Influence of blood group and von Willebrand factor on population pharmacokinetics and dose individualization of recombinant factor VIII in Taiwanese patients with haemophilia A.

INTRODUCTION: The large interpatient variability in the pharmacokinetic (PK) parameters of recombinant Factor VIII (rFVIII) observed in haemophilia A hinders efficient and cost-beneficial prophylactic regimen initiation. Identification of factors influencing the PK of rFVIII may shed more light on personalised treatment. AIM: This study aimed to develop a population PK model in the Taiwanese haemophilia A and evaluate the current national health insurance (NHI) reimbursement guidelines of Taiwan for haemophilia treatment. METHODS: A population PK analysis was established based on 69 Taiwanese with moderate or severe haemophilia A. A nonlinear mixed-effects modelling (NONMEM® ) was used to estimate PK parameters and their variabilities. A Monte Carlo simulation was performed to evaluate different prophylactic regimens. RESULTS: A two-compartment model with first-order elimination best described the rFVIII data. Weight-based allometric scaling was related to clearance and central volume of distribution. Blood type and baseline von Willebrand factor (VWF) were significant covariates for clearance. For single dose simulations, a time achieving target level (> 1 IU/dL) was associated with increasing rFVIII dose and VWF level. The multiple dose simulations showed that > 96.4% of patients with high VWF level (> 200%) had predicted trough level > 1 IU/dL for all dosing regimens (15-40 IU/kg, two to three times weekly). However, for twice weekly dosing, lower percentage (47.62-62.20%) of patients with blood group O and low VWF level (< 50%) achieved a predicted trough level > 1 IU/dL. CONCLUSION: The population PK of rFVIII was successfully developed. Dose adjustment based on blood type and VWF level should be considered.

Tracking Antioxidant Status in Spinal Cord Injured Rodents: A Voltammetric Method Suited for Clinical Translation.

BACKGROUND: Spinal cord injury (SCI) triggers a signalling cascade that produces oxidative stress and damages the spinal cord. Voltammetry is a clinically accessible technique to detect, monitor, and guide correction of this potentially reversible secondary injury mechanism. Voltammetry is well suited for clinical translation because the method is inexpensive, simple, rapid, and portable. Voltammetry relies on the measurement of anodic current from a reagent-free, electrochemical reaction on the surface of a small electrode. METHODS: The present study tested the use of new disposable carbon nanotube based screen printed electrodes (CNT-SPE) for the voltammetric measurement of antioxidant current (AC). Spinal cord, cerebrospinal fluid, and plasma were obtained from Sprague-Dawley rats after SCI. Locomotor function after SCI was assessed by using the Basso, Beattie, Bresnahan (BBB) score. RESULTS: The more severe SCI caused a decline in spinal cord AC419 at 10 minutes (P < 0.05), 4 hours (P < 0.0001), and 1 day (P < 0.01) after injury compared with sham controls. It also caused a decline in plasma AC375 at 1 (P < 0.001) and 3 days (P < 0.05) after injury compared with their pre-injury baseline. Spinal cord AC419 correlated with plasma AC375 (r = 0.49, P < 0.01) and BBB score (r = 0.66, P < 0.0001) at 1 day after SCI. CONCLUSIONS: AC measured by CNT-SPE demonstrated a time- and severity-dependent decline after SCI. Plasma AC could serve as a surrogate marker for spinal cord AC.

Detection of Neurotransmitters by Three-Dimensional Laser-Scribed Graphene Grass Electrodes.

Carbon nanomaterials possess superb properties and have contributed considerably to the advancement of integrated point-of-care chemical and biological sensing devices. Graphene has been widely researched as a signal transducing and sensing material. Here, a grass-like laser-scribed graphene (LSG) was synthesized by direct laser induction on common polyimide plastics. The resulting LSG grass was employed as a disposable electrochemical sensor for the detection of three neurotransmitters, dopamine (DA), epinephrine (EP), and norepinephrine (NE), and in the presence of uric acid and ascorbic acid as potential interferants, using differential pulse voltammetry and cyclic voltammetry. The LSG grass sensor achieved sensitivities of 0.243, 0.067, and 0.110 µA µM-1 for DA, EP, and NE, respectively, whereas the limits of detection were 0.43, 1.1, and 1.3 µM, respectively. The selectivity of LSG grass was excellent for competing biomarkers with high structural similarity (EP vs NE and EP vs DA). The exceptional performance of LSG grass for DA, EP, and NE detection holds a promising future for carbon nanomaterial sensors with unique surface morphologies.

Indications, techniques, and clinical outcomes of thoracic duct interventions in patients: a forgotten literature?

BACKGROUND: The evolution of the "gut-lymph concept" has promoted thoracic duct (TD) lymph drainage as a possible treatment to reduce systemic inflammation and end-organ dysfunction in acute illness. The aim was to review the published experience of thoracic duct interventions (TDIs) aimed at improving clinical outcomes. METHODS: A search of three databases (MEDLINE, EMBASE, and EMBASE CLASSIC) over the last 60 y. The indications for intervention, the technique, and clinical outcomes were reviewed. RESULTS: There were a wide range of indications for TDI. These included reducing rejection after transplantation, treating inflammatory diseases, and reducing chronic failure of the liver, kidney, and heart. The techniques included TD cannulation and lymphovenuous fistula. The outcomes were variable and often equivocal, and this appears to reflect poor design quality. There is clinical equipoise regarding a therapeutic role of (TD lymph drainage in acute pancreatitis, and probably other acute diseases. CONCLUSIONS: Until well-designed clinical trials are undertaken, the clinical benefits of TDIs will remain promising, but uncertain.