Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis

This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection model

Nutrient release from decomposing leaf litter of temperate deciduous forest trees along a gradient of increasing tree species diversity

Jacob M, Weland N, Platner C, Schaefer M, Leuschner C, Thomas FM. Nutrient release from decomposing leaf litter of temperate deciduous forest trees along a gradient of increasing tree species diversity. SOIL BIOLOGY & BIOCHEMISTRY. 2009;41(10):2122-2130.In the litter of six deciduous tree species (Fagus sylvatica, Tilia spp., Fraxinus excelsior, Carpinus betulus, Acer pseudoplatanus and Acer platanoides) and in stand-specific litter mixtures, we compared mass loss and nutrient release across diversity levels along a gradient of decreasing proportion of Fagus in stands with similar environmental and physical soil conditions. The litterbag studies ran over 22 months. The decomposition rate constants (k) of the temperate forest species ranged from k = 0.5 for Fagus to k = 1.5-2 for all other tree species. In Fagus, k was closely negatively correlated with the thickness of the litter layer and positively correlated with soil pH and isopod abundance. k was significantly higher in the mixed species stands (except for Carpinus and Fraxinus) and was positively correlated with earthworm abundance. Over the whole incubation time, nutrient amount and release rates of N, P, K, Ca and Mg as well as C-related ratios showed significant differences between tree species but no consistent differences among the diversity levels. Initial C-related nutrient ratios of the leaf litter and abundance of mesofauna and macrofauna were correlated with the length of time lag before nutrient release. We conclude that the mere number of tree species is not the main driver of nutrient release and decomposition processes, but that key groups of the decomposer fauna as well as the characteristic traits of the individual tree species are decisive. (C) 2009 Elsevier Ltd. All rights reserved

Uncovering trophic positions and food resources of soil animals using bulk natural stable isotope composition

Despite the major importance of soil biota in nutrient and energy fluxes, interactions in soil food webs are poorly understood. Here we provide an overview of recent advances in uncovering the trophic structure of soil food webs using natural variations in stable isotope ratios. We discuss approaches of application, normalization and interpretation of stable isotope ratios along with methodological pitfalls. Analysis of published data from temperate forest ecosystems is used to outline emerging concepts and perspectives in soil food web research. In contrast to aboveground and aquatic food webs, trophic fractionation at the basal level of detrital food webs is large for carbon and small for nitrogen stable isotopes. Virtually all soil animals are enriched in 13 C as compared to plant litter. This 'detrital shift' likely reflects preferential uptake of 13 C-enriched microbial biomass and underlines the importance of microorganisms, in contrast to dead plant material, as a major food resource for the soil animal community. Soil organic matter is enriched in 15 N and 13 C relative to leaf litter. Decomposers inhabiting mineral soil layers therefore might be enriched in 15 N resulting in overlap in isotope ratios between soil-dwelling detritivores and litter-dwelling predators. By contrast, 13 C content varies little between detritivores in upper litter and in mineral soil, suggesting that they rely on similar basal resources, i.e. little decomposed organic matter. Comparing vertical isotope gradients in animals and in basal resources can be a valuable tool to assess trophic interactions and dynamics of organic matter in soil. As indicated by stable isotope composition, direct feeding on living plant material as well as on mycorrhizal fungi is likely rare among soil invertebrates. Plant carbon is taken up predominantly by saprotrophic microorganisms and channelled to higher trophic levels of the soil food web. However, feeding on photoautotrophic microorganisms and non-vascular plants may play an important role in fuelling soil food webs. The trophic niche of most high-rank animal taxa spans at least two trophic levels, implying the use of a wide range of resources. Therefore, to identify trophic species and links in food webs, low-rank taxonomic identification is required. Despite overlap in feeding strategies, stable isotope composition of the high-rank taxonomic groups reflects differences in trophic level and in the use of basal resources. Different taxonomic groups of predators and decomposers are likely linked to different pools of organic matter in soil, suggesting different functional roles and indicating that trophic niches in soil animal communities are phylogenetically structured. During last two decades studies using stable isotope analysis have elucidated the trophic structure of soil communities, clarified basal food resources of the soil food web and revealed links between above- and belowground ecosystem compartments. Extending the use of stable isotope analysis to a wider range of soil-dwelling organisms, including microfauna, and a larger array of ecosystems provides the perspective of a comprehensive understanding of the structure and functioning of soil food webs

CMS : the TriDAS Project Technical Design Report; v.1, the Trigger Systems

CM