Optimizing study design in LPS challenge studies for quantifying drug induced inhibition of TNFα response: Did we miss the prime time?

In this work we evaluate the study design of LPS challenge experiments used for quantification of drug induced inhibition of TNFα response and provide general guidelines of how to improve the study design. Analysis of model simulated data, using a recently published TNFα turnover model, as well as the optimal design tool PopED have been used to find the optimal values of three key study design variables – time delay between drug and LPS administration, LPS dose, and sampling time points – that in turn could make the resulting TNFα response data more informative. Our findings suggest that the current rule of thumb for choosing the time delay should be reconsidered, and that the placement of the measurements after maximal TNFα response are crucial for the quality of the experiment. Furthermore, a literature study summarizing a wide range of published LPS challenge studies is provided, giving a broader perspective of how LPS challenge studies are usually conducted both in a preclinical and clinical setting

Second-generation TNFα turnover model for improved analysis of test compound interventions in LPS challenge studies

This study presents a non-linear mixed effects model describing tumour necrosis factor alpha (TNFα) release after lipopolysaccharide (LPS) provocations in absence or presence of anti-inflammatory test compounds. Inter-occasion variability and the pharmacokinetics of two test compounds have been added to this second-generation model, and the goal is to produce a framework of how to model TNFα response in LPS challenge studies in vivo and demonstrate its general applicability regardless of occasion or type of test compound. Model improvements based on experimental data were successfully implemented and provided a robust model for TNFα response after LPS provocation, as well as reliable estimates of the median pharmacodynamic parameters. The two test compounds, Test Compound A and roflumilast, showed 81.1% and 74.9% partial reduction of TNFα response, respectively, and the potency of Test Compound A was estimated to 0.166 \ub5mol/L. Comparing this study with previously published work reveals that our model leads to biologically reasonable output, handles complex data pooled from different studies, and highlights the importance of accurately distinguishing the stimulatory effect of LPS from the inhibitory effect of the test compound

Volatile organic compound emissions from Scots pine : mechanisms and description by algorithms

The mechanisms of volatile organic compound (VOC) emissions from Scots pine (Pinus sylvestris L.) were investigated in laboratory experiments. The plants emitted mainly monoterpenes and acetone. Isoprene was emitted only in small amounts, but the mechanisms of its emissions were similar to those of the other compounds. Isoprene, acetone, and monoterpene emissions from Scots pine could be well described by an algorithm that considers emissions caused by evaporation of VOCs out of pools and emissions in parallel with their biosynthetic production. Monoterpene emissions were mainly affected by temperature. In some cases, monoterpene emissions were also influenced by photosynthetic active radiation implying that monoterpene emissions from Pinus sylvestris occur from storage pools as well as from processes that are linked to monoterpene biosynthesis. The coupling of monoterpene emissions with photosynthesis was confirmed by results of experiments with (CO2)-C-13, The (CO2)-C-13 exposure resulted in emission of C-13 labeled monoterpenes during (CO2)-C-13 exposure as well as during the night following the exposure. Similar results were also obtained for isoprene emissions. Scots pine emitted isoprene during illumination as well as in darkness. The emitted isoprene was labeled during (CO2)-C-13 exposure and in the night following the exposure. The results obtained for monoterpene emissions in the laboratory were compared to those of outdoor measurements with Scots pine. While the temperature dependencies of emission rates were comparable to those obtained from laboratory experiments, a PAR dependence was not detectable. Temperature variations during outdoor measurements prevented a detection of this dependence.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000171044200034&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Meteorology & Atmospheric SciencesSCI(E)55ARTICLED1720483-2049110