New therapies in acute decompensated heart failure

PURPOSE OF REVIEW: Hospitalization and mortality rates associated with heart failure are persistently high. This is due partly to aging of the population but mostly to delayed progress in the pharmacological treatment of decompensated heart failure. We will review the current recommendations and most recent advancement in the pharmacological treatment of acute decompensated heart failure while providing a systematic approach to the management of this prevalent condition. RECENT FINDINGS: Loop diuretics, nitrates and inotropes such as dobutamine and milrinone are the current mainstay of acute heart failure management although their associated morbidity and possible mortality have raised serious concerns. Recent vasoactive agents such as Nesiritide, Tolvaptan and more recently the inotropic agent Levosimedan could offer improved hemodynamics and congestive relief to patients in acute pulmonary edema. SUMMARY: Despite the promising results of these agents, further clinical trials are required prior to their international approval as first-line therapy. Although we can be optimistic that these vasoactive drugs might have favorable clinical outcomes and improve the intricate management of decompensated heart failure, their associated mortality benefit remains unclear and controversial.     

Ulcerogenicity devoid novel non-steroidal anti-inflammatory agents (NSAIDS): syntheses,computational studies,and activity of 5-aryliden-2-imino-4-thiazolidinones

A series of new 5-aryliden-2-imino-4-thiazolidinones (5a–e and 6a–e) were synthesized via a three-step reaction and characterized by physicochemical and spectral data. The uniqueness of the derivatives lies in the fact that none of them had an acidic group, like conventional NSAIDS, but exhibited significant in vivo activity in acute inflammation models. In particular, 5-(3-chlorobenzyliden)-2-(pyridin-2-yl-imino)-4-thiazolidinone(5a) and 5-(3-chlorobenzyliden)-2-(5-methylisoxazol-3-yl-imino)-4-thiazolidinone (6a) showed remarkable paw oedema inhibition (67.76 and 74.47 % oedema inhibition, respectively, after 3 h) comparable to that of Ibuprofen (74.56 % oedema inhibition, after 3 h) at half of the dose of the standard drug. Also, compounds 5a (72.86 %) and 6a (80.20 %) were found to possess significant inhibition of albumin denaturation when screened for in vitro anti-inflammatory activity. In addition, these compounds were docked into the known active site of COX-2 protein using Glide XP and QPLD algorithms, and the binding-free energy was calculated using Prime MM/GBSA simulation methods. The combined use of molecular docking and MM/GBSA methods gave a good correlation between the predicted binding-free energy and experimentally determined biological activities. It was also evident from the docking results that 2-methylisoxazolylimino or 2-(pyridin-2-yl-imino substitution and 3-chloro moiety on 5-benzylidin nucleus of these 4-thiazolidinone derivatives can easily occupy the COX-2 binding pocket, considered as the critical interaction for COX-2 inhibition. Moreover, pharmacokinetic properties of all the synthesized compounds were predicted, with good results. Further, the synthesized derivatives showed neither acute toxicity nor symptoms of gastric ulceration, at extended doses, owing to the absence of an acidic group.     

The molecular switch that activates the cell wall anchoring step of pilus assembly in gram-positive bacteria

Cell surface pili in gram-positive bacteria orchestrate the colonization of host tissues, evasion of immunity, and the development of biofilms. Recent work revealed that pilus assembly is a biphasic process wherein pilus polymerization is catalyzed by a pilus-specific sortase followed by cell wall anchoring of the pilus that is promoted by the housekeeping sortase. Here, we present molecular genetic and biochemical studies of a heterotrimeric pilus in Corynebacterium diphtheriae, uncovering the molecular switch that terminates pilus polymerization in favor of cell wall anchoring. The prototype pilus contains a major pilin (SpaA) forming the shaft, a tip pilin (SpaC), and another minor pilin (SpaB). Cells lacking SpaB form pilus fibers, but they are largely secreted in the medium, a phenotype also observed when cells lack the housekeeping sortase. Furthermore, the average pilus length is greatly increased in the absence of SpaB. Remarkably, a SpaB mutant that lacks the cell wall sorting signal but contains a critical lysine residue is incorporated in the pilus. However, the resulting pili fail to anchor to the cell wall. We propose that a specific minor pilin acts as the terminal subunit in pilus assembly. Cell wall anchoring ensues when the pilus polymer assembled on the pilus-specific sortase is transferred to the minor pilin presented by the housekeeping sortase via lysine-mediated transpeptidation.