Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia.

Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.

A novel technique of harmonic tissue dissection reduces seroma formation after modified radical mastectomy compared to conventional electrocautery: a single-blind randomized controlled trial.

BACKGROUND: Seroma is the most frequent postoperative complication following breast cancer surgery. Our aim was to evaluate the effect of the harmonic focus scalpel versus electrocautery in reducing seroma formation post-mastectomy and axillary clearance. METHODS: A prospective randomized controlled trial study was conducted at the Department of Surgery of Suez Canal University Hospital from April 26th 2014 to 30th June 2016. Seventy-two women, in whom a mastectomy and axillary clearance for breast cancer were performed, were randomly allocated to either harmonic dissection (n = 36) or electrocautery (n = 36). RESULTS: The mean operative time was significantly longer for harmonic dissection compared with electrocautery (2.63 ± 0.41 vs. 1.75 ± 0.26 h; p < 0.0001). In addition, a significantly smaller amount of intraoperative blood loss (69.4 ± 25.1 vs. 255.5 ± 41.6 ml; p = 0.002) and total drainage volume (1277.8 ± 172.5 ml vs. 3300 ± 167.5 ml; p = 0.002) were found in the harmonic group. Moreover, there was a significant reduction in the time of drain removal (10.9 ± 1.12 vs. 15.9 ± 1.44; p = 0.001) and the incidence of seroma formation after drain removal [8.3% vs 33.3%; p = 0.003] in the harmonic group compared with those in the electrocautery group. CONCLUSION: Harmonic dissection technique leads to significant decreases in intraoperative blood loss, total drainage volume and postoperative seroma in terms of shorter drain duration with a minimal increase in the operative time and better quality of life. Here, we recommend the use of the harmonic dissection technique in mastectomy and axillary clearance.

A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo.

Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.