Realisation of very high voltage electrode-nozzle systems for MEMS

A number of applications would benefit from MEMS devices that can produce very strong electrical fields with high potential differences; in particular the production and acceleration of ions or charged droplets for spacecraft or biomedical applications. We have carried out investigations into the use of silicon dioxide as an insulator in MEMS devices designed for such applications. The work focuses on axisymmetric electrode configurations that produce 108 V/m electrical fields close to the axis, in vacuum. To accelerate ions to high velocities (>100 m/s) potentials of over 1 kV are required. MOS devices, consisting of aluminium insulated from the silicon substrate by SiO2, were produced with a number of different geometries. Thermal oxides of 2 µm thickness and thermal oxides augmented by 2 µm of CVD oxide were tested for the maximum voltage held before permanent destruction. The insulator surface between two electrodes placed 50 µm apart, successfully held voltages of over 3 kV without surface flashover. We have shown that breakdown occurred through the oxide with a mean hold-off voltage of 1340 V for 2 µm oxides and 2960 V for 4 µm oxides. In the course of the experiments, we have found the importance of chip cleanliness, voltage polarity and the external measuring circuit

Exploration of the nicotinamide-binding site of the tankyrases,identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/b-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted isoquinolin-1-ones were designed as inhibitors to explore the structure–activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki–Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O- demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the parasubstituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies

Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metabolism and Disposition

ABSTRACT: The synthetic opioid fentanyl undergoes extensive metabolism in humans. Systemic elimination occurs primarily by hepatic metabolism. When administered as a lozenge for oral transmucosal absorption, swallowed fentanyl is subject to first pass metabolism in the liver and possibly small intestine. Little is known, however, about the identity and formation of human fentanyl metabolites. This investigation identified routes of human liver microsomal fentanyl metabolism and their relative importance, tested the hypothesis that fentanyl is metabolized by human duodenal microsomes, and identified the predominantly responsible cytochrome P450 isoforms. A GC/MS assay using deuterated internal standards was developed for fentanyl metabolites. Piperidine N-dealkylation to norfentanyl was the predominant pathway of liver microsomal metabolism. Amide hydrolysis to despropionylfentanyl and alkyl hydroxylation to hydroxyfentanyl were comparatively minor pathways. Hydroxynorfentanyl was identified as a minor, secondary metabolite arising from N-dealkylation of hydroxyfentanyl. Liver microsomal norfentanyl formation was significantly inhibited by the mechanism-based P450 3A4 inhibitor troleandomycin and the P450 3A4 substrate and competitive inhibitor midazolam, and was significantly correlated with P450 3A4 protein content and catalytic activity. Of six expressed human P450 isoforms (P450s 1A2, 2B6, 2C9, 2D6, 2E1, and 3A4), only P450 3A4 exhibited significant fentanyl dealkylation to norfentanyl. These results indicate the predominant role of P450 3A4 in the primary route of hepatic fentanyl metabolism. Human duodenal microsomes also catalyzed fentanyl metabolism to norfentanyl; the average rate was approximately half that of hepatic metabolism. Rates of duodenal norfentanyl formation were diminished by troleandomycin and midazolam, and were significantly correlated with P450 3A4 activity, suggesting a prominent role for P450 3A4. These results demonstrate that human intestinal as well as liver microsomes catalyze fentanyl metabolism, and N-dealkylation by P450 3A4 is the predominant route in both organs. The fraction of fentanyl lozenge that is swallowed likely undergoes significant intestinal, as well as hepatic, first-pass metabolism. Intestinal and hepatic first-pass metabolism, as well as systemic metabolism, may be subject to individual variability in P450 3A4 expression and to drug interactions involving P450 3A4. The synthetic opioid fentanyl, after iv administration, is cleared predominantly by hepatic biotransformation (1,2). Fentanyl metabolism is extensive and rapid. Less than 8% administered iv to volunteers was eliminated unchanged, with approximately 6% appearing in urine and 1% excreted in the stool (1), and only 2% was eliminated intact in the urine of surgical patients (3). Metabolites appeared in plasma within 2 min, and plasma metabolite radioactivity exceeded that of parent drug after 30 min (1). More than 80% of the dose was recovered as metabolites, with 76% appearing in the urine and 8% in feces (1). Although these early investigations established the importance of fentanyl biotransformation, the identity of the metabolite(s) was not established. A few subsequent investigations identified some fentanyl metabolites in humans