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Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure–activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.

An understanding of expenditure patterns is vital to travel organizers and destination marketers. Using surveys conducted by the Barcelona Tourism Board (Turisme de Barcelona), this study profiled the trip by purpose: leisure or business, and investigated the relationships between travel expenditure, length of stay, repeat visits and satisfaction. Different trip-related and socio-demographic variables, such as trip purpose, number of nights spent and repeat visits were found to contribute to explaining the expenditure variations. The theoretical model is based on the literature, and puts forward different hypotheses, which are tested using SEM. The findings show behavioural differences between those groups and are useful for tourism managers of urban destinations.

This article analyses tourist demand in relation to the city of Barcelona, with the aim of defining the effect of tourist expenditure on tourist behaviour in urban destinations. The relationships between motivation, satisfaction, length of stay and repeat visits are studied for leisure and business travellers. Tourist expenditure is used as a moderating effect, and is made up of three groups described under tourist expenditure: light, medium and heavy spenders. The theoretical model is based on the literature, and puts forward different hypotheses, which are tested using SEM with multi-group analysis. Data collection was carried out on the basis of surveys conducted by Barcelona Tourism Board, Turisme de Barcelona, among tourists during their stay in the destination. The sample used comprises 12,965 tourists who stayed overnight in Barcelona between 2009 and 2011. The results show the behavioural differences between the groups, as well as the degree of support for the hypotheses. Furthermore, these results are used for proposing management strategies for urban destinations.

Abediterol is a novel potent, long-acting inhaled β(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human β(2)-adrenoceptor and a functional selectivity over β(1)-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human β(2)-adrenoceptor (E(max) = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC(50) = 1.9 ± 0.4 nM; t½ onset = 7-10 min) is not significantly different from that of formoterol, but its duration of action (t½ ∼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t½ = 36 h) than salmeterol (t½ = 6 h) and formoterol (t½ = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.

Estrogen receptor (ER) beta agonists have been demonstrated to possess anti-inflammatory properties in inflammatory disease models. The objective of this study was to determine whether ERbeta agonists affect in vitro and in vivo preclinical models of asthma. mRNA expression assays were validated in human and rodent tissue panels. These assays were then used to measure expression in human cells and our characterized rat model of allergic asthma. ERB-041 [7-ethenyl-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol], an ERbeta agonist, was profiled on cytokine release from interleukin-1beta-stimulated human airway smooth muscle (HASM) cells and in the rodent asthma model. Although ERbeta expression was demonstrated at the gene and protein level in HASM cells, the agonist failed to have an impact on the inflammatory response. Similarly, in vivo, we observed temporal modulation of ERbeta expression after antigen challenge. However, the agonist failed to have an impact on the model endpoints such as airway inflammation, even though plasma levels reflected linear compound exposure and was associated with an increase in receptor activation after drug administration. In these modeling systems of airway inflammation, an ERbeta agonist was ineffective. Although ERbeta agonists are anti-inflammatory in certain models, this novel study would suggest that they would not be clinically useful in the treatment of asthma.

Since the discovery of the first matrix metalloproteinase (MMP), this ever-growing family of proteinases has been the subject of intense research. Although it was initially believed that MMPs were solely involved in matrix turnover and degradation, there are now data suggesting MMPs are actively involved in the inflammatory process. In previous studies, we have demonstrated an increase in MMP expression in human cell-based assays and in preclinical rat models of airway inflammation. Therefore, the aim of this study was to characterize the role of MMPs in these models by profiling the impact of a broad-spectrum MMP inhibitor. In lipopolysaccharide (LPS)-stimulated THP-1 cells and primary human lung tissue macrophages, the MMP inhibitor had no significant effect on the release of tumor necrosis factor-alpha, interleukin (IL)-8, IL-1beta, growth-regulated oncogene-alpha, macrophage inflammatory protein-1alpha, or IL-6 whereas dexamethasone has a significant impact on all cytokines from both cell types. Similarly, in the more biologically complex LPS-driven rat model of airway inflammation, the MMP inhibitor did not have an impact on mediator release and cellular burden. The compound did, however, significantly reduce levels of lung MMP-9. Furthermore, in a "disease" model, the compound did not affect cellular inflammation but did significantly reduce elastase-induced experimental emphysema. In summary, these data demonstrate for the first time that MMPs do not play a role in the increase in inflammatory mediators or cellular burden observed in these preclinical models. However, they do appear to be involved in the elastase-driven breakdown of airway structure, which is not due to a direct effect of the stimulus.

This report represents a preliminary attempt to define the best avenues of approach for selecting animals adapted to a tropical environment by using a climatic chamber as a means of testing their adaptability.Several studies have been recently published that describe differences in the reactions of animals of various breeds as they are subjected to high ambient temperatures (Kibler and Brody, 1951; McDowell et al.,1954). In all these studies, however, the animals tested were born and reared in temperate climates, so that they may not have been physiologically adjusted to the new environment to the fullest extent possible. All animals used in the present study were born at or near Turrialba, and had always lived in ambient temperatures of about 20° C., and in the high humidity characteristic of a rain forest type of tropical climate. Furthermore, this study presents some new and significant comparisons between the behavior of animals toward tests conducted at night and in the daytime.