A Combination of Budesonide and the SH-Metabolite I of Erdosteine Acts Synergistically in Reducing Chemiluminescence during Human Neutrophil Respiratory Burst

Abstract

Activated neutrophils can release superoxide anion and nitric oxide (NO), which subsequently combine with each other to yield peroxynitrite anions, powerful and harmful oxidants that preferentially mediate the oxidation of the thiol groups in proteins and non-protein molecules. These oxidants play a direct role in the inflammatory process in chronic obstructive pulmonary disease and asthma by increasing the number of neutrophils and macrophages that induce a self-sustaining phlogogenic loop. Budesonide (BUD) and erdosteine (a muco-active drug which, after metabolization, produces an active metabolite (Met I) with a sulfhydryl group) are both active in reducing the release of superoxide anion, NO and peroxynitrite, and can be administered to patients with respiratory diseases. The aim of this study was to investigate the possible synergistic in vitro effect of BUD and Met I on chemiluminescence generation during fMLP-stimulated respiratory bursts of human neutrophils with the NO donor L-arginine, added to the incubating medium. The investigated BUD concentrations ranged from 6 × 10^–8 to 1 × 10^–6 mol/l in logarithmic scale and a significant and progressive reduction in luminol-amplified chemiluminescence (LACL) was observed at concentrations ranging from 2.5 × 10^–7 to 1 × 10^–6 mol/l. The investigated concentrations of Met I varied from 0.62 to 10 µg/ml. No significant changes were observed at 0.62, 1.25, and 2.5 µg/ml, but a significant decrease in LACL was observed at 5 and 10 µg/ml. When the two drugs were combined, there was a greater significant decrease in LACL versus the single drugs with the combinations of BUD 1 × 10^–6 mol/l plus Met I 10 µg/ml, BUD 5 × 10^–7 mol/l plus Met I 5 µg/ml, BUD 2.5 × 10^–7 mol/l plus Met I 2.5 µg/ml, and BUD 1.25 × 10^–7 mol/l plus Met I 1.25 µg/ml. A further interesting finding was that the combination of BUD 2.5 × 10^–7 mol/l plus Met I 2.5 µg/ml and BUD 1.25 × 10^–7 mol/l plus Met I 1.25 µg/ml significantly decreased LACL, whereas the single concentrations had no significant effect, thus indicating the possibility of extending the duration of the effect. Our findings indicate a synergistic antioxidant effect when BUD and Met I are given together, which is of interest for counteracting the airway phlogosis involved in many respiratory diseases.

Erdosteine Prevents Colonic Inflammation Through Its Antioxidant and Free Radical Scavenging Activities

“…MPO enzyme of the neutrophils catalyzes the formation of such potent cytotoxic oxidants as HOCl from H 2 O 2 and chloride ions and N-chloramines. These oxidants play a direct role in the inflammatory process in chronic inflammatory processes by increasing the number of neutrophils and macrophages that induce a self-sustaining phlogogenic loop [35]. Infiltration of leukocytes into the mucosa has been suggested to contribute significantly to the tissue necrosis and mucosal dysfunction associated with colitis [34] because they are the producers of pro-inflammatory mediators and a major source of reactive oxygen radicals in the inflamed colon mucosa [36].…”

Protective Effects of Erdosteine and Vitamins C and E Combination on Ischemia–Reperfusion-Induced Lung Oxidative Stress and Plasma Copper and Zinc Levels in a Rat Hind Limb Model

“…The role of neutrophils and oxidative damage in the lung after lower I/R injury is well documented [1,[24][25][26][27]. It was demonstrated that limb I/R injury could not only lead to increased vascular permeability in the skeletal muscle but in the lung as well [28].…”

Erdosteine modulates radiocontrast‐induced hepatotoxicity in rat

“…Erdosteine is a muco-active drug which, after metabolization produces an active metabolite called Met I with sulfhydryl group. 25 We observed significant protective effect of erdosteine on oxidative stress in liver of rats during RCM-induced I/R injury because it is both active in reducing the release of superoxide anion, nitric oxide and peroxynitrite. 26,27 Yagmurca et al 28 demonstrated that erdosteine treatment against doxorubicin-induced hepatotoxicity improved increased TBARS level.…”

“…We observed significant protective effect of erdosteine on GSH levels in liver of RCM-induced I/R injury in rats because the metabolization of mucoactive drug erdosteine produces an active metabolite (Met I) with a reducing SH group. 25,35 In addition to its mucolytic action, Met I also is an useful antioxidant. 13 In current study, we showed histopathological changes such as cellular disruption, cell vacuolization and central necrosis in rats received RCM.…”