9 research outputs found
Performance analysis of wireless LANs: an integrated packet/flow level approach
In this paper we present an integrated packet/flow level modelling approach for analysing flow throughputs and transfer times in IEEE 802.11 WLANs. The packet level model captures the statistical characteristics of the transmission of individual packets at the MAC layer, while the flow level model takes into account the system dynamics due to the initiation and completion of data flow transfers. The latter model is a processor sharing type of queueing model reflecting the IEEE 802.11 MAC design principle of distributing the transmission capacity fairly among the active flows. The resulting integrated packet/flow level model is analytically tractable and yields a simple approximation for the throughput and flow transfer time. Extensive simulations show that the approximation is very accurate for a wide range of parameter settings. In addition, the simulation study confirms the attractive property following from our approximation that the expected flow transfer delay is insensitive to the flow size distribution (apart from its mean)
Protein binding of rifampicin is not saturated when using high-dose rifampicin
Contains fulltext :
202599.pdf (publisher's version ) (Closed access)BACKGROUND: Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. OBJECTIVES: To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. METHODS: Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64 mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10 mg/kg daily) or high-dose (35 mg/kg) rifampicin up to steady-state. The performance of total AUC0-24 to predict unbound AUC0-24 was evaluated. RESULTS: The in vitro free fraction of rifampicin remained unaltered ( approximately 9%) up to 21 mg/L and increased up to 13% at 41 mg/L and 17% at 64 mg/L rifampicin. The highest (peak) concentration in vivo was 39.1 mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC0-24in vivo was 13.3% (range = 8.1%-24.9%) and 11.1% (range = 8.6%-13.6%) for the standard group and the high-dose group, respectively (P = 0.214). Prediction of unbound AUC0-24 based on total AUC0-24 resulted in a bias of -0.05% and an imprecision of 13.2%. CONCLUSIONS: Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range
Mesenchymal stem cells control alloreactive CD8+CD28- T cells
CD28/B7 co-stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients. However, cells lacking CD28 are not susceptible to belatacept treatment. As CD8+CD28- T-cells have cytotoxic and pathogenic properties, we investigated whether mesenchymal stem cells (MSC) are effective in controlling these cells. In mixed lymphocyte reactions (MLR), MSC and belatacept inhibited peripheral blood mononuclear cell (PBMC) proliferation in a dose-dependent manner. MSC at MSC/effector cell ratios of 1:160 and 1:2·5 reduced proliferation by 38·8 and 92·2%, respectively. Belatacept concentrations of 0·1μg/ml and 10μg/ml suppressed proliferation by 20·7 and 80·6%, respectively. Both treatments in combination did not inhibit each other's function. Allostimulated CD8+CD28- T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α. While belatacept did not affect the proliferation of CD8+CD28- T cells, MSC reduced the percentage of CD28- T cells in the proliferating CD8+ T cell fraction by 45·9% (P=0·009). CD8+CD28- T cells as effector cells in MLR in the presence of CD4+ T cell help gained CD28 expression, an effect independent of MSC. In contrast, allostimulated CD28+ T cells did not lose CD28 expression in MLR-MSC co-culture, suggesting that MSC control pre-existing CD28- T cells and not newly induced CD28- T cells. In conclusion, alloreactive CD8+CD28- T cells that remain unaffected by belatacept treatment are inhibited by MSC. This study indicates the potential of an MSC-belatacept combination therapy to control alloreactivity
Performance analysis of WLANs: an integrated packet/flow level approach
We present an integrated packet/flow level model for WLAN performance analysis. It captures the statistical characteristics of the transmission of individual packets at the MAC layer, and includes the system dynamics due to the initiation and completion of data flow transfers. The processor sharing-based model is analytically tractable and yields a simple approximation for the expected flow transfer time. Extensive simulations show that the approximation is very accurate for a wide range of parameter settings
Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling
Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement