Pharmacology and Clinical Efficacy of Erdosteine in Chronic Obstructive Pulmonary Disease

Maurizio Moretti

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

Abstract and Introduction

Erdosteine is a multimechanism, mucolytic agent that decreases the sputum viscoelastic properties and bacterial adhesion to the cell membrane, endowed with bronchial anti-inflammatory activity and a scavenging effect on free oxidant radicals. Erdosteine is a prodrug and metabolite I is the active metabolite of erdosteine owing to its free thiol group. In acute infective exacerbation of chronic bronchitis or chronic obstructive pulmonary disease (COPD), adding erdosteine to standard treatment significantly modified the outcome by improving the symptoms and reducing the length of disease. Furthermore, erdosteine has shown a synergism with antibiotic therapy. In stable COPD patients, long-term treatment with erdosteine had a protective effect against exacerbations by reducing the rate of exacerbations and hospitalizations in the study period. A total of 8 months of treatment with erdosteine significantly improved the patients' health status and preserved lung function. Erdosteine has a scavenging effect on free oxidant radicals by a direct and indirect antioxidative effect and the final result is a protective effect against tissue damage, as demonstrated in animal studies. In view of the persuasive evidence that oxidative stress is important in the pathophysiology of COPD, erdosteine appears to be a logical approach to therapy.

At least half of smokers will develop chronic bronchitis (CB), cough and sputum without lung-function impairment, and up to 15% will develop chronic obstructive pulmonary disease (COPD) symptoms plus lung-function impairment. COPD is a major and increasing health problem, which is predicted to become the third most common cause of death and the fifth most common cause of disability in the world by 2020.^[1]

COPD has a very complex pathogenesis, in which the typically occurring airflow limitation is only the final consequence of a cascade of events that start much earlier than the appearance of the clinical symptoms of the disease.

Actually, COPD is considered as an inflammatory disease caused mainly by oxidative stress.^[2] Oxidants encompass reactive oxidant species (ROS; e.g., hydrogen peroxide, superoxide anion and hydroxyl radical), reactive nitrogen species and various others. ROS are at the basis of the process of COPD development; ROS can derive from exogenous (mainly cigarette smoke and air pollution) or endogenous sources (activation of neutrophils, epithelial cells and other phagocitic cells due to bacterial or viral infections or cigarette smoke). Oxidants are associated with direct toxicity to key lung structures and/or as mediators in a variety of processes that may promote the development of COPD. For example, oxidants increase mucus production and mucus viscoelastic properties, impairing mucociliary clearance and provoking airway bacterial colonization, chronic cough and bronchial obstruction. Oxidants activate proteases, such as collagenases, inactivate antiproteases, such as α1-antitrypsin, and shift the proteaseantiprotease balance towards increased proteolysis;^[3] the consequence is the progressive destruction of the structures, which leads to emphysema, commonly present in the advanced stages of COPD.^[4,5] The anatomical and functional damages described briefly explain the clinical picture of COPD: mucus hypersecretion, cough and dyspnea; moreover, it is clear why the airflow limitation that is the typical feature of COPD is only partially reversible. There is also increasing evidence that oxidative stress is involved in the pathogenesis of systemic phenomena, such as skeletal muscle dysfunction and, perhaps, even the increased cardiovascular risk of mortality that results from COPD.^[67]

People with CB or COPD may experience recurrent exacerbations with worsening symptoms or greater volume or purulence of sputum. These exacerbations contribute to morbidity and poorer health, as well as to increased healthcare costs. Although these exacerbations can be treated acutely with antibiotics or steroids, it would be useful to have other treatments that reduced the frequency and duration of acute exacerbations. The management of individual patients with COPD should be guided by the symptoms and disability that they experience. Management of COPD usually involves preventive measures, such as smoking cessation, medical treatments and pulmonary rehabilitation. Medical treatments include bronchodilators, corticosteroids, antibiotics and mucolytic agents. Mucolytics are administered to reduce sputum viscoelastic properties and improve sputum production.

In the acute setting, such as exacerbation of CB or COPD, addition of mucolytic agents to standard treatment improves the symptoms and reduces the time of disease. In clinically stable COPD, treatment with mucolytics is associated with a reduction in acute exacerbations and length of illness. The Cochrane systematic review provided a helpful analysis of relevant randomized, controlled trials of different mucolytic agents.^[8] The analysis concluded that these drugs, taken long term, could be most useful in patients who have repeated, prolonged or severe exacerbations of COPD. Hence, in some European and extra-European countries, mucolytics are prescribed widely since they appear to reduce the frequency of exacerbations and/or reduce symptoms in patients with CB or COPD. Some of these drugs, such as thiol agents, also have antioxidative effects that may contribute to their clinical effects.

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Cite this: Pharmacology and Clinical Efficacy of Erdosteine in Chronic Obstructive Pulmonary Disease - Medscape - Dec 01, 2007.

Classification of Mucolytic Agents: Direct Agents
Breaking the mucus fibrillar network by a direct action Thiols Erdosteine Acetylcysteine Mesna Enzymes Recombinant human DNAse

Classification of Mucolytic Agents: Indirect Agents
Modifying mucus secretion Carbocysteine Bromhexine Iodides Guaifenesin Decreasing the adhesiveness of the mucus layer Ambroxol

Erdosteine: Relationship of Pharmacological Activity and Clinical Efficacy
Erdosteine preclinical and clinical pharmacology	Erdosteine Phase III/IV studies
Mucolytic activity
Direct effect on ciliary movement in an animal study^[26]
Reduction in sputum viscosity and elasticity in COPD patients clinically stable and during exacerbation^[4,10]	Faster improvement of clinical symptoms in acute exacerbation of COPD^[29,31]
Improved mucociliary transport in COPD^[25]	Faster improvement of clinical symptoms in children with acute infections of the lower respiratory tract^[30,32]
Reduction of sputum production during exacerbation of CB^[24,27]
Antibacterial activity
Metabolite I reduces in vitro bacterial adhesion to cell surface^[15]
Metabolite I has been shown to increase the inhibitory properties of clarythromycin and ciprofloxacin bacterial adhesiveness on the cell surface^[16,17]	Faster improvement of clinical symptoms during infective exacerbation of CB and COPD by adding erdosteine to standard antibiotic therapy^[29,31]
Erdosteine 300 mg b.i.d. increases amoxycillin concentration in sputum of COPD patients during acute exacerbation^[28]	Faster improvement of clinical symptoms in children with acute airway infection by adding erdosteine to standard antibiotic therapy^[30,32]
Antioxidant and anti-inflammatory activity
Metabolite I inhibits ROS produced in vitro by neutrophils^[18,20]
In stable COPD patients, active smokers, erdosteine 600 mg/day significantly decreased serum concentrations of ROS and reduced sputum proinflammatory cytokines and 8-isoprostane levels^[33,34]	Erdosteine decreased serum thiobarbituric acid reactive substance, a marker of membrane lipid peroxidation in healthy smokers, 5 and 30 min after smoking compared with presmoking concentration^[35]
Metabolite I antagonizes in vitro the smoke-induced depression of polymorphonuclear leukocytes chemotaxis^[22]
Protection of α-1 antitrypsin from the inactivation due to cigarette smoke^[36]	12-week treatment with erdosteine 300 mg b.i.d. improved clinical parameters in stable COPD patients compared with the placebo group^[27,43]
Increased glutathione level in plasma^[37] and in bronchoalveolar secretions^[14] in CB patients	8-month treatment with erdosteine in stable COPD patients significantly reduced exacerbation and hospitalization rate, improved the patients’ health status and preserved lung-function decline^[45]
Inhibited or reduced tissue damage induced by drugs, anticancer and toxic agents, and the ischemia-reperfusion injury, in animal models, mediated by products of oxidative stress^[23]

b.i.d. = Twice daily; CB = Chronic bronchitis; COPD = Chronic obstructive pulmonary disease; ROS = Reactive oxygen species.

Sidebar: Key Issues

Chronic obstructive pulmonary disease (COPD) is considered an inflammatory disease caused mainly by oxidative stress. Mucus production is part of the pathophysiological picture of COPD and is associated with poorer healthcare outcomes and an increased rate of exacerbations. In turn, exacerbations lead to increased morbidity, poorer quality of life and escalating healthcare costs.
Management of COPD should be designed to provide symptomatic relief and improve patient’s quality of life.
Erdosteine is a prodrug characterized by the presence of two sulfur atoms within the molecule. Following oral administration, erdosteine is stable in the stomach; when passing to a more alkaline environment, the thiolactone ring slowly opens, achieving, in the bloodstream, the complete transformation to metabolite I, which is the active metabolite by its free thiol group.
Erdosteine results in four major pharmacological activities: antioxidant, anti-inflammatory, antibacterial and mucolytic activity.
These pharmacological activities were tested both in preclinical investigations in animal and in vitro models, and in human clinical trials.
Metabolite I has a powerful action against reactive oxygen species (ROS) produced in vitro by neutrophils at experimental concentration within the range measured in plasma after oral administration of erdosteine.
Systemic administration of erdosteine inhibited or reduced tissue damage induced by drugs, anticancer and toxic agents, and the ischemia-reperfusion injury, in animal models. Erdosteine prevented the accumulation of free oxygen radicals when their production was accelerated and increased antioxidant cellular protective mechanisms. The final result was a protective effect on tissues that reduced lipid peroxidation, neutrophil infiltration and cell apoptosis mediated by noxious agents.
In stable COPD patients, and active smokers, erdosteine 600 mg/day significantly decreased the serum concentrations of ROS after 4 days and reduced sputum proinflammatory cytokines and 8-isoprostane levels from day 7 to 10 of treatment. These data indicate that erdosteine inhibited the oxygen radicals and the subsequent inflammation; these effects appear correlated with its direct antioxidative effect and/or increased antioxidative cellular protective mechanisms.
In healthy smokers, erdosteine decreased serum thiobarbituric acid reactive substance, a marker of membrane lipid peroxidation, 5 and 30 min after smoking, compared with presmoking concentration.
Metabolite I reduced in vitro the bacterial adhesion to cell surfaces. Furthermore, metabolite I has been shown to increase the inhibitory properties of clarythromycin and ciprofloxacin bacterial adhesiveness on the cell surface.
Erdosteine 300 mg twice daily increased sputum amoxycillin concentrations in patients with acute exacerbations of chronic bronchitis.
The free sulfhydryl group of metabolite I breaks the disulfide bridges of mucus glycoproteins, resulting in reduced sputum physical properties and improved mucociliary transport in patients with acute and chronic mucus hypersecretion.
In acute exacerbation of CB or COPD, adding erdosteine to standard treatment significantly modified the outcome by improving the symptoms and reducing the length of disease.
In stable COPD patients, long-term treatment with erdosteine significantly reduced the number of exacerbations and hospitalizations, improved the patients’ health status, maintained this improvement over the 8-month trial and preserved lung function.
Clinical studies confirm that erdosteine 600/900 mg/day is well tolerated, with a safety profile comparable to placebo.

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