Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease

β-Blockers reduce mortality and improve symptoms in people with heart disease. However, current clinically available β-blockers have poor selectivity for the cardiac β1-adrenoceptor (AR) over the lung β2-AR. Unwanted β2-blockade risks causing life-threatening bronchospasm and a reduction in the efficacy of β2-agonist emergency rescue therapy. Thus current life-prolonging β-blockers are contraindicated in people with both heart disease and asthma. Here we describe NDD-713 and NDD-825, novel highly β1-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays using human receptors expressed in CHO cells demonstrate that NDD-713 and NDD-825 have nanomolar β1-AR affinity, greater than 500-fold β1-AR vs β2-AR selectivity and no agonism. Studies in conscious rats demonstrated that they are orally bioavailable and cause pronounced β1-mediated reduction of heart rate while showing no effect on β2-mediated hindquarters vasodilatation. The compounds also have good disposition properties and show no adverse toxicological effects. They potentially offer a truly cardioselective β-blocker therapy for the large number of people with heart and respiratory, or peripheral vascular comorbidities

Synthesis and in vitro and in vivo characterization of highly β1-Selective β-Adrenoceptor partial agonists

β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of −7.75 and −5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β1- selectivity

Sport policy convergence: a framework for analysis

This is an Accepted Manuscript of an article published by Taylor & Francis Group in European Sport Management Quarterly on 30th April 2012, available online at: http://www.tandfonline.com/10.1080/16184742.2012.669390The growth in the comparative analysis of sport management processes and policy has led to an increased interest in the concept of convergence. However, the concept is too often treated as unproblematic in definition, measurement and operationalisation. It is argued in this paper that a more effective framework for examining claims of convergence is one that analyses the concept in terms of seven dimensions which can be explored through a mix of quantitative and qualitative methods of data collection. It is also argued that a deeper understanding of the process of convergence can be gained by operationalising the concept in the context of a selected range of meso-level theories of the policy process or of specific aspects of the process. The proposed analytic framework provides not only a definition of convergence but also the basis for a more nuanced investigation of hypotheses of convergence

Recommendations for effective documentation in regional anesthesia: an expert panel Delphi consensus project

Background and objectives: Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Methods: Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. Results: Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. Conclusion: By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia

(13)Carbon and (15)nitrogen isotopes in autopsy liver tissue samples from Greenlandic Inuit and Danes: consumption of marine versus terrestrial food

International audienceBackground: 13C and 15N isotopes in human tissue reflects the relative proportions of marine and terrestrial food consumed by the individual. Objective: To measure 13C and 15N in liver tissue from Greenlandic Inuit and Danes Methods: Liver tissue was obtained at autopsy in 1992-1994 from 60 Inuit (median age 61 y) and in 1986 from 15 Danes (median age 84 y). By sieving, liver tissue was separated in a "cellular fraction" and a "connective tissue fraction". 13C and 15N in dry liver tissue was measured on a mass spectrometer. δ13C indicates 13C content relative to IAEA-CH-6 Reference Standard. δ15N indicates 15N content relative to Atmospheric Nitrogen Reference Standard. Results: Inuit: Median δ13C was -21.2‰ in cellular and -20.0‰ in connective tissue fractions (p=0.001). Median δ15N was 10.6‰ in both cellular and connective tissue. Body mass index was negatively correlated with δ13C in connective tissue (rs=-0.42, p=0.057). Danes: Median δ13C was -27.0‰ in cellular and -24.3‰ in connective tissue (p=0.11). Median δ15N was 9.5‰ in cellular and 8.9‰ in connective tissue (p=0.5). Inuit had higher δ13C than Danes in both cellular and connective tissue (p<0.001) as well as higher δ15N in cellular tissue (p=0.01). Conclusions: Inuit displayed considerable variation in the ratio between marine/terrestrial food consumption, because elderly Inuit still adhere to the traditional hunters food of marine origin, whereas younger urbanized Inuit consume more terrestrial Western fare. Danes consumed food of almost exclusively terrestrial origin. Key words: 13Carbon; Denmark; Greenland; Inuit; liver; 15Nitrogen