Saturday, 23 May 2009

Pharmacology and Clinical Efficacy of Erdosteine in COPD

Abstract

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.

Introduction

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 protease–antiprotease 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.[6–7]

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.

Overview of the Market

Mucolytic agents are classified as direct and indirect agents according to their pharmacodynamic activity.[9] Direct agents include thiol compounds, which break the disulfide bridges of mucus glycoproteins by free sulfhydryl groups, and enzymes, such as recombinant human DNAse, which digests extracellular DNA ( Box 1 ). Indirect agents include different molecules that modify mucus secretion by their own mechanism of action ( Box 2 ).

Introduction to Erdosteine

Erdosteine is manufactured by Edmond Pharma (Milan, Italy) and commercialized in 42 countries in Europe and worldwide under different trade names (e.g., Erdotin®, Erdomed® and Mucotec®). The drug was introduced as a mucolytic agent for chronic pulmonary diseases more than 10 years ago. Its effect is based on the breaking of the disulfide bridges of mucus glycoproteins, resulting in reduced sputum physical properties in patients with acute and chronic mucus hypersecretion.[10] Guidelines recommend its use to increase cough clearance[11] and the drug is prescribed widely for this purpose in many European and extra-European countries. However, the favorable effects of erdosteine extend much further than modulation of mucus viscosity and increase of tracheobronchial clearance; experimental and clinical studies evidenced four major pharmacological activities: antioxidant, anti-inflammatory, antibacterial and mucolytic activity.

Chemistry

The chemical name of erdosteine is N-(carboxymethylthioacetyl) homocysteine thiolactone, which has the appearance, as raw material, of a white microcrystalline powder with a mild characteristic smell. The erdosteine molecule (Figure 1) is characterized by the presence of two sulfur atoms, one in the aliphatic side chain and the second enclosed in the heterocyclic ring (thiolactone). With these two blocked thiol groups, erdosteine is an inactive prodrug.

Click to zoom Figure 1.

Erdosteine and its metabolite I.

Figure 1.

Erdosteine and its metabolite I.

Erdosteine is stable only in the dry state or in acidic media. 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, N-thiodiglycolylhomocysteine, which is the active metabolite of erdosteine owing to this free thiol group (Figure 1).

Pharmacokinetics & Metabolism

Erdosteine, administered in single doses to normal adult volunteers, exhibits linear kinetics from 150 to 1200 mg. Plasma concentrations of the active metabolite I are approximately fivefold higher than those of erdosteine. After multiple doses (300-mg three-times daily for 8 days), the pharmacokinetics of erdosteine and metabolite I were comparable to a single administration of 900 mg, indicating no accumulation or metabolic activation after repeated dosing. Erdosteine is mainly excreted in the urine as an inorganic sulfate.[12]

Detectable levels of metabolite I can be found after 10 h, indicating a prolonged serum availability of the free thiol group and supporting twice-daily administration. No other metabolite was detected. In particular, the plasma concentration of homocysteine, considered a potential end product of erdosteine metabolism, was unchanged after repeated dosing.[13] Relevant to its pharmacological activity, both erdosteine and metabolite I were found in bronchial secretions in patients treated with erdosteine 300 mg twice daily for 1 week, with a significant increase of glutathione levels.[14]

The free SH group in metabolite I results in multiple pharmacological acivities, namely:

  • Mucolytic activity

  • Antibacterial activity

  • Antioxidant activity

  • Anti-inflammatory activity

These pharmacological activities were tested both in preclinical investigations in animal and in vitro models, and in human clinical trials.

Preclinical Investigations

Antibacterial Activity: in Vitro Study

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]

Antioxidant Activity

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.

Clinical Investigations

Effect on Mucus Rheological Properties

The free sulfhydryl group of metabolite I breaks the disulfide bridges of mucus glycoproteins, resulting in reduced sputum physical properties in patients with acute and chronic mucus hypersecretion. The effect of erdosteine on mucus rheological properties was evaluated in patients with exacerbation of COPD.[24] Patients receiving erdosteine had statistically significant reduction in sputum viscosity both at day 3 and at the end of the treatment compared with the placebo group. Similar results were obtained on sputum elasticity.

The efficacy of erdosteine on sputum rheological parameters was also evaluated in patients with clinically stable COPD.[10] A statistically significant reduction in sputum viscosity was observed in the erdosteine group, both when compared with pretreatment values and in comparison with placebo. Patients receiving erdosteine showed a significant decrease in fucose and dry macromolecular weight, markers of mucus glycoprotein content.

A mucolytic drug that reduces mucus rheological properties should also improve mucociliary clearance. In fact, the effect of erdosteine on mucociliary transport assessed by a modified broncho-fiber-optic technique was shown in a double-blind, placebo-controlled study in CB patients receiving 8-day treatment with placebo or erdosteine 900 mg/day.[25] Erdosteine significantly improved mucociliary transport compared with placebo. These data confirm the positive effect of erdosteine on ciliary movement in animal studies.[26]

Several studies have also demonstrated the effectiveness of erdosteine in reducing the volume of bronchial secretions during exacerbation of CB.[24,27]

Synergism With Antibiotic Therapy

Clinical studies showed that erdosteine increases sputum antibiotic concentrations in patients with acute exacerbations of CB and COPD.[28,29] A double-blind, placebo-controlled clinical trial evaluated the penetration of amoxycillin into the sputum after single and multiple oral antibiotic doses administered either alone or in combination with erdosteine.[28] Significant higher amoxycillin concentration was found in sputum but not in serum of patients treated with amoxycillin plus erdosteine; the effect persisted for a longer period. Sputum viscosity and body temperature also declined at a faster rate in the erdosteine group than in the control group. The authors argued that the mucolytic activity of erdosteine could improve amoxycillin diffusion in bronchial secretions.

The synergism of erdosteine with antibiotic therapy has been studied in several clinical trials in adult and pediatric patients with different antibiotics, such as amoxycillin,[29,30] ciprofloxacin[31] and ampicillin.[32] These studies demonstrate that the addition of erdosteine to different classes of antibiotics in acute infections of lower respiratory tract can induce a faster improvement of clinical symptoms compared with the antibiotic treatment alone.

Antioxidant & Anti-Inflammatory Activity

Dal Negro et al. assessed the effect of 10-day treatment with erdosteine at a dose of 900 mg/day on ROS in peripheral blood and chemotactic cytokines (IL-6 and IL-8) in bronchial secretions of stable COPD patients who were active smokers.[33] Erdosteine significantly decreased the serum concentrations of ROS and proinflammatory cytokines. The decrease of ROS was significant after only 4 days of treatment and was maintained up to day 10, whereas lower cytokine levels were seen starting from day 7. The results of this study have been confirmed by a double-blind, placebo-controlled trial in stable COPD patients receiving erdosteine at the dose of 600 mg/day; interestingly, the study showed a reduction of sputum 8-isoprostane, a product of lipid peroxidation, only in the erdosteine group, which was statistically significant after 10 days of treatment.[34] These data show that erdosteine inhibits the oxygen radicals and the subsequent inflammation. These positive effects correlate with erdosteine's direct antioxidative effect and/or increased antioxidative cellular mechanisms.

A study also evaluated the markers of bronchial inflammation in patients with clinically stable COPD.[10] In the group receiving erdosteine, the concentrations of bronchial inflammation markers (i.e., albumin, IgG and DNA) decreased after 2 weeks of treatment compared with the placebo group. In the same group, a slight increase in sputum total IgA, lactoferrin and lysozyme was observed. These findings demonstrate a reduction of the inflammatory process of bronchial mucosa.

Antioxidative Activity in Healthy Smokers. In a placebo-controlled, double-blind clinical study, healthy smokers received erdosteine 175-mg twice daily for 1 month, without quitting the smoking habit.[35] In this study, the authors investigated the acute effect of smoking a single cigarette on serum TBARS marker of membrane lipid peroxidation and cellular injury. TBARS concentrations decreased 5 and 30 min after smoking compared with presmoking concentrations in the erdosteine group; the difference with the placebo group was statistically significant. This protective effect of erdosteine after exposure to an oxidative stress factor suggests that erdosteine might be a preventive agent for smoking-induced lipid peroxidation.

Erdosteine also protects α-1 antitrypsin from inactivation due to cigarette smoke[36] and increases glutathione plasma level in CB patients.[37]

Clinical Efficacy

The clinical efficacy of erdosteine has been evaluated in more than 30 clinical studies involving patients with COPD and CB with acute exacerbation or who are clinically stable. Clinical trials have compared the efficacy of erdosteine with placebo and other treatments, including other mucolytic agents ( Table 1 ).

Treatment of Acute Exacerbations of CB & COPD

Erdosteine has been shown to improve the outcome of acute exacerbations of CB and COPD in several comparative studies. An international, multicenter, prospective, double-blind, parallel-group clinical trial was conducted in acute exacerbation of COPD (European Chronic Obstructive Bronchitis Erdosteine Study [ECOBES]).[29] A total of 237 patients with acute exacerbations were randomized into two comparable groups to receive, for a minimum of 7 to a maximum of 10 days, either amoxycillin 500 mg three-times daily plus erdosteine (300 mg twice daily) or amoxycillin 500 mg three-times daily plus placebo. The primary efficacy end point was the global clinical assessment (GCA), a cumulative index of six different measurements, including sputum parameters (appearance and viscosity) and functional signs (difficulty to expectorate, rhonchi at auscultation, cough and dyspnea intensity). These parameters were measured at admission, after 3–4 days and at the end of treatment (7–10 days), and were scored using a four-point graded scale. The final score was expressed as a value obtained from the addition of the various scores for these parameters. Clinical symptoms improved significantly in the group receiving erdosteine and amoxycillin compared with the group receiving amoxycillin alone, as indicated by the GCA score, with an earlier improvement in the group receiving erdosteine. In fact, after 7–10 days, sputum viscosity, sputum appearance and functional signs of COPD improved with erdosteine plus amoxycillin, with a significant difference from days 3–4 up to day 10.

Similar results were reported in another multicenter, randomized, double-blind clinical trial versus placebo during exacerbation of COPD.[31] The study compared two groups treated with ciprofloxacin at the dose of 500 mg twice daily plus placebo and ciprofloxacin 500 mg twice daily plus erdosteine 300 mg twice daily. The erdosteine group demonstrated a significant and faster improvement of clinical symptoms compared with the group receiving ciprofloxacin alone. The efficacy of erdosteine has been compared with that of other mucolytic agents and was shown to be at least similar (but often consistently higher). Two studies were undertaken to examine the efficacy and tolerability of erdosteine versus ambroxol in patients with acute exacerbation of CB receiving concomitant antibiotic therapy.[38,39] Patients receiving erdosteine had a faster and significant reduction in the severity and frequency of cough compared with the group receiving ambroxol, and also experienced a faster and more consistent decrease of sputum viscosity and/or volume. Similar to erdosteine, NAC contains a sulfhydryl group responsible for its pharmacological activity. NAC is a mucolytic agent with antioxidant activities through its direct antioxidant properties and indirect role as a precursor in glutathione synthesis.[40]

Two studies have compared the efficacy and safety profile of erdosteine and NAC used in combination with antibiotics in acute exacerbation of COPD. Both treatments produced a significant improvement in all clinical parameters when compared with baseline. In one study, conducted in 195 patients with COPD and bronchial infection, the extent of improvement from baseline was similar for the two treatments; however, a forced expiratory volume in 1 s (FEV1) increase of 14% from baseline was observed in the patients treated with erdosteine and not in those treated with NAC.[41] In the second study, erdosteine showed a significantly faster onset of effect compared with NAC on sputum volume, sputum viscosity and cough frequency.[42] Erdosteine also showed a better tolerance compared with NAC, in terms of adverse gastrointestinal side effects.

Short-Term Treatment in Stable COPD

The efficacy of erdosteine in the treatment of clinically stable COPD was evaluated in two crossover, double-blind, placebo-controlled studies.[27,43] In both studies, short treatment (<12>

Long-Term Treatment in Stable COPD

Two long-term trials showed that erdosteine treatment was able to decrease the incidence of acute exacerbations in patients with stable COPD.[44,45] The Erdosteine on Quality of Life (EQUALIFE) study, a double-blind, multicenter study enrolled 155 COPD patients (80% males) treated with erdosteine 600 mg/day or placebo for up to 8 months, in addition to the usual therapies.[45] The main objectives were to assess the number of exacerbations, the number and duration of hospitalizations, quality of life and the overall disease-related costs compared with placebo. The study enrolled patients with moderate-to-severe COPD defined by the Global Initiative for Obstructive Lung Disease (GOLD) diagnostic criteria[46] with mean FEV1% pred. of 59.4 and 59.0 in the erdosteine and placebo group, respectively. A total of 30% of the patients received inhaled steroids plus bronchodilators in the two study groups.

In the group of patients treated with erdosteine, a statistically significant reduction of exacerbations, hospitalizations and number of days in hospital was observed; moreover, a significant improvement of the quality of life was obtained compared with placebo. In fact, over the 8 months of the study patients treated with erdosteine had 30% fewer exacerbations and 58% fewer days in hospital than patients with placebo. Erdosteine improved and maintained the health-related quality of life, assessed using both generic (Short Form-36) and disease-specific (St George's Respiratory Questionnaire) questionnaires. Finally, the overall disease-related costs were lower in the erdosteine group. Safety was excellent, with the incidence of adverse events not different between erdosteine and placebo.

A recent post hoc analysis of the EQUALIFE study showed the positive effects of adding erdosteine into routine bronchodilator therapy in moderate and severe COPD patients. The addition of erdosteine on the top of combination therapy of inhaled steroids and bronchodilators significantly reduced the exacerbation and hospitalization rates compared with the group receiving the routine inhalation treatment alone,[47] suggesting that adding erdosteine to inhaled steroids could lead to a relevant advantage in terms of antioxidant/anti-inflammatory effects, as indicated previously by the synergistic activity observed in vitro.[21]

Safety & Tolerability

Erdosteine has no direct effect on gastric mucus since both thiol groups are blocked within the molecular structure. Clinical studies demonstrate that erdosteine has good gastric tolerability after oral administration, both during short- and midterm treatment[29,41,43] and during chronic use,[42] unlike other compounds with similar therapeutic indications. It is well known that thiol agents have a high incidence – estimated at approximately 20% – of gastrointestinal side effects, such as nausea, heartburn and stomach pain. The incidence of these adverse effects decreases to approximately 7% with erdosteine, which is no higher than placebo, demonstrating an excellent safety profile (Figure 2).[48] In patients receiving erdosteine in association with amoxycillin, the occurrence of adverse events, namely those relevant to gastrointestinal area, was comparable to the group of patients treated with the antibiotic alone (7.5 vs 11.1%).[29]

Click to zoom Figure 2.

Frequency of adverse reactions with erdosteine, reference drugs and placebo.

Figure 2.

Frequency of adverse reactions with erdosteine, reference drugs and placebo.

Compounds containing thiol groups often have an unpleasant smell and after intake may frequently cause gastric reflux. These problems do not occur with erdosteine. Taste disturbances (e.g., ageusia and dysgeusia) were reported occasionally.[21,48] There is no evidence of interaction between erdosteine and other drugs, expecially antibiotics (e.g., β-lactams, erythromycin and trimethoprim–sulfamethoxazole), theophylline and β2-agonists,[48] while other thiol agents may interact with antibiotics by inactivating them.[49]

Specific trials of erdosteine in geriatric subjects and in patients suffering from mild renal or hepatic failure did not show any impact on the rates of adverse reactions. However, it is suggested to halve the erdosteine dose in patients affected by severe hepatic or renal failure with a creatinine clearance less than 25 ml/min.

The postmarketing safety data on more than 30 million patients treated (including ∼7.4 million children) have always shown that erdosteine is very well tolerated and devoid of any safety concerns.[50]

Conclusion

Erdosteine is an original mucoactive molecule, synthesized and developed by Edmond Pharma, and registered in many countries worldwide. There is evidence, both in preclinical and clinical studies, that erdosteine decreases the sputum rheological properties and the daily sputum volume by improving tracheobronchial clearance. Furthermore, erdosteine reduces the bacterial adhesion to mucosal cells and is endowed with local anti-inflammatory activity and a scavenging effect on free oxidant radicals by a direct and indirect antioxidative effect.

In acute exacerbation of CB or COPD, addition of erdosteine to standard treatment significantly modified the outcome by improving the symptoms and reducing the length of disease. In stable COPD patients, the EQUALIFE study demonstrated that erdosteine had a protective effect against exacerbations of COPD: patients treated with erdosteine had 30% fewer exacerbations and 58% fewer days in hospital in the study period. Erdosteine treatment of 8 months significantly improved patients' health status and preserved lung function. The mean total COPD-related disease costs per patient were lower in the erdosteine group than in the placebo group over the study period. These results, together with the drug's safety profile, suggest that erdosteine is likely to provide an important contribution to the therapy of patients with symptomatic COPD.

Expert Commentary

Mucus production is a relevant pathophysiological picture of CB and COPD and is associated with worse healthcare outcomes and an increased rate of exacerbations. Overall, results from clinical studies show that erdosteine is an effective treatment in patients with CB and COPD, both clinically stable and during exacerbation. Erdosteine results in a faster symptom improvement compared with other mucolytic agents. Furthermore, erdosteine has demonstrated a synergism with antibiotic therapy and a relevant direct antioxidative effect.

Erdosteine is effective when administered as a long-term treatment over an 8-month period in COPD patients. In fact, the drug is associated with health outcome benefits, including fewer exacerbations and hospitalizations and improved quality of life. Clinical studies also confirm that erdosteine 600 mg/day is well tolerated, with a safety profile comparable to placebo. In view of the persuasive evidence that oxidative stress is important in the pathophysiology of COPD, erdosteine, with its effective antioxidative activity, appears to be a logical approach to therapy.

Five-Year View

Mucolytic agents decrease mucus viscoelastic properties, improve mucociliary clearance and decrease sputum production and appear designed to provide symptomatic relief to mucus hypersecretion in COPD. A recent systematic analysis of mucolytic agents concluded that these drugs, taken long term, could be very useful in patients who have repeated, prolonged or severe exacerbations of COPD. However, there is also increasing evidence that oxidative stress is involved in the pathogenesis of local lung inflammation, as well as in systemic phenomena, such as skeletal muscle dysfunction and, perhaps, even the increased cardiovascular risk of mortality that results from COPD. Hence, mucolytic agents with a specific antioxidative activity appear to be a logical approach to COPD therapy. In the next few years, clinical studies are needed to confirm, in COPD patients, the systemic effect shown by thiol agents in animal studies.

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.
Source : http://www.medscape.com/viewarticle/566582

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