ABSTRACT:The purpose of this study was to investigate the metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid receptor agonist, in humans. In a two-part, open-label design study, five healthy male subjects received a p. Fluticasone furoate [(6␣,11␤,16␣,17␣)-6,9-difluoro-17-{[(fluoromethyl)-thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl-2-furancarboxylate] is a new enhanced-affinity glucocorticoid receptor agonist. It is a synthetic fluorinated corticosteroid that has been developed as an intranasal treatment for patients with symptoms of rhinitis. Fluticasone furoate, otherwise known as GW685698X, is not a salt or prodrug because the entire molecule is required for pharmacological activity. It has similar or greater potency than other clinically used corticosteroids (including mometasone furoate, budesonide, fluticasone propionate, and the active principle of ciclesonide) for the glucocorticoid receptor and against the proinflammatory transcription factors nuclear factor B (NF-B), activation protein-1, and tumor necrosis factorinduced interleukin-8 cytokine production (Salter et al., 2007). Agonism of the glucocorticoid receptor is known to suppress the activation of downstream transcription factors, such as NF-B and activation protein-1, and to activate the glucocorticoid response element transactivation pathway (Rhen and Cidlowski, 2005). Inhibition of the NF-B pathway, in particular, is thought to be intimately involved in the anti-inflammatory activity of glucocorticoids because it is a key pathway in the synthesis of a number of inflammatory cytokines (Karin et al., 2004). It is well documented that topical glucocorticoids interact with many of the inflammatory pathways, and there is a large body of clinical evidence to support their use for the treatment of rhinitis, asthma, and chronic obstructive pulmonary disease (Goodman and Gilman, 2006). The purpose of the present study was to investigate the metabolism and disposition of [ 14 C]fluticasone furoate after p.o. and i.v. administration to healthy male subjects. These dose routes were used as surrogates for the intranasal and inhalation routes, from which the majority of the dose is likely to be swallowed. The p.o. route acted as a surrogate for the portion of an intranasal or inhaled dose that is swallowed, and the i.v. route represented the portion absorbed locally into the systemic circulation.

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.

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Recently there has been a revived interest in high temperature molten salt battery systems, particularly sodium-sulphur and sodium metal-chloride, SMC. In particular SMC batteries have high theoretical specific energies and open circuit potentials (787 Whkg-1 and 2.58 V for Ni cell chemistry). They comprise a liquid Na anode, solid beta-alumina electrolyte and a metal chloride cathode which also contains sodium tetrachloroaluminate, NaAlCl4 as a secondary electrolyte [1]. However, battery performance is constrained by cathode underperformance resulting in obtainable specific energies in the region of 120 Wh kg-1 [2]. The best performing cathode formulations contain both Fe and Ni as active cathode materials, with an excess of Ni to prevent Cl2 liberation on overcharge. The excess Ni and NaAlCl4 increase the weight of the battery, while not contributing to the output, therefore reducing the specific energy. Additional reductions in performance are attributed to the cell chemistry occurring in the cathode. Alternative cathode formulations could enhance the performance of this battery technology and enable its application for grid storage. This should be achieved while maintaining the existing technologies high abundance of raw materials used in the manufacturing process. This talk presents our research on the chemical processes occurring in the cathode for cell chemistries based on various transition metals, particularly Fe, Co, Ni, Zn and Cu, over the temperature range 200°C to 400°C. Cyclic voltammetry on polished coated wire tip electrodes have been used to determine the diffusion coefficients of the metal ions diffusing through their respective metal chloride layers. In situ Raman spectroscopy has been undertaken to develop a better understanding of the processes occurring to form the metal chlorides. [1]          J. Coetzer, J. Power Sources (1986) 18 377 [2]          R.C. Galloway & S. Haslam, J. Power Sources (1999) 80 164

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