A preliminary assessment of the effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using implanted pacemaker methodology

Aims ATI-2042 (budiodarone) is a chemical analogue of amiodarone with a half life of 7 h. It is electrophysiologically similar to amiodarone, but may not have metabolic and interaction side effects. The sophisticated electrocardiograph logs of advanced DDDRP pacemakers were used to monitor the efficacy of ATI-2042. The aim of this study was to determine the preliminary efficacy and safety of ATI-2042 in patients with paroxsymal atrial fibrillation (PAF) and pacemakers. Methods and results Six women with AF burden (AFB) between 1 and 50% underwent six sequential 2-week study periods. Patients received 200 mg bid of ATI-2042 during Period 2 (p2), 400 mg bid during p3, 600 mg bid during p4, 800 mg bid during p5, and no drug during baseline and washout (p1 and p6). Pacemaker data for the primary outcome measure AFB were downloaded during each period. Mean AFB decreased between baseline and all doses: AFB at baseline (SD) was 20.3 ± 14.6% and mean AFB at 200 mg bid was 5.2 ± 4.2%, at 400 mg bid 5.2 ± 5.2%, at 600 mg bid 2.8 ± 3.4%, and at 800 mg bid 1.5 ± 0.5%. The mean reductions in AFB at all doses of ATI-2042 were statistically significant (P < 0.005). Atrial fibrillation burden increased in washout. Atrial fibrillation episodes tended to increase with ATI-2042, but this was offset by substantial decreases in episode duration. ATI-2042 was generally well tolerated. Conclusion ATI-2042 effectively reduced AFB over all doses studied by reducing mean episode duration. A large-scale study will be required to confirm this effect

Das Marchen als Grenzerfahrung: Zur Polysemie von Ursprung, Auszug und Heimkehr

My dissertation examines concepts of Home and Otherness in selected nineteenth-century fairy tales (by Amalia Schoppe, Heinrich Heine, Elisabeth Ebeling, Marie von Ebner-Eschenbach, Hugo von Hofmannsthal). Influenced by Benedict Anderson\u27s concept of imagined communities and Susanne Zantop\u27s investigations of colonial fantasies, I analyze the fairy tale\u27s traditional plot (home/stasis, journey/crisis, homecoming/stasis) and its juxtaposition of home and foreignness as a template for group affiliations based on race, gender, religion, culture, and nation. Rather than viewing the spheres of home and the foreign land as separate entities, however, I center my discussion on the hero(ine)\u27s deliberate transgression of the imagined boundaries that establish and segregate two distinct spaces. ^ The fairy tale\u27s plot, the hero(ine)\u27s quest, is traditionally characterized by essential differences between familiar and unfamiliar spheres and by an effort to (re)construct a primordial harmony. Taking into consideration recent debates on cultural and individual identity in postcolonial, feminist and cultural studies (e.g., Bhabha, Stanford Friedman, Sollors, Clifford), I focus on the process of border-crossing as negotiations and constructions of (cultural, national, racial, gender, or modern) identity. I interpret the hero(ine)\u27s quest as an ongoing formation and reformation of home (roots) through the encounter of Otherness (routes), and the protagonist\u27s return---the fairy tale\u27s happy end---as a possible symbiosis between roots and routes (Stanford Friedman). ^ This approach establishes nineteenth-century fairy tales as spaces of identity that do not only (re)present a certain cultural community but also, and more importantly, identify an increasing need to defend, negotiate or reject an isomorphism of Home in a century of enormous sociopolitical changes, increasing individual choices, and multiplying meanings of identity. Thus, my dissertation offers an original perspective on the cultural importance and the (ongoing) popularity of the genre: I argue that the imagination of hybrid identities, produced by varying practices of border-crossing, is a crucial characteristic of the genre, and that it is the attraction and/or aversion to hybridity that causes the German obsession with fairy tales (Zipes) in the nineteenth century and ever after.

Beta 3-adrenoceptor in rat aorta: molecular and biochemical characterization and signalling pathway

1. We have previously demonstrated that β(3)-adrenoceptor (β(3)-AR) stimulation induces endothelium-dependent vasorelaxation in rat aorta through the activation of an endothelial NO synthase associated with an increase in intracellular cGMP. The aim of the present study was to localise β(3)-AR to confirm our functional study and to complete the signalling pathway of β(3)-AR in rat aorta. 2. By RT–PCR, we have detected β(3)-AR transcripts both in aorta and in freshly isolated endothelial cells. The absence of markers for adipsin or hormone-sensitive lipase in endothelial cells excluded the presence of β(3)-AR from adipocytes. The localization of β(3)-AR in aortic endothelial cells was confirmed by immunohistochemistry using a rat β(3)-AR antibody. 3. To identify the G protein linked to β(3)-AR, experiments were performed in rat pre-treated with PTX (10 μg kg(−1)), a G(i/0) protein inhibitor. The blockage of G(i/0) protein by PTX was confirmed by the reduction of vasorelaxation induced by UK 14304, a selective α(2)-AR agonist. The cumulative concentration-response curve for SR 58611A, a β(3)-AR agonist, was not significantly modified on aorta rings from PTX pre-treated rats. 4. At the same level of contraction, the relaxations induced by 10 μM SR 58611A were significantly reduced in 30 mM-KCl pre-constricted rings (E(max)=16.7±8.4%, n=5), in comparison to phenylephrine (0.3 μM) pre-constricted rings (E(max)=49.11±11.0%, n=5, P<0.05). In addition, iberotoxin (0.1 μM), glibenclamide (1 μM) and 4-aminopyridine (1 mM), selective potassium channels blockers of K(Ca), K(ATP), and K(v) respectively, decreased the SR 58611A-mediated relaxation. 5. We conclude that β(3)-AR is preferentially expressed in rat aortic endothelial cells. β(3)-AR-mediated aortic relaxation is independent of G(i/0) proteins stimulation, but results from the activation of several potassium channels, K(Ca), K(ATP), and K(v)

Effect of dronedarone on renal function in healthy subjects

What is already known about this subjectCreatinine clearance (CL) is used to assess glomerular filtration rate (GFR). However, it is known to slightly overestimate the true GFR, due to renal tubular secretion of creatinine.During phase I-III clinical trials, a 10–15% increase in serum creatinine has been observed both in healthy subjects and patients receiving the new antiarrhythmic agent dronedarone.What this study addsDronedarone affects the renal handling of creatinine and N-methylnicotinamide, two cations, while leaving unchanged GFR, assessed through sinistrin CL, and renal plasma flow and anion secretion, assessed through para-amino-hippurate CL.This suggests a specific action of dronedarone on renal organic cation transport explaining the limited, reversible effect of dronedarone on serum creatinine, which must not be interpreted as reflecting an impairment of renal function, but which may indicate an interaction potential with cationic drugs