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

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

CM