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

Untersuchung organischer Spurengase in der Troposphäre : globale Verteilung, jahreszeitliche Variationen und langfristige Trends

In this study the spatial and temporal variations of the mixing ratios of organic trace gases in the lower troposphere were investigated . Air samples were collected in stainless steel canisters and analyzed for their contents of carbon dioxide, carbon monoxide, methane, nonmethane hydrocarbons and halocarbons. Characterizations of the used gas chromatographic systems and the resuits of international intercomparison experiments showed that the analytical methods are suitable for the measurement of organic trace gases at Iow concentration levels. The latitudinal distribution of trace gases in the boundary layer over the Atlantic was measured during the cruise of the German research vessel `Polarstern' as part of the ALBATROSS campaign (October/November 1996) . The measurements covered a latitude range between 67°N and 45°S . In this work the distribution of some halogenated hydrocarbons in marine air was measured for the First time . Highest mixing ratios of hydrocarbons and several anthropogenic halocarbons (CH2C1-,, CHCL, 1,2-C 2H4C12 , C7HC13, C2CL und CH3Br) were observed in the Northern Hemisphere between 42°N to 67°N latitude. The mixing ratios of 1,1-dichloroethene, 1,1,1-trichloroethane, dibromomethane, tribromomethane and iodomethane showed a rather uniform distribution in both hemispheres . The observed mixing ratios of methylchloride and tetrachloromethane showed Iow maxima near the equator. The seasonal variations of the mixing ratios of organic trace gases were measured in whole air samples collected in Alert (Canadian Arctic) over a time period of 7 years between January 1989 and July 1996 . The resuits allowed to estimate lang term trends of mixing ratios for a number of compounds . The mixing ratios of most hydrocarbons decreased between 2.2 to 14 .4 % per year. Except tetrachloroethene, for other halocarbons (CH3CI, CH-C12 and C,HCL), no significant trends of the Fnixing ratios were found. Tetrachloroethene showed an annual decrease of 8 .3 % per year. The observed mixing ratios of the trace gases showed pronounced seasonal variations with maxima in winter and minima in sumrner. These variations are mainly caused by the meteorologieal conditions in the Arctic. The ratios of winter and summer concentrations were different for each compound. The plot of the winter/summer ratio as a function of the reaction rates with OH radicals showed a maximum for C4-C5 -alkanes. A global Chemical Tracer Model (CTM) allowed a qualitative simulation of the observed seasonal variations. For the quantitative description of the observed data with the CTM local sources of hydrocarbons are necessary. The estimated source strength ranged from less then 0 .09 up to 0 .9 ng .m 2 . s -' depending an the hydrocarbon . Due to the location of Alert the ocean is discussed as a local source for these hydrocarbon

Diffusion technique for the production of gas standards for atmospheric measurements

For the calibration of gas chromatographic measurements of volatile organic compounds in ambient air samples, standard gas mixtures at low concentrations are needed with high accuracy. For this purpose we developed a diffusion device combined with a dynamic dilution system. Pure liquid compounds are placed in glass vials. They diffuse through a capillary on top of each vial into a diffusion chamber flushed with synthetic air. In an additional dynamic dilution step the final concentration is adjusted with a flow of purified synthetic air to typical mixing ratios between several ppt (v/v) and ppb (v/v). The diffusion rates are determined from the mass loss of the vials. Extensive tests over 21 months showed that the diffusion rates varied little with time, between 1.4% and 3.1%, depending on the compound. The system proved to be suitable for compounds with a wide range of boiling points, from 305 K (1,1-dichlorethene) to 418 K (1,2-dimethylbenzene) The diffusion device was applied to a gas chromatographic system with a flame ionization detector and an electron-capture detector. The linearity of the diffusion device was checked with different standard mixtures with mixing ratios ranging from 0.32 ppt (v/v) (tribromomethane) to 1353 ppt (v/v) (n-pentane). The regression analysis of peak area versus concentration showed excellent agreement among the standards for each compound with correlation coefficients (r(2)) between 0.9826 and 0.9998. The temporal stability of the diffusion device was determined from more than 270 measurements of one standard mixture. The reproducibility of the peak areas ranged between 2.2% and 12.7% depending on the compound. (C) 1999 Elsevier Science B.V. All rights reserved

Meridional distribution of hydroperoxides and formaldehyde in the marine boundary layer of the Atlantic (48N - 35S) measured during the ALBATROSS campaign

AbstractGas phase H2O2, organic peroxides, and formaldehyde (HCHO) have been measured in situ during October/November 1996 on board RV Polarstern in surface air over the Atlantic from 48°N-35°S with different analytical methods. The results indicate that recombination and self-reactions of peroxy radicals largely dominate over scavenging by NO. The peroxy radical chemistry was governed by the photooxidation of CH4 and CO, as could be deduced from our failure to detect organic hydroperoxides other than CH3OOH (methyl hydroperoxide (MHP)). Hydroperoxide and formaldehyde mixing ratios were highest within the tropics with peak values of around 2000 parts per trillion by volume (pptv) (H2O2), 1500 pptv (MHP), and 1000 pptv (HCHO). In the case of H2O2 and MHP we observed diurnal variations of the mixing ratios in the tropical North Atlantic and derived deposition rates of around (1.8±0.6) 10-5 s-1 for H2O2 and (1.2±0.4) 10-5 s-1 for MHP. The measured MHP/(H2O2+MHP) and MHP/HCHO ratios corresponded to 0.32±0.12 and 0.87±0.4, respectively. HCHO mixing ratios observed during the expedition were significantly higher than predicted by current photochemical theory based on the photooxidation of CH4 and CO