquelético/diagnóstico , Prevalencia , Riesgo , Factores Sexuales , Encuestas y CuestionariosRESUMEN
BACKGROUND: A quantitative description of bleeding symptoms in type 1 von Willebrand disease (VWD) has never been reported. OBJECTIVES: The aim was to quantitatively evaluate the severity of bleeding symptoms in type 1 VWD and its correlation with clinical and laboratory features. PATIENTS AND METHODS: Bleeding symptoms were retrospectively recorded in a European cohort of VWD type 1 families, and for each subject a quantitative bleeding score (BS) was obtained together with phenotypic tests. RESULTS: A total of 712 subjects belonging to 144 families and 195 controls were available for analysis. The BS was higher in index cases than in affected family members (BS 9 vs. 5, P < 0.0001) and in unaffected family members than in controls (BS 0 vs. -1, P < 0.0001). There was no effect of ABO blood group. BS showed a strong significant inverse relation with either von Willebrand ristocetin cofactor (VWF:RCo), von Willebrand antigen (VWF:Ag) or factor VIII procoagulant activity (FVIII:C) measured at time of enrollment, even after adjustment for age, sex and blood group (P < 0.001 for all the four upper quintiles of BS vs. the first quintile, for either VWF:RCo, VWF:Ag or FVIII:C). Higher BS was related with increasing likelihood of VWD, and a mucocutaneous BS (computed from spontaneous, mucocutaneous symptoms) was strongly associated with bleeding after surgery or tooth extraction. CONCLUSIONS: Quantitative analysis of bleeding symptoms is potentially useful for a more accurate diagnosis of type 1 VWD and to develop guidelines for its optimal treatment.
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Hemorragia/diagnóstico , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/genética , Sistema del Grupo Sanguíneo ABO , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Europa (Continente) , Factor VIII/biosíntesis , Factor VIII/química , Salud de la Familia , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , Ristocetina/química , Encuestas y Cuestionarios , Enfermedades de von Willebrand/sangre , Factor de von Willebrand/químicaRESUMEN
BACKGROUND: von Willebrand disease (VWD) type 1 is a congenital bleeding disorder caused by genetic defects in the von Willebrand factor (VWF) gene and characterized by a reduction of structurally normal VWF. The diagnosis of type 1 VWD is difficult because of clinical and laboratory variability. Furthermore, inconsistency of linkage between type 1 VWD and the VWF locus has been reported. OBJECTIVES: To estimate the proportion of type 1 VWD that is linked to the VWF gene. PATIENTS AND METHODS: Type 1 VWD families and healthy control individuals were recruited. An extensive questionnaire on bleeding symptoms was completed and phenotypic tests were performed. Linkage between VWF gene haplotypes and the diagnosis of type 1 VWD, the plasma levels of VWF and the severity of bleeding symptoms was analyzed. RESULTS: Segregation analysis in 143 families diagnosed with type 1 VWD fitted a model of autosomal dominant inheritance. Linkage analysis under heterogeneity resulted in a summed lod score of 23.2 with an estimated proportion of linkage of 0.70. After exclusion of families with abnormal multimer patterns the linkage proportion was 0.46. LOD scores and linkage proportions were higher in families with more severe phenotypes and with phenotypes suggestive of qualitative VWF defects. About 40% of the total variation of VWF antigen could be attributed to the VWF gene. CONCLUSIONS: We conclude that the diagnosis of type 1 VWD is linked to the VWF gene in about 70% of families, however after exclusion of qualitative defects this is about 50%.
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Ligamiento Genético , Enfermedades de von Willebrand/genética , Enfermedades de von Willebrand/terapia , Adolescente , Adulto , Anciano , Coagulación Sanguínea , Niño , Preescolar , Europa (Continente) , Salud de la Familia , Femenino , Genes Dominantes , Humanos , Lactante , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Linaje , Factores de Riesgo , Enfermedades de von Willebrand/diagnóstico , Factor de von Willebrand/genéticaRESUMEN
BACKGROUND: Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). OBJECTIVE: Kids A-LONG was a phase 3 open-label study evaluating the safety, efficacy and pharmacokinetics of a longer-acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of < 1 IU dL(-1) [< 1%]). METHODS: The study enrolled 71 subjects. The starting rFVIIIFc regimen was twice-weekly prophylaxis (Day 1, 25 IU kg(-1) ; Day 4, 50 IU kg(-1) ); dose (≤ 80 IU kg(-1) ) and dosing interval (≥ 2 days) were adjusted as needed. A subset of subjects had sequential pharmacokinetic evaluations of FVIII and rFVIIIFc. The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included pharmacokinetics, annualized bleeding rate (ABR), and number of infusions required to control a bleed. RESULTS: No subject developed an inhibitor to rFVIIIFc. Adverse events were typical of a pediatric hemophilic population. The rFVIIIFc half-life was prolonged relative to that of FVIII, consistent with observations in adults and adolescents. The median ABR was 1.96 overall, and 0.00 for spontaneous bleeds; 46.4% of subjects reported no bleeding episodes on study. Ninety-three per cent of bleeding episodes were controlled with one to two infusions. The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg(-1) . At study end, 62 of 69 subjects (90%) were infusing twice weekly. Among subjects who had been previously receiving FVIII prophylaxis, 74% reduced their dosing frequency with rFVIIIFc. CONCLUSION: Twice-weekly infusions with rFVIIIFc were well tolerated and yielded low bleeding rates in children with severe hemophilia A.
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Coagulantes/administración & dosificación , Factor VIII/administración & dosificación , Hemartrosis/tratamiento farmacológico , Hemartrosis/prevención & control , Hemofilia A/tratamiento farmacológico , Hemofilia A/prevención & control , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Factores de Edad , Anticuerpos Neutralizantes/sangre , Australia , Niño , Preescolar , China , Coagulantes/efectos adversos , Coagulantes/inmunología , Coagulantes/farmacocinética , Esquema de Medicación , Europa (Continente) , Factor VIII/efectos adversos , Factor VIII/inmunología , Factor VIII/farmacocinética , Femenino , Semivida , Hemartrosis/sangre , Hemartrosis/diagnóstico , Hemofilia A/sangre , Hemofilia A/diagnóstico , Humanos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/inmunología , Infusiones Intravenosas , Masculino , América del Norte , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/farmacocinética , Factores de Riesgo , Índice de Severidad de la Enfermedad , Sudáfrica , Resultado del TratamientoRESUMEN
OBJECTIVES: The declining incidence of tuberculosis (TB) in developed countries has recently been reversed with the advent of HIV disease. This study proposes to document in vitro T-cell responses to mycobacterial antigens in HIV-infected individuals. DESIGN: T-cell-mediated immunity is recognized as one of the mechanisms of defence against TB. The cellular immunodeficiency and the importance of TB in the context of HIV disease has prompted use of in vitro assays of lymphocyte proliferation and cytolytic activity. METHODS: Peripheral blood mononuclear cells isolated from 29 HIV-infected patients (four with recent TB) and 11 healthy volunteers were stimulated with purified protein derivative (PPD). The responding blasts were presented to autologous antigen-primed macrophages to measure specific cytolytic T-lymphocyte (CTL) activity in vitro. RESULTS: T-cell proliferative responses were significantly lower in late stages of HIV disease. The degree of specific CTL activity was higher in healthy individuals than in Centers for Disease Control (CDC) stage II-III (P = 0.037), and CDC stage IV patients (P = 0.029). CONCLUSIONS: The clinical presentation of TB tends to be typical in early stages of HIV disease and atypical in late stages. The manifestations reflect the degree of immunodepression. This study documents the declining proliferative and cytolytic T-cell-mediated responses in HIV patients with progression of immunodeficiency.
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Antígenos Bacterianos/inmunología , Citotoxicidad Inmunológica , Infecciones por VIH/inmunología , Mycobacterium tuberculosis/inmunología , Linfocitos T Citotóxicos/inmunología , Adolescente , Adulto , Epítopos/inmunología , Femenino , Humanos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Tuberculina/inmunologíaRESUMEN
Allogenic proteins that contaminate intermediate purity clotting factor concentrates may activate the immune system of HIV-infected haemophilic patients. In 37 haemophilic patients infected with HIV who had originally been treated with intermediate purity factor VIII concentrate and then changed to monoclonally-purified high purity factor VIII concentrate the rates of CD4+ decline (10(9)/l per year) were 0.06 before and 0.02 after a switch to high purity products (p = 0.01). The median follow-up of patients after the switch to high purity products was 1.7 years (range 0.2 to 3 years). This significant change in the rate of CD4 decline was independent of the starting CD4 count, age and antiretroviral therapy. This result is consistent with those from randomised trials of the introduction of high-purity concentrate. Given the strong association between the CD4+ count and survival, treatment with high purity rather than intermediate purity clotting factor concentrate may confer a survival benefit for HIV-infected haemophilic patients.
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Recuento de Linfocito CD4 , Factor VIII/uso terapéutico , Infecciones por VIH/sangre , Hemofilia A/sangre , Infecciones Oportunistas Relacionadas con el SIDA/prevención & control , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Progresión de la Enfermedad , Factor VIII/aislamiento & purificación , Fluconazol/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hemofilia A/complicaciones , Hemofilia A/terapia , Humanos , Masculino , Persona de Mediana Edad , Pentamidina/uso terapéutico , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Zidovudina/uso terapéuticoRESUMEN
In a study to demonstrate the safety and pharmacokinetics (half-life and recovery) of two different method M purified AHF (Hemofil-M) concentrates processed in the USA and Spain, two different methods of factor VIII assay (one-stage clotting and chromogenic) have been compared in vivo. The study was a single centre blinded, randomised, crossover study. Twelve patients with severe haemophilia A (VIII:C < 2 u/dl) were divided into two subgroups of six. None had received factor VIII concentrate within 48 h preceding the study. Twenty-four pharmacokinetic studies were performed in the 12 patients. Each subgroup received two different lots of study material (US and Spanish) at a dose of 50 u/kg seven days apart. A second randomisation was nominal potency, high: 1000 u or mid: 500 u per vial. The potency label was a one-stage clotting assay using the mega I standard. A standard pharmacokinetic study was performed over 24 h and each blinded sample was analysed in duplicate by a one-stage clotting (aPTT) and a chromogenic (Chromogenix AB; CS) assay at the Royal Free and NIBSC. Pharmacokinetic modelling was performed. The mean label for Hemofil-M using the chromogenic substrate assay was 79% that using the one stage assay (Mega I standard). The recovery was 17-28% higher measured by chromogenic compared to the clotting assay. Since most clinicians use the clotting assay, potency labelling using the chromogenic assay, will overestimate predicted Hemofil-M recovery by as much as 25%.
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Bioensayo/métodos , Factor VIII/farmacocinética , Factor VIII/administración & dosificación , Semivida , Humanos , Especificidad por SustratoRESUMEN
The effects of one month's treatment with each of nifedipine, verapamil, diltiazem, propranolol and placebo, given in random order, on fasting plasma glucose, haemoglobin Alc, serum fructosamine, immunoreactive insulin, cholesterol, and triglyceride were studied in a group of 19 patients with hypertension and non-insulin dependent diabetes mellitus. The metabolic effects of the active drugs were generally small but fasting plasma glucose was increased by propranolol from 9.3 +/- 3.0 to 10.4 +/- 3.4 mmol/l (P less than 0.01) (mean +/- SD) and to 10.1 +/- 3.2 mmol/l (P less than 0.05) by nifedipine. Serum fructosamine was increased from 2.75 +/- 0.53 to 2.89 +/- 0.62 mmol/l (P less than 0.05) by diltiazem and to 2.91 +/- 0.65 (P less than 0.05) by propranolol. Verapamil increased fasting serum immunoreactive insulin: diltiazem and propranolol tended to reduce it. Propranolol but not the other drugs significantly increased serum triglyceride. Calcium antagonists may be preferable to beta adrenoceptor blockers for the treatment of hypertensive diabetics. Of the three calcium antagonists we studied, verapamil may have advantages over nifedipine and diltiazem.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Diltiazem/uso terapéutico , Hipertensión/tratamiento farmacológico , Nifedipino/uso terapéutico , Propranolol/uso terapéutico , Verapamilo/uso terapéutico , Anciano , Glucemia/análisis , Presión Sanguínea/efectos de los fármacos , Colesterol/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diltiazem/efectos adversos , Femenino , Fructosamina , Hemoglobina Glucada/análisis , Frecuencia Cardíaca/efectos de los fármacos , Hexosaminas/sangre , Humanos , Hipertensión/complicaciones , Insulina/inmunología , Masculino , Persona de Mediana Edad , Nifedipino/efectos adversos , Propranolol/efectos adversos , Triglicéridos/sangre , Verapamilo/efectos adversosRESUMEN
We describe the first case of Budd-Chiari syndrome due to homozygosity for factor V Leiden resulting in resistance to activated protein C. This is now recognized as the most common procoagulant disorder, and may account for many cases of Budd-Chiari syndrome previously though to be idiopathic or due to a latent myeloproliferative disorder. A further unique feature of this case is that the patient required orthotopic liver transplantation following failure of portacaval shunting and progressive hepatic necrosis. We demonstrated that liver transplantation resulted in correction of the serum coagulation abnormality; however, it is unlikely to have cured the disorder as platelet factor V would still be of the Leiden phenotype.