Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.
As a monophyletic group, the myxobacteria are known to produce a broad spectrum of secondary metabolites. However, the degree of metabolic diversity that can be found within a single species remains unexplored. The model species Myxococcus xanthus produces several metabolites also present in other myxobacterial species, but only one compound unique to M. xanthus has been found to date. Here, we compare the metabolite profiles of 98 M. xanthus strains that originate from 78 locations worldwide and include 20 centimeter-scale isolates from one location. This screen reveals a strikingly high level of intraspecific diversity in the M. xanthus secondary metabolome. The identification of 37 nonubiquitous candidate compounds greatly exceeds the small number of secondary metabolites previously known to derive from this species. These results suggest that M. xanthus may be a promising source of future natural products and that thorough intraspecific screens of other species could reveal many new compounds of interest.Prokaryotes continue to provide important leads in the search for medically important bioactive natural products (1, 11). In particular, the myxobacteria have emerged as a promising source of natural products that exhibit highly diverse structures and biological activities (9). While most myxobacterial genera produce secondary metabolites, difficulties with cultivation and genetic manipulation hinder exploitation of the biosynthetic potential of many species. In contrast, the relatively fast growth and extensive genetic characterization of Myxococcus xanthus make the identification of natural products in this model species of particular interest.Myxococcus xanthus has been thoroughly investigated due to its amazing social behaviors, which include coordinated swarming over surfaces and a complex life cycle that culminates in the formation of multicellular fruiting bodies under starvation conditions (23). However, little attention has been paid to secondary metabolite production in this model species. M. xanthus strain DK1622 is the genotype most commonly studied with respect to social interactions and development. This strain has been found to produce several secondary metabolites, including the myxochromids (27), myxalamids (13), the antibiotic myxovirescin (8), and the siderophore myxochelin (15) (Fig. 1A). The molecular basis of synthesis for these compounds has been studied in some detail (25,26,30) and has been greatly facilitated by the availability of the DK1622 genome sequence (10). Very recently, a novel secondary metabolite class unique to M. xanthus, the DKxanthenes, was characterized and was shown to be essential for viable-spore formation (18). Additional reports of secondary metabolites from M. xanthus are limited to cittilin (20) and the antibiotics saframycin (12) and althiomycin (16).Most of these M. xanthus compounds are polyketides or nonribosomal peptides or hybrids thereof, and their biosynthesis is accomplished by large multienzyme complexes, the polyketide synthases (PKSs) or the nonri...
A liquid chromatography-electrospray ionization-time-of-flight mass spectrometry (HPLC/ESI-TOF-MS) procedure was developed to characterize changes induced in Nicotiana attenuata leaves 1 h and 5 days after wounding and application of Manduca sexta elicitors. The constancy of the measurement conditions was first confirmed for 22 selected analytes spanning the entire chromatogram. Using the Profile Analysis software, we extracted 367 buckets, which were analyzed by principal component analysis and two-factorial ANOVA. One hundred seventy-three buckets were found to be statistically regulated, 128 due to time effects, and 85 due to treatment effects. In vivo 15N-isotope labeling was used to facilitate the annotation and the interpretation of the fragmentation pattern of nitrogen-containing metabolites, and a correlation analysis was performed to test mathematical relationships existing among potential in-source fragments. Additionally, tandem MS measurements of the most regulated ions are presented. Altogether, this study defines a framework for the mining and annotation of major herbivory-elicited changes in Nicotiana attenuata.
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