Pharmacokinetics and pharmacodynamics of a new recombinant FVIII (N8) in haemophilia A mice

Summary. N8 is a new recombinant factor VIII (rFVIII) compound produced and formulated without human‐ or animal‐derived protein. The aims of the present studies were to evaluate the pharmacokinetics and pharmacodynamics properties of N8 and to compare with a commercially available rFVIII product (Advate^®) in haemophilia A mice. The pharmacokinetics were evaluated after single i.v. administration of 80, 120 and 280 IU kg^?1 of N8 and Advate^® and measurements of FVIII blood concentrations as a function of time. The efficacy and dose response curves of N8 and Advate^® (1–200 IU kg^?1) were evaluated in a tail bleeding model. Furthermore, the effects in a newly developed haemophilia knee joint haemarthrosis model were investigated. No significant differences were found in the pharmacokinetic parameters between N8 and Advate^®. The clearances were 11 ± 1 vs. 10 ± 2 mL h^?1 kg^?1 (P = 0.14) and the half‐lives 7.2 ± 0.9 vs. 7.7 ± 1.4 h (P = 0.31) after administration of N8 and Advate^® respectively. Dose‐independent pharmacokinetics was shown, and comparable efficacy and potency were shown between N8 and Advate^® in the tail bleeding model. Both compounds normalized the bleeding at the dose of 200 IU kg^?1, and for blood loss ED₅₀ values of 27 IU kg^?1 (N8) and 28 IU/kg (Advate^®) were found (P = 0.97). In the haemarthrosis model, treatment with N8 and Advate^® at 200 IU kg^?1 reduced the mean increase in the joint diameter significantly from 1.23 ± 0.19 to 0.32 ± 0.08 mm (P < 0.01) and 0.25 ± 0.08 mm (P < 0.001) respectively. Pharmacokinetics and pharmacodynamics of N8 and Advate^® were comparable after i.v. administration to haemophilia A mice.     

Management of muscle haematomas in patients with severe haemophilia in an evidence-poor world

Treatment studies in haemophilia focus on joint bleeds; however, some 10-25% of bleeds occur in muscles. This review addresses management of muscle haematoma in severe haemophilia, defines gaps in the published evidence, and presents a combined clinician and physiotherapist perspective of treatment modalities. The following grade 2C recommendations were synthesized: (i) Sport and activity should be based on individual factor levels, bleeding history and physical characteristics, (ii) Musculoskeletal review aids the management of children and adults, (iii) 'Time to full recovery' should be realistic and based on known timelines from the healthy population, (iv) Diagnosis should be carried out by both a clinician and physiotherapist, (v) Severe muscle bleeds should be treated similarly to surgical patients: a 50% trough for 10-14 days followed by high-level prophylaxis, (vi) Protection, rest, ice, compression and elevation should be implemented in the acute stage, and (vii) Physiotherapy and rehabilitation should be divided into: control of haemorrhage (phase 1); restoration of Range of Movement (ROM) and strength (phase 2); functional rehabilitation and return to normal living (phase 3). Recommendations specifically for inhibitor patients include: (i) Minor to moderate bleeds should be managed by home-treatment within 1 h of bleed onset using either one injection of rFVIIa 270 μg kg(-1), or two to three injections of rFVIIa 90 μg kg(-1) (2-3 h intervals), or FEIBA 50-100 U kg(-1) (repeated at 12-hourly intervals, if necessary) and (ii) Severe muscle bleeds should be supervised by the treatment centre and include bypassing agents until clinical improvement is observed.     

Limited in-depth invasion of Fusobacterium nucleatum into in vitro reconstructed human gingiva

ObjectiveFusobacterium nucleatum is an opportunistic pathogen with a key role in subgingival plaque formation and it is found in increased numbers in periodontally affected sites. This study aimed to investigate the potential of F. nucleatum to penetrate and induce alterations in an in vitro reconstructed human gingival mucosa model.MethodsThree-dimensional (3D) organotypic models of human gingiva were engineered using primary gingival keratinocytes and fibroblasts. The reconstructed tissues were challenged with four different strains of fluorescently labelled F. nucleatum in suspension placed on top of epithelial layers. Confocal laser scanning was used to assess the presence of fusobacteria through the organotypic model. Apoptosis (cleaved caspase-3) and cell proliferation (Ki-67) were evaluated by the use of immunohistochemistry in 3D-tissue models. Quantitative real-time PCR was performed to investigate the mRNA expression for MMP-13 and E-cadherin in both 3D-tissues and monolayers.ResultsF. nucleatum invaded the superficial epithelial layers of gingival 3D-tissue models. Challenged tissues showed accentuated shedding of superficial layers and increased number of cleaved caspase-3 and Ki-67 positive cells than controls, although not statistically significant. Levels of E-cadherin and MMP-13 mRNA were not significantly perturbed in multilayer culture. A variable and disproportionate response of MMP-13 mRNA level resulted in challenged primary keratinocytes in monolayers, compared to multilayer culture.ConclusionThese results indicate that F. nucleatum is able to invade superficially a differentiated, stratified gingival epithelium in vitro and triggers the efficient elimination of bacterial infection through epithelial shredding without causing a permanent damage of the tissue.     

Common mental disorders and long‐term sickness absence in a general working population. The Hordaland Health Study

Objective: To examine and compare the prospective effect of the common mental disorders (CMD) anxiety and depression on duration and recurrence of sickness absence (SA), and to investigate whether the effect of CMD on SA is detectable over time. Method: Information from a large epidemiological health study (N = 13 436) was linked with official records of SA episodes lasting ≥16 days up to 6 years after participation. Common mental disorders were assessed with the Hospital Anxiety and Depression Scale (HADS). Associations were analysed with Cox regression and multinomial logistic regression models controlling for potential covariates. Results: Comorbid anxiety and depression, and anxiety only were significant risk factors for SA after adjusting for covariates, whilst depression only was not. Anxiety and depression were stronger predictors for longer duration of SA episodes compared with shorter duration and associated with more frequent recurrence of SA. There was a general trend toward the effect of CMD on SA becoming weaker over time; however, the effect of anxiety only on SA remained stable throughout the follow‐up. Conclusion: Common mental disorders are long‐lasting predictors of onset, duration and recurrence of SA. Anxiety appears to be a more important contributor to long‐term SA than previously described in the literature.     

Muscle phenotype in patients with myotonic dystrophy type 1

Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. Methods: In 38 patients, muscle strength was tested by hand‐held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na⁺‐K⁺ pump content. Results: Muscle strength correlated with a decline in Na⁺‐K⁺ pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na⁺‐K⁺ pump content. Histopathologically, we found few centrally placed nuclei (range 0.2–6.9%). Conclusions: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1. Muscle Nerve 47:409‐415, 2013     

Aerobic training in persons who have recovered from juvenile dermatomyositis

A recent study has shown that 36 persons who had recovered from juvenile dermatomyositis (JDM) have on average an 18% decrease in maximal oxygen uptake. The objective of this study was to investigate the effect of a 12-week aerobic training program in this group, and assess whether aerobic training can normalize aerobic capacity to the expected level for age and gender.The patients participating in the study, one male and nine females (16–42 years of age), were in remission from JDM, defined as no clinical or biochemical evidence of disease activity and no medical treatment for 1 year. The patients had a median disease duration of 3.4 years (1.4–10.3), a median treatment duration of 2.4 years (0.4–9.3) and a median duration of remission of 7.0 years (1.2–30.0).Patients trained at home on a cycle ergometer for 12 weeks at a heart rate interval corresponding to 65% of their maximal oxygen uptake (VO_2max)_. VO_2max and maximal workload (W_max) were determined before and after the 12-week training period through an incremental cycling test to exhaustion. The patients served as their own controls.Eight patients with JDM in remission completed the 12-week exercise program; one patient completed 9 weeks out of the 12-week program and one dropped out of the study. Training increased VO_2max and W_max by 26% and 30% (P < 0.001). Creatine kinase (CK) levels were normal pre-training and did not change with training, reflecting no muscle damage. We also found that at a given workload, heart rate was lowered significantly after the 12-week training period, indicating an improvement in cardiovascular fitness.This study shows that 12 weeks of moderate-intensity aerobic training is an effective and safe method to increase oxidative capacity and fitness in persons who have recovered from JDM. The results indicate that the low oxidative capacity in JDM patients in remission is reversible and can be improved. Thus, we recommend frequent aerobic training to be incorporated into supervised physiotherapy sessions in the treatment of JDM patients in remission.