Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676.

Positron emission tomography (PET) is widely applied in central nervous system (CNS) drug development for assessment of target engagement in vivo. As the majority of PET investigations have addressed drug interaction at a single binding site, findings of multitarget engagement have been less frequently reported and have often been inconsistent with results obtained in vitro. AZD3676 [N,N-dimethyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl) benzofuran-2-carboxamide] is a novel combined serotonin (5-hydroxytryptamine) 5-HT1A and 5-HT1B receptor antagonist that was developed for the treatment of cognitive impairment in Alzheimer's disease. Here, we evaluated the properties of AZD3676 as a CNS drug by combining in vitro and ex vivo radioligand binding techniques, behavioral pharmacology in rodents, and PET imaging in nonhuman primates. Target engagement in the nonhuman primate brain was assessed in PET studies by determination of drug-induced occupancy using receptor-selective radioligands. AZD3676 showed preclinical properties consistent with CNS drug potential, including nanomolar receptor affinity and efficacy in rodent models of learning and memory. In PET studies of the monkey brain, AZD3676 inhibited radioligand binding in a dose-dependent manner with similar affinity at both receptors. The equally high affinity at 5-HT1A and 5-HT1B receptors as determined in vivo was not predicted from corresponding estimates obtained in vitro, suggesting more than 10-fold selectivity for 5-HT1A versus 5-HT1B receptors. These findings support the further integrated use of PET for confirmation of multitarget occupancy of CNS drugs. Importantly, earlier introduction of PET studies in nonhuman primates may reduce future development costs and the requirement for animal experiments in preclinical CNS drug development programs.

Removal of pharmaceutical residues using ozonation as intermediate process step at Linköping WWTP, Sweden.

Pilot tests as basis for the design, implementation and operation of a future full-scale oxidation plant completing the existing sewage treatment in Linköping, Sweden, were performed. Using an ozonation step between bio-sedimentation and post-denitrification processes, the primary goal was the removal of the highest priority substances to effluent water levels that will not cause adverse effects in the recipient considering the natural dilution. The study included initial emission screenings, dose control trials, treatment performance studies and eco-toxicity studies. At an ozone dose of 5 mg O3/L, most substances could be removed. Ecotoxicological tests showed no negative effect for the tested ozone doses. High levels of oxygen into the denitrification could be rapidly reduced in the biology. The number of bacteria in the treated water could be significantly reduced even at relatively low ozone doses. Based on these results, the planning for the full-scale implementation of the treatment system was initiated in 2015.

Pharmaceutical residues in sewage sludge: effect of sanitization and anaerobic digestion.

The fate of pharmaceutical residues in treatment of WWTP sludge was evaluated during mesophilic anaerobic digestion (AD) and six sanitization technologies (pasteurization, thermal hydrolysis, advanced oxidation processes using Fenton's reaction, ammonia treatment, thermophilic dry digestion, and thermophilic anaerobic digestion). Sludge spiked with a selection of 13 substances was used and in total 23 substances were detected. A correlation between substance lipophilicity and sludge partitioning was found after sample centrifugation, with e.g., SSRI drugs (90-99%) and estrogens (96-98%) mainly found in the solid phase. A correlation between lipophilicity and persistence of pharmaceutical residues during AD was also detected, indicating that hydrophobic substances are less available to degrading microorganisms. Overall, AD was found to be the most effective technology in reducing a wide spectrum of organic substances (in average ca 30% reduction). Similar effects were obtained for both AD treatments, suggesting that temperature (mesophilic or thermophilic) is less important for micropollutant reduction. Advanced oxidation processes using Fenton's reaction also affected several compounds, including substances showing general stability over the range of treatments such as carbamazepine, propranolol, and sertraline. Pasteurization, ammonia treatment, and thermophilic dry digestion exhibited relatively modest reductions. Interestingly, only thermal hydrolysis efficiently removed the ecotoxicologically potent estrogenic compounds from the sludge.

Phenethyl nicotinamides, a novel class of Na(V)1.7 channel blockers: structure and activity relationship.

The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile.

Evaluation of ninhydrin as a fingermark visualisation method - A comparison between different procedures as an outcome of the 2017 collaborative exercise of the ENFSI Fingerprint Working Group.

In 2017 the Fingerprint Working Group (EFP-WG) of the European Network of Forensic Science Institutes (ENFSI) undertook a collaborative exercise (CE) with the aim of assessing the use of ninhydrin as a fingermark development technique in the laboratory. The test was prepared and managed by the officially established advisory group. The characteristics of the CE are summarised. The results indicate that ninhydrin is a robust methodology. Unexpected negative outcomes have been outlined and discussed, followed by an overview of the knowledge that has been gained.

Investigating weathering in light diesel oils using comprehensive two-dimensional gas chromatography-High resolution mass spectrometry and pixel-based analysis: Possibilities and limitations.

Petroleum-derived fuels are chronically spilled in urbanized areas, affecting the environment and the population's health. Forensic investigations of oil spills aim to find the responsible source of the spills. Weathering processes (dissolution, evaporation, photo-oxidation and biodegradation) change the chemical composition of the spills and hamper the matching of spill-source pairs, especially for light diesel oils (i.e. n-C9 - n-C20) in which the source diesels can be very similar due to the refining process and only compounds resistant to short- or middle-term weathering are present. In this study, comprehensive two-dimensional gas chromatography - high resolution mass spectrometry (GC × GC - HRMS) and pixel-based analysis were combined for: i) improve the identification of very similar diesel oils, and ii) identify weathering-resistant compounds that can also distinguish samples from different sources. Diesel oils from two sources that have been exposed to different degrees of evaporation, photo-oxidation and biodegradation in a laboratory setup. The study revealed the tentatively identified octanoic acid methyl ester and n-nonaldehyde were more resistance to evaporation than hydrocarbons < n-C15. Furthermore, the hydrocarbons > n-C17 could be used for source-apportionment of all the diesel oils susceptible to evaporation and photo-oxidation, but only pristane and phytane were also more resistant to biodegradation. Naphthenes, bicyclic sesquiterpanes and adamantanes were more resistant to only photo-oxidation and biodegradation. GC × GC - HRMS enhanced the separation of the highly similar naphthenes in the diesel oils; however, the diagnostic power for forensic spill investigations was still similar to 1D GC - HRMS.

Predicting human exposure of active drug after oral prodrug administration, using a joined in vitro/in silico-in vivo extrapolation and physiologically-based pharmacokinetic modeling approach.

INTRODUCTION: Predicting the pharmacokinetics (PK) of prodrugs and their corresponding active drugs is challenging, as there are many variables to consider. Prodrug conversion characteristics in different tissues are generally measured, but integrating these variables to a PK profile is not a common practice. In this paper, a joined in vitro/in silico-in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic (PBPK) modeling approach is presented to predict active drug exposure in human after oral prodrug administration. METHODS: Physico-chemical and in vitro assays as well as in silico predictions were proposed to characterize key pharmacokinetic properties (e.g. clearance, volume of distribution, conversion rates) of three marketed prodrugs. These data were used to parameterize a PBPK model for simulating human PK profiles of the active drugs after prodrug administration, which were compared to literature data by evaluating the accuracy and uncertainty of the predictions. RESULTS: For mycophenate mofetil and midodrine the PK of their active moieties could be adequately predicted. The assumptions of the PBPK-IVIVE approach were valid, i.e. being hepatically cleared, converted in the gut lumen, blood and liver and not metabolized in the gut wall. However, the observed profiles after oral bambuterol administration clearly fell outside the prediction interval as the PBPK model failed to predict the observed bioavailability. DISCUSSION: Adding quantitative information about prodrug conversion in the gut, liver and blood to a PBPK model for the absorption, distribution, metabolism and excretion (ADME) properties of prodrugs and their active moieties resulted, retrospectively, in reasonable predictions of the human PK when the ADME properties are well understood. Also in a prospective compound selection process, this integrative approach can improve decision making on prodrug candidates by putting relative differences in prodrug conversion of a large number of candidates into the perspective of their human PK profile, before conducting any in vivo experiments.