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Critical to the feasibility of electrochemical reduction of waste NOx (NOxRR), as a sustainable pathway and to close the NOx cycle for the emerging NH3 economy, is the requirement of inexpensive, scalable and selective catalysts that can generate NH4+ with high yield, as indicated by our economic modelling. To this end, we carry out density functional theory (DFT) calculations to investigate the possible contribution of oxygen vacancy (OV) defects in NOxRR catalysis, discovering that an increase in defect density within CuO is leading to a decrease in adsorption energy for NO3− reactants. Using these findings as design guidelines, we develop defective CuO nanomaterials using flame spray pyrolysis (FSP) and mild plasma treatment, that can attain a NH4+ yield of 520 μmol cm−2 h−1 at a cell voltage of 2.2 V within a flow electrolyser with good stability over 10 h of operation. Through our mechanistic investigation, we establish the beneficial role of oxygen vacancy defects (with one free electron) in CuO for NOxRR and we reveal a direct correlation of oxygen vacancy density with the NH4+ yield, arising from improved NO3− adsorption, as evidenced from our theoretical calculations. Our findings on defect engineering to improve NH4+ yield and its economic feasibility display the potential of NOxRR as an alternative pathway to generate green NH3, which can also serve as an energy vector for the emerging hydrogen economy and close the NOx cycle.

What is already known about this subject • The pharmacokinetics of duloxetine have been assessed in a number of clinical studies. • Duloxetine is eliminated through oxidative metabolism via CYP1A2 and, to a lesser degree, CYP2D6. • There is strong evidence that the prevalence of CYP2D6 phenotypes and the activity of CYP1A2 enzyme activity differ between Japanese and Caucasians. • Given the characteristics of duloxetine metabolism, there is good reason to assess pharmacokinetic differences between Japanese and Caucasians. What this study adds • Duloxetine pharmacokinetics in Japanese or Caucasian subjects is not meaningfully different after single or multiple doses of duloxetine. • The magnitude of pharmacokinetic differences between groups is small relative to the pharmacokinetic variability in either group, and these small differences can be accounted for by differences in body weight. • The result of this study suggests that different dose recommendations for Caucasian or Japanese patients are not likely to be necessary. Aims To compare single- and multiple-dose duloxetine pharmacokinetics between healthy Japanese and Caucasians. Methods Twenty-four subjects of each race were given single oral doses of duloxetine (20, 40 and 60 mg) in a randomized, double-blind study. Another 20 subjects of each race received 20, 40 mg or placebo (2 : 2 : 1) twice-daily for 5 days. Results Following single doses, the mean duloxetine Cmax and AUC were approximately 20% greater in Japanese. This difference could be explained by the 15% lower average body weight in Japanese. Similar results were observed following multiple dosing. Conclusion Duloxetine pharmacokinetics are not meaningfully different between Japanese and Caucasians.

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 μg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUC τ , s s ) and C m i n , s s but caused a 17% decrease in mean plasma digoxin C m a s , s s (1.40 to 1.16 ng/mL) and an increuse in digoxin t m a x , s s (median increase, 2.5 hours). Although the decrease in digoxin C m a x , s s was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Background and Objectives Duloxetine, a potent dual reuptake inhibitor of serotonin and norepinephrine currently undergoing clinical investigation for treatment of depression and stress urinary incontinence, has the potential to act as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our objectives were to determine the effect of duloxetine on the pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics (study 2). Methods Subjects were healthy men and women between 21 and 63 years old. All subjects were genotypically CYP2D6 extensive metabolizers. In study 1, 50 mg of desipramine was administered as a single dose alone and in the presence of steady-state duloxetine 60 mg twice daily. In study 2, steady-state pharmacokinetics of duloxetine 40 mg once daily were determined in the presence and absence of steady-state paroxetine 20 mg once daily. Results Duloxetine increased the maximum plasma concentration of desipramine 1.7-fold and the area under the concentration-time curve 2.9-fold. Paroxetine increased the maximum plasma concentration of duloxetine and the area under the concentration-time curve at steady state 1.6-fold. Reports of adverse events were similar whether duloxetine was administered alone or in combination with desipramine or paroxetine. Conclusion Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine. Clinical Pharmacology & Therapeutics (2003) 73, 170–177; doi: 10.1067/mcp.2003.28