The later that a molecule or molecular class is lost from the drug development pipeline, the higher the financial cost. Minimizing attrition is therefore one of the most important aims of a pharmaceutical discovery programme. Novel technologies that increase the probability of making the right choice early save resources, and promote safety, efficacy and profitability. Metabonomics is a systems approach for studying in vivo metabolic profiles, which promises to provide information on drug toxicity, disease processes and gene function at several stages in the discovery-and-development process.

Metabonomics: a platform for studying drug toxicity and gene function

An adaptive interface for a programmable system, for predicting a desired user function, based on user history, as well as machine internal status and context. The apparatus receives an input from the user and other data. A predicted input is presented for confirmation by the user, and the predictive mechanism is updated based on this feedback. Also provided is a pattern recognition system for a multimedia device, wherein a user input is matched to a video stream on a conceptual basis, allowing inexact programming of a multimedia device. The system analyzes a data stream for correspondence with a data pattern for processing and storage. The data stream is subjected to adaptive pattern recognition to extract features of interest to provide a highly compressed representation that may be efficiently processed to determine correspondence. Applications of the interface and system include a video cassette recorder (VCR), medical device, vehicle control system, audio device, environmental control system, securities trading terminal, and smart house. The system optionally includes an actuator for effecting the environment of operation, allowing closed-loop feedback operation and automated learning.

Adaptive pattern recognition based control system and method

To apply genomic knowledge effectively in drug discovery, mechanistic connectivities between genetic variation and disease processes need to be established via systems biology approaches. Humans have hundreds of functionally specialized cell types that interact differentially with environmental factors to influence disease development and to modulate the effects of drugs. Metabonomics can provide a means of modelling these interactions, but the relationships between 'endogenous' metabolic processes (coded in the genome and intrinsic to cellular function) and 'xenobiotic' (foreign compound) metabolism are poorly understood, especially with respect to environmental factors. We present an overview of 'global' mammalian metabolic conversions that should be accounted for in human systems biology models and propose a new probabilistic approach to help understand gene–disease relationships and vexed issues of idiosyncratic drug toxicity.

Understanding 'Global' Systems Biology: Metabonomics and the Continuum of Metabolism

Damascene copper electroplating for on-chip interconnections, a process that we conceived and developed in the early 1990s, makes it possible to fill submicron trenches and vias with copper without creating a void or a seam and has thus proven superior to other technologies of copper deposition. We discuss here the relationship of additives in the plating bath to superfilling, the phenomenon that results in superconformal coverage, and we present a numerical model which accounts for the experimentally observed profile evolution of the plated metal.

Damascene copper electroplating for chip interconnections

The mammalian gut microbiota interact extensively with the host through metabolic exchange and co-metabolism of substrates. Such metabolome-metabolome interactions are poorly understood, but might be implicated in the aetiology of many human diseases. In this paper, we assess the importance of the gut microbiota in influencing the disposition, fate and toxicity of drugs in the host, and conclude that appropriate consideration of individual human gut microbial activities will be a necessary part of future personalized health-care paradigms.

Gut microorganisms, mammalian metabolism and personalized health care

1. A combined in vivo and in vitro study has been devised to investigate an observation, obtained by 1H NMR of urine, that Alp:AprSD (Wistar derived) rats kept under standard husbandry conditions did not excrete urinary hippuric acid (HA). meta-(hydroxyphenyl)-propionic acid ?m-HPPA? was identified as the major aromatic component in urine samples lacking HA. 2. Examination of urine from Alp:APrSD and Zucker (obese negative) rats fed various diets showed that the lack of HA/presence of m-HPPA was due to diet and not to the strain of animal. This observation was reinforced by the demonstration that the administration of benzoic acid (BA) to rats not previously excreting urinary HA resulted in the return of this component to the urinary excretion profile. Thus rats receiving the standard diet were still capable of glycine conjugation. 3. Changing the diet of rats excreting m-HPPA led to the cessation of m-HPPA excretion and the return of HA urine excretion. Interestingly, switching back to the original diet did not cause the loss of HA and the re-emergence of m-HPPA. 4. In vitro studies on the two enzyme systems responsible for glycine conjugation (benzoyl CoA:synthetase and benzoyl CoA:glycine N-acyltransferase) in isolated liver mitochondria showed that m-HPPA did not inhibit either enzyme. However, m-HPPA was not found to be a substrate for the first reaction step explaining why it was found in the urine as the free acid and not as a glycine conjugate. 5. The absence and presence of m-HPPA and hippuric acid is suggested to be due to a combination of differences in dietary precursors of substrates for glycine conjugation and a dietary dependent redistribution of the intestinal microflora responsible for breakdown of plant phenolics and aromatic amino acids. Taken collectively this study emphasises how a simple diet change can cause a profound change in metabolism.

Effect of diet on the urinary excretion of hippuric acid and other dietary-derived aromatics in rat. A complex interaction between diet, gut microflora and substrate specificity

Superheated heavy water can be used as the eluent for reversed-phase chromatography with on-line HPLC-NMR and HPLC-NMR-MS detection. The method has been demonstrated for the separation of model drugs (analgesics and caffeine) on a poly(styrene-divinylbenzene) stationary phase in isothermal and temperature-programmed modes. One- and two-dimensional spectra could be obtained with less interference from the mobile phase than with conventional HPLC-NMR eluents. Unlike supercritical fluid chromatography-NMR, the spectra could be measured at room temperature and atmospheric pressure. The combination of superheated water HPLC-NMR-MS chromatography enables both NMR and MS spectra to be obtained simultaneously for the same sample.

Superheated Heavy Water as the Eluent for HPLC-NMR and HPLC-NMR-MS of Model Drugs

The ultimate goal of this paper is to print radio frequency (RF) and microwave structures using a 3-D platform and to pattern metal films on nonplanar structures. To overcome substrate losses, air core substrates that can readily be printed are utilized. To meet the challenge of patterning conductive layers on complex or nonplanar printed structures, two novel self-aligning patterning processes are demonstrated. One is a simple damascene-like process, and the other is a lift-off process using a 3-D printed lift-off mask layer. A range of microwave and RF circuits are designed and demonstrated between 1 and 8 GHz utilizing these processes. Designs are created and simulated using Keysight Advanced Design System and ANSYS High Frequency Structure Simulator. Circuit designs include a simple microstrip transmission line (T-line), coupled-line bandpass filter, circular ring resonator, T-line resonator, resonant cavity structure, and patch antenna. A commercially available 3-D printer and metal sputtering system are used to realize the designs. Both simulated and measured results of these structures are presented.

Demonstration of RF and Microwave Passive Circuits Through 3-D Printing and Selective Metalization

1. The metabolic fate and urinary excretion of 2-bromo-4-trifluoromethylaniline has been studied in rat using 19F-NMR spectroscopic and directly coupled HPLC-NMRMS methods. The compound was dosed to Sprague-Dawley rats (50 mg kg−, i.p.) and urine collected over 0-8, 8-24 and 24-48 h post-dosing. 2. A total urinary recovery of 53.5 ± 7.0% of the dose was achieved up to 48 h after dosing. The major metabolite in the urine was identified as 2-amino-3-bromo-5-trifluoromethylphenylsulphate accounting for a total of 35.7 ± 6.2% of the dose. 3. Further metabolites detected were 2-bromo-4-trifluoromethylphenylhydroxylamine-N-glucuronide (9.7 ± 0.2% of the dose), 2-bromo-4-trifluoromethylaniline-N-glucuronide (3.0 ± 0.3%) and 2-amino-3-bromo-5-trifluoromethylphenylglucuronide (2.8 ± 0.4). Minor metabolites, including 2-bromo-4-trifluoromethylphenylhydroxylamine-O-glucuronide, 2-amino-3-bromo-5-trifluoromethylphenol and 2-bromo-4- trifluoromethylphenylsulphamate, in total accounted for 2.3 ± 0.9% of the dose. 4. Di...

19F-NMR and directly coupled HPLC-NMR-MS investigations into the metabolism of 2-bromo-4- trifluoromethylaniline in rat: a urinary excretion balance study without the use of radiolabelling

The use of HPLC-NMR-MS for the detection and identification of the metabolites of ibuprofen present in a solid phase extract of human urine is described. Gradient reversed-phase HPLC was used to separate the components present in the extract, which were then characterised by a combination of stopped-flow1H NMR and on line electrospray-MS. This approach led to the rapid identification of the known phase 1 human metabolites of ibuprofen, including hydroxy- and carboxy- metabolites, together with their respective glucuronide conjugates. In addition a probable artefact resulting from the dehydration of one of the side chainhydroxylated glucuronides was also identified.

The application of high performance liquid chromatography, coupled to nuclear magnetic resonance spectroscopy and mass spectrometry (HPLC-NMR-MS), to the characterisation of ibuprofen metabolites from human urine

B. Wright

Papers

Effect of diet on the urinary excretion of hippuric acid and other dietary-derived aromatics in rat. A complex interaction between diet, gut microflora and substrate specificity

Superheated Heavy Water as the Eluent for HPLC-NMR and HPLC-NMR-MS of Model Drugs

Demonstration of RF and Microwave Passive Circuits Through 3-D Printing and Selective Metalization

19F-NMR and directly coupled HPLC-NMR-MS investigations into the metabolism of 2-bromo-4- trifluoromethylaniline in rat: a urinary excretion balance study without the use of radiolabelling

The application of high performance liquid chromatography, coupled to nuclear magnetic resonance spectroscopy and mass spectrometry (HPLC-NMR-MS), to the characterisation of ibuprofen metabolites from human urine