Pharmacology and Clinical Efficacy of Erdosteine in Chronic Obstructive Pulmonary Disease

Maurizio Moretti

Disclosures

Expert Rev Resp Med. 2007;1(3):307-316. 

In This Article

Preclinical Investigations

Bacterial adhesion to airway mucosa causes airway bacterial colonization, which is a potential pathogenic condition, especially in CB and COPD. The antiadhesive activity of metabolite I has been demonstrated in an in vitro assay.[15] In this assay, the study drugs (i.e., erdosteine, metabolite I and N-acetylcysteine [NAC]) were pre-incubated with bacteria that were then challenged with human buccal mucosa cells in order to observe their degree of adhesiveness. Incubation of bacteria (Staphylococcus aureus and Escherichia coli) with metabolite I at different concentrations induced a significant reduction in bacterial adhesiveness, starting from 2.5 µg/ml, meanwhile NAC was devoid of antiadhesive activity.

The sulfhydryl group of metabolite I might inhibit the binding of bacterial fimbriae to the cell receptors. In vitro bacterial adherence is reduced with metabolite I at a concentration close to the serum peak value obtained after oral administration of erdosteine 300 mg. Furthermore, metabolite I has been shown to increase the inhibitory properties of clarythromycin and ciprofloxacin on in vitro bacterial adhesiveness.[16,17]

Decrease of ROS Production: in Vitro Studies. Metabolite I has an antioxidative activity by scavenging the ROS derived from inflammatory cells. The direct free radical scavenging activity of metabolite I, NAC, S-carboxymethylcysteine and ambroxol has been examined in vitro by determining their effects on the induced luminol-dependent chemiluminescence (LDCL).[18] Compared with controls, the LDCL of neutrophils was significantly inhibited by metabolite I, at a concentration of 100 µmol/l. Similar results were obtained by glutathione under the same test conditions. All other tested compounds were found to be inactive at this concentration.

Furthermore, Braga et al. have shown that metabolite I has a powerful action against ROS produced in vitro by neutrophils at experimental concentrations within the range measured in plasma after oral administration of erdosteine.[19]

Metabolite I can also inhibit the nitric oxide (NO)-derived peroxynitrite production as shown in the same in vitro model of activated human polymorphonuclear cells (PMNs) by adding levo-arginine (L-Arg) as a NO donor. When L-Arg was added, LDCL increased by 46–67% compared with basal values and metabolite I dose dependently reduced LDCL to a larger extent compared with when L-Arg was not added to the reaction medium.[20] Interestingly, the antioxidant effect of metabolite I proved to be synergistic to that of budesonide in the same model of stimulated human PMN respiratory bursts; the decrease of LDCL was significantly greater with the combination versus the single drugs. Moreover, a significant activity of the combination was also observed at lower concentrations at which the single drugs were not effective.[21]

Protective Action on Smoke-Induced Peripheral Neutrophil Dysfunction. The protective effect of erdosteine on smoke-induced peripheral neutrophil dysfunction has been assessed. Exposure to cigarette smoke in vitro reduces the chemotactic responsiveness of polymorphonuclear leukocytes due to modifications of the leukocyte receptor. Cigarette smoke contains ROS that are responsible for the membrane receptor desensitization; metabolite I antagonizes in vitro the smoke-induced depression of chemotaxis.[22]

Antioxidative Activity in Animal Models. There are several experimental evidences in animals that support the protective effect of erdosteine in various types of tissue injury mediated by products of oxidative stress.[23] Oxidative stress arises when there is an imbalance between oxidants and antioxidants, and this is assumed to play a key role in the pathogenesis of miscellaneous diseases.

Animals were used in different experimental settings: an untreated group was used as a control and the other groups received the toxic agent or the toxic agent plus erdosteine. In these studies, the systemic administration of erdosteine reduced the tissue and/or plasma concentration of xanthine oxidase and adenosine deaminase, enzymes that amplify a free radical-generating effect contributing to tissue damage. Conversely, erdosteine was shown to increase the tissue or serum concentration of superoxide dismutase, catalase, glutathione peroxidase and endogenous antioxidants, which play a role in the prevention of oxidative injury. The final result was a tissue protection assessed directly by histologic studies or indirectly by assaying products of oxidative damage as thiobarbituric acid-reactive substance (TBARS) levels, which indicates membrane lipid peroxidation and cellular injury.

There is great evidence that erdosteine inhibits or reduces tissue damage induced by drugs, anticancer and toxic agents, and the ischemia–reperfusion injury in animal models.[23] In summary, systemic administration of erdosteine prevents the accumulation of free oxygen radicals when their production is accelerated and increases antioxidative cellular protective mechanisms. The final result is a protective effect on tissues, which reduces lipid peroxidation, neutrophil infiltration and cell apoptosis mediated by noxious agents.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....