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Erdosteine, Cara Terkini Untuk Pengobatan PPOK
22.07 | 
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Chronic Obstructive Pulmonary Disease (COPD) atau Penyakit Paru Obstrutif Kronis (PPOK) atau juga disebut Penyakit Paru Obstruktif Menahun (PPOM) adalah merupakan penyebab terbanyak untuk morbiditas dan mortalitas di seluruh dunia dan menghasilkan beban ekonomi dan sosial secara substansial dan meningkat.
Pada PPOK saat ini dianggap sebagai patologi non-infektif kedua yang paling sering di seluruh dunia. Diperkirakan bahwa sekitar 2,75 juta kematian disebabkan setiap tahun oleh PPOK dan ramalan oleh World Health Report (2000) memperkirakan bahwa angka ini akan berlipat ganda dalam tahun 2030.
(catatan: untuk yang tidak lancar berbahasa inggris silahkan translate dengan google)
The collective term COPD encompasses two previously used diagnoses, i.e. chronic bronchitis and emphysema and, according to current pathogenetic theories, is considered to be sustained by chronic lung inflammation and remodelling associated to persistent airflow obstruction not fully reversible with inhaled bronchodilators.
Chronic bronchitis (CB) is one of the most common health problems in the industrialised world. Epidemiological studies have reported incidences of chronic bronchitis of about 20% in the adult population. The term “chronic bronchitis” may be attributed to clinical conditions of different aetiology, incidence and severity. However, common features are represented by mucus hypersecretion, mucus retention in small peripheral and larger central airways, mucus-enriched exudates partially occluding small airways, associated to varying degrees of poorly reversible airway obstruction.
The most commonly recognized risk factor for CB/COPD is cigarette smoking (and/or other environmental pollution factors) initiating and maintaining a cascade of events responsible for the clinical manifestations of the disease:
Smoking cessation is the single most effective preventative measure to reduce exposure to CB/COPD risk factors, being however a difficult measure to implement.
Hence, the strong need for medications that can effectively break the vicious circle and prevent disease progression. So far, none of the existing medications for COPD have been shown to modify the progressive lung function decline and the systemic complications that are the hallmarks of the disease.
Pharmacologic therapy for COPD is used to decrease symptoms and/or complications, and to improve patients’ quality of life. Antibiotics are effective in the acute bacterial exacerbations but have no role in the long-term prevention of exacerbations.
Although improving symptoms, anti-oxidants/mucolytics have not yet demonstrated their efficacy in the preemptive management of the infections and in delaying lung function deterioration.
Any new drug being able to act on the above mentioned pathogenetic mechanisms will be ideal candidate to fill the gap in the presently available medical armamentarium.
Erdosteine, thanks to its multiple mechanisms of action, has the potential to be a good candidate in this respect.
Erdosteine, chemically N-(carboxymethylthioacetyl) homocysteine thiolactone, is a pro-drug characterised by the presence of two blocked thiol groups. The thiolactone ring, which is relatively weak and stable only in dry or acidic conditions (such as in the stomach), in a more alkaline environment opens achieving a complete transformation to active species owing to the presence of a free thiol group available for pharmacological activity.
N-thiodiglycolylhomocysteine (Met I) is the active metabolite of erdosteine, reaching peak plasma concentrations within two hours, that are 3 to 4 times higher compared to those of intact erdosteine.
1.1.1. Dosage forms
The following pharmaceutical forms have been developed and already registered in several countries:
Erdosteine is an original compound, developed by Edmond Pharma – Milan, Italy – and covered by the European Patent No. 0061386, which has been extended in several other countries.
Supplementary Protection Certificate (SPC) were obtained in a few countries, extending the patent protection up to 2006.
A novel manufacturing process was patented on June 1993.
A European Patent on the bacterial anti-adhesion activity has been granted in December 2004.
1.1.3. Marketing Authorisation
Marketing Authorisation for Erdosteine has been granted in 43 countries worldwide (18 in Europe).
1.2. Mechanisms of action
As previously described, four inter-related etiopathogenetic events link risk factors (e.g. cigarette smoking, pollution, etc.) to disease progression to irreversible deterioration of lung function, and erdosteine has been extensively proved to be effective on all of these events, thanks to multiple pharmacological properties:
Erdosteine has been shown to be an effective muco-modulatory agent that can:
It has been demonstrated in a placebo-controlled trial in patients with CB exacerbation that erdosteine significantly decreases mucus viscosity and elasticity.
A second placebo-controlled study in patients with stable CB has shown that erdosteine provides a statistically significant decrease in the viscosity and glycoprotein content of mucus.
Erdosteine improves mucociliary clearance indirectly through its effect on mucus rheological properties and directly acting on ciliary movement.
In a double-blind study, patients with CB were randomised to either placebo or erdosteine for 8 days. Mucociliary transport (MCT), assessed by a modified bronchofiberscopic technique at the start and at the end of treatment, demonstrated a significant improvement of the rapidity of MCT by 57% and reached a MCT rate comparable to that of healthy non-smokers in 37.5% of treated patients.
Erdosteine reduces the volume of expectorations.
In a placebo-controlled trial in patients with CB exacerbations, a significant fluidifying action on bronchial secretions was exerted by erdosteine, with an early increase of expectorations (day 2) but a net volume decrease at the end of treatment4.
These results have been confirmed by another placebo-controlled trial involving 100 patients with stable CB5.
1.2.2 Antibacterial activity
Infective acute exacerbations represent an important cause of morbidity in CB/COPD patients and significantly contribute to the poor outcome of the disease. About 70% of these exacerbations are caused by bacterial infections.
Bacterial colonisation requires bacterial adhesion which occurs through the formation of bonds between cell receptors, adhesions and bacterial filament structures (fimbriae).
1. Direct effects on bacterial adhesion
Erdosteine has proved to have important anti-adhesive activity. The anti-adhesive effects are exerted through an interfering mechanism at the level of bacterial fimbriae. Incubation of bacteria with erdosteine metabolite Met I - at concentrations that can be attained in bronchial mucus after oral administration of therapeutic doses - led to a significant reduction in bacterial adhesion to human mucosa epithelial cells. No reduction in bacterial adhesion was obtained with N-acetylcysteine.
2. Increase in sputum concentration of antibiotics
A double-blind, placebo-controlled trial in patients with acute CB exacerbations has shown that erdosteine can increase antibiotic (amoxycillin) concentrations in the sputum and enhance pathogen clearance. Mean serum amoxycillin concentrations did not differ between the two groups at the end of the study, however sputum amoxycillin concentrations were significantly higher in patients treated with amoxycillin plus erdosteine, and persisted for a longer period.
This effect is thought to be related to the reduction in the viscosity of the bronchial secretions and to an improvement in the mucociliary transport. As a consequence, amoxycillin penetrates better into the mucus from either the bloodstream or the bronchial mucosa. Thus, higher local antibiotic concentrations are achieved and bacteria are more effectively suppressed.
These findings were confirmed in an international, multicentre, double-blind, parallel-group trial was conducted in 237 CB/COPD patients during acute exacerbation8. The addition of erdosteine to amoxycillin improved the outcome of infective exacerbations, by resolving symptoms earlier without increasing the incidence of adverse effects.
1.2.3 Anti-oxidant / anti-inflammatory activity
Reactive oxygen species (ROS) are associated to a direct toxicity to key lung structures and/or mediate a variety of processes implicated in the progression of COPD, in particular:
Erdosteine has a marked direct scavenging activity on free radicals and increases the endogenous levels of anti-oxidants.
In addition, erdosteine has been shown to exert a consistent local anti-inflammatory activity, and could therefore provide clinical benefit in controlling symptoms, preventing exacerbations and, possibly, slowing the progression of the disease.
The antioxidant / anti-inflammatory effects of erdosteine have been demonstrated in several studies, both in vitro and in vivo.
1. Decrease in ROS production
In several in vitro experiments erdosteine has shown a strong scavenging activity against the most important ROS, such as hypochlorous acid, hydrogen peroxideand superoxide anion and was able to significantly decrease superoxide and peroxynitrite production.
As an example, the respiratory burst by human activated neutrophils was significantly inhibited by Met I, while other tested compounds, including N-acetylcysteine and ambroxol, were found to be inactive at similar concentrations.
2. Protective effects on tissue injuries mediated by products of oxidative stress
Several in vivo animal experiments have confirmed the efficacy of erdosteine in preventing or reducing free-radical oxidant-induced organ damage.
As an example, in a mouse model of acute lung injury induced by hypochlorous acid (ROS produced by activated neutrophils), erdosteine could significantly prevent tissue injury, while other tested mucoactive compounds (ambroxol and carboxy-methyl-cysteine) had little effect.
Furthermore, erdosteine has been shown to significantly reduce the organ damage induced by cisplatin, doxorubicin and bleomycin; tissue injury induced by sepsis and hemorrhagic shock in the lung; the nicotine-induced apoptosis of pulmonary and cardiac cells; the ischemia-reperfusion injury in rat kidney and rabbit spinal cord; the liver fibrosis in an experimental model of biliary obstruction; the acute colonic inflammation induced by the contact-sensitizing allergen TNBS through an excessive ROS production.
3. Increase of glutathione (GSH) levels in plasma and broncho-alveolar lavage (BAL) fluid
A study has compared the effects of erdosteine and N-acetylcysteine on plasma/BAL concentrations of GSH.
The results have shown a significantly higher increase in plasma and BAL fluid levels of GSH with erdosteine as compared with N-acetylcysteine.
4. Protection against smoke-induced a1-antitrypsin inactivation
Smoking reduces a1-antitrypsin activity in inhibiting the elastase-induced alveolar destruction.
A four-week double-blind placebo-controlled study was performed to evaluate the effect of erdosteine on a1-antitrypsin.
The study confirmed that cigarette smoke causes functional impairment of lung a1-antitrypsin activity, and that erdosteine, administered for at least 1 month, effectively reduces a1-antitrypsin inactivation.
5. Protective activity against smoke-induced peripheral neutrophil dysfunction
Neutrophils play a primary role in host defence against acute infections and their chemotactic activity is essential to their recruitment at the site of infection. Polymorphonuclear leukocytes (PMN) from peripheral blood of smokers exhibit depressed chemotaxis when compared with non-smokers.
The protective effect of erdosteine on smoke-induced peripheral neutrophil dysfunction has been assessed both in healthy subjects exposed to smoke and in smokers with bronchitis.
A 2-week treatment with erdosteine could restore the reduced chemotactic responsiveness of PMN cells from both healthy and CB subjects.
6. Reduction of markers of bronchial inflammation
A placebo-controlled study in patients with clinically stable CB/COPD has shown the effects of erdosteine on bronchial inflammation markers. The concentrations of some markers of bronchial inflammation (e.g. albumin, IgG and DNA) decreased after 2 weeks of treatment while the IgA/albumin, lactoferrin/albumin and lysozyme/albumin ratios significantly increased. No important changes were observed in the placebo group. These results suggest a reduction of the inflammatory process and an enhancement of the defence mechanisms.
7. Effects of Erdosteine on ROS production, e-NO, pro-inflammatory cytokines and lipid peroxidation in current smoker COPD patients
In a first pilot study conducted in ten patients treated with erdosteine for 10 days, a significant decrease of ROS and eNO was observed starting from day 4, accompanied by a decrease of pro-inflammatory cytokines, such as IL-6, IL-8 and TNFa.
A subsequent, double-blind, placebo-controlled study conducted in 20 patients with the same characteristics of the pilot phase, the significant reduction compared to placebo was confirmed for ROS and IL-8. In this study, erdosteine could significantly reduce in bronchial secretions 8-isoprostane, an indicator of lipid peroxidation. The difference vs. placebo became significant at day 10 of treatment.
A third placebo- and active-controlled study conducted in patient with the same clinical characteristics have demonstrated that a difference in the pharmacological profile of erdosteine compared to N-acetylcysteine. In fact, NAC significantly reduced ROS in a comparable manner, however, differently from erdosteine, NAC was ineffective on lipid peroxidation, since it induced only a transient decrease of 8-isoprostane on Day 4 that became negligible six days later.
8. Enhancement of FEV1 response to salbutamol in current smoker COPD patients.
In the above mentioned placebo- and active-controlled study, erdosteine was also shown to improve the reversibility to short-acting ß2-agonists. Oxidative stress is supposed to impair ß2-adrenoceptor function and this contributes to airway obstruction.
The results of the study show that erdosteine restores short-term reversibility in these COPD patients, previously poorly responsive to ß2 adrenergics. This activity of erdosteine does not seem to be related to the ROS scavenging effects, since NAC (which proved equal on ROS) was not effective on this parameter. Rather, it could be linked to the inhibiting effects exerted by erdosteine on lipoperoxidation.
1.3. Clinical Efficacy
The clinical efficacy of erdosteine has been evaluated in more than 30 clinical studies involving about 3,500 patients in a range of disease conditions, including acute CB/COPD exacerbations, stable COPD, E.N.T. hypersecretory diseases and lower respiratory tract infections in children.
Several of these studies were controlled trials comparing erdosteine with other mucolytics (N-acetylcysteine, ambroxol, sobrerol).
Overall, the results of the studies indicate that erdosteine, administered orally, is an effective treatment in patients with respiratory diseases characterized by mucus hypersecretion.
Erdosteine results in fast symptom amelioration (sometimes faster than active comparators), can positively influence respiratory function parameters, and has a protective effect against acute exacerbations.
In the treatment of acute CB/COPD exacerbations, erdosteine has been shown a synergistic activity with antibiotics, improving the outcome of the acute episodes.
1.3.1 Efficacy in stable CB/COPD
The efficacy of erdosteine in the treatment of chronic obstructive bronchial diseases in stable hypersecretive phase was evaluated in a crossover, double-blind, placebo-controlled study performed in 100 patients treated with erdosteine or placebo for 4 weeks.
The results of the study showed that erdosteine:
is an effective therapy for stable CB/COPD: The global efficacy score (combined score for dyspnoea, cough quality and frequency, quality of sputum and apparent viscosity of sputum, assessed on a four-point scale) evolved significantly in favour of erdosteine, while no significant changes occurred during the placebo period.
significantly improves some spirometric parameters (FEV11 and Tiffeneau index)
allows a significant reduction in the use of “rescue” ß2-agonists
shows a side-effect profile comparable to placebo.
A randomized, double-blind, placebo-controlled, parallel group study has been performed to evaluate the efficacy of erdosteine versus placebo for 21 days in 170 patients with stable hypersecretory CB/COPD.
The results of the study confirmed that erdosteine:
is an effective and well tolerated therapy for stable CB/COPD: The global efficacy index (combined score for frequency and severity of cough, chest discomfort and dyspnoea, assessed on a five-point scale) was significantly lower (i.e. an improvement) in the erdosteine group compared to placebo at day 21 despite a not negligible placebo effect.
significantly ameliorates sputum viscosity (already from the first days of treatment).
1.3.2 Long-term treatment of CB/COPD: Prevention of seasonal exacerbations
A double-blind, placebo-controlled study was carried out in order to evaluate the potential of erdosteine administered for 6 months in 184 patients with CB/COPD to prevent seasonal exacerbations.
The findings of this study demonstrated that a long-term treatment with erdosteine:
significantly reduces the incidence of acute exacerbations compared to placebo
when exacerbations occurred, symptoms (relating to mucus characteristics, cough and difficulty of expectoration) were significantly less severe in patients taking erdosteine
the number of days off work was found to be considerably lower in patients receiving erdosteine
the excellent tolerability of erdosteine was confirmed.
In conclusion, there is evidence that a long-term treatment with erdosteine can exert a protective effect in patients with CB/COPD, significantly reducing the number of exacerbations and, when they occur, significantly decreasing their severity.
A long term randomized, double-blind multicentre study has been carried out in 155 patients in order to investigated the effect of 8 months treatment with erdosteine compared with placebo in stable COPD patients. Patients continued to receive their regular COPD treatment with the addition of erdosteine or placebo The primary endpoint of the study was to assess the effect of erdosteine on exacerbation rate, quality of life and disease costs over 8 months of treatment.
The study has shown that:
patients treated with erdosteine long-term have significantly fewer exacerbations and spend less days in hospital that did patients receiving placebo
in patients treated with erdosteine, there is a clinically and statistically significant improvement of Quality of Life, as assessed through the St. George’s Respiratory Questionnaire (for each domain and for the total scores)
at the end of the 8-month treatment, there was a better performance in the 6MWT and a better lung function (FEV1) in patients treated with erdosteine.
lower mean total costs (direct medical, direct non-medical and workdays lost) per patient receiving erdosteine compared to placebo treatment were calculated (decreased by 30%).
1.3.3 Treatment of acute COPD exacerbations: Synergism with the antibiotic therapy
An international, multicentre, randomised, double-blind, parallel-group study was conducted with the aim of demonstrating that erdosteine can improve the efficacy of amoxicillin in the treatment of patients during acute infective exacerbations without negatively affecting tolerability.
Two hundred thirty seven patients were enrolled; all were treated with amoxicillin and randomly allocated to receive erdosteine or placebo for 7-10 days, while maintained on their standard COPD regimen.
The primary efficacy endpoint was the global clinical assessment (CGA), the sum of the scores for six parameters (sputum appearance, sputum viscosity, difficulty at expectoration, auscultation, cough and dyspnea), each scored on a scale of 0 to 3 with 3 being worst.
Clinical improvement was experienced by patients in both treatment groups, as expected due to the concomitant antibiotic therapy; however, the erdosteine-treated patients showed a significantly greater reduction in the GCA compared to placebo. The reduction of GCA was 31% at day 3 and 60% at day 7 in the erdosteine group compared to 22% and 41%, respectively, for the placebo-treated patients. Each of the individual components of the GCA also showed a significant improvement.
Moreover the overall physician judgement of efficacy was significantly in favour of the combination.
The safety profile of erdosteine in association with amoxicillin was comparable to that of amoxicillin alone.
The results of the study indicate that the outcome of infective exacerbations is modified earlier and to a deeper degree by the synergistic activity of erdosteine and the antibiotic without a risk of increased side effects.
A multicentre, randomised, double-blind clinical study versus placebo was conducted in 200 patients with acute exacerbations of chronic bronchitis (cough with difficult expectoration, mucopurulent and viscous sputum, fever >38ºC, and ciprofloxacin-sensitive bacteria on culture). All patients received ciprofloxacin and were randomized to erdosteine or placebo for 7 days.
The primary efficacy assessment was a Global Efficacy Index consisting of the scores of six parameters (sputum viscosity and appearance, difficulty in expectoration, abnormalities at auscultation, cough and dyspnea), each evaluated on a range from 0 to 3 with 3 being the worst.
The treatment with erdosteine in association to ciprofloxacin resulted in significantly greater reduction in the Global Efficacy Index (a decrease indicating clinical improvement) at day 3 and day 7 compared to ciprofloxacin alone (plus placebo). Erdosteine also significantly reduced the 24-hour sputum volume, a secondary efficacy outcome.
1.3.4 Comparison with ambroxol
Mucolytic agents, such as the expectorant ambroxol, are commonly used to improve sputum characteristics in respiratory disorders.
A randomised, single-blind study has compared the efficacy of erdosteine and ambroxol in patients with COPD exacerbations treated for 5 days.
The results of the study show that:
erdosteine is significantly more effective than ambroxol for cough severity, and signs of catarrhal encumbrance at auscultation
erdosteine show a faster and more consistent reduction of expectoration difficulty (by 59.3% at day 2 and 88.9% at day 5) than ambroxol (28.1% and 56.3%)
the reduction of sputum viscoadhesiveness is numerically in favour of erdosteine (by 37.5% at day 2 and 52.5% at day 5) compared to ambroxol (by 15.8% and 36.8%)
A second randomised, single-blind study has evaluated the efficacy of erdosteine compared to ambroxol in hospitalised patients with acute infective exacerbations, all under antibiotic treatment.
The results of the study show that:
patients receiving erdosteine have a more rapid improvement of cough frequency (p<0.01) and cough severity (p<0.05) at day 3 compared to ambroxol-treated patients.
mucociliary transport (likely linked to sputum adhesiveness and ciliary function) was improved by both treatments, however a numerical difference in favour of erdosteine was observed (improvement of 74.6% vs. 57.5%)
treatment with erdosteine was associated with a more favourable evolution of the spirometric index FEV1 than ambroxol.
In a third study comparing erdosteine and ambroxol in patients with acute exacerbations, there were no significant differences in the clinical efficacy criteria, although the improvement was sometimes numerically greater in erdosteine- than in ambroxol- treated patients.
Overall, these findings suggest that erdosteine has a superior therapeutic efficacy compared to ambroxol, especially regarding the onset of effects.
1.3.5 Comparison with N-acetylcysteine (NAC)
A commonly used drug in the treatment of chronic bronchopneumopathies is N-acetylcysteine, a drug showing similar mucolytic properties, but often associated to GI side effects and unpleasant taste. The tolerability of erdosteine may be better, since it is a prodrug stable at acidic pH, and its SH groups become available only after metabolization.
Four studies have compared erdosteine and NAC in patients with acute CB exacerbations.
A randomised study performed in 50 patients treated for 7-10 days showed that both treatments significantly improved the efficacy parameters of cough and sputum appearance, viscosity and volume by treatment end, however:
erdosteine was significantly faster than NAC in improving sputum viscosity and cough frequency (at day 2 and 4)
a significantly greater reduction of sputum volume was obtained by erdosteine from day 6 onwards
a statistically significant increase of FVC in comparison to baseline values was achieved only in the erdosteine group
erdosteine had a more favourable safety profile than NAC. No side effects were reported in the erdosteine group, while patients treated with NAC reported nausea (2 cases), pyrosis (4 cases) and halitosis (7 patients).
In the other studies, consistent results were observed, in particular:
while clinical and spirometric criteria improved with both treatments, the volume of expectoration decreased more significantly with erdosteine
a more rapid resolution of symptoms was observed with erdosteine
a significant increase of FEV1 (by 14%) was only observed in erdosteine-treated patients
erdosteine was better tolerated than NAC.
1.3.6 E.N.T. (rhynopharyingitis, sinusitis)
Two studies conducted in patients with acute and chronic exacerbated infections of upper respiratory airways have shown that erdosteine ameliorates clinical symptoms to a similar extent than NAC, but is better tolerated.
1.3.7 Acute lower respiratory tract diseases in children
Due to its favourable pharmacological properties, the synergistic activity with antibiotics, and the good tolerability profile, the efficacy of erdosteine was evaluated on special populations, such as children suffering from lower respiratory tract diseases.
In a first double-blind study, 100 children (aged 2-4 yrs) and 100 (aged 5-10 yrs) suffering from acute hypersecretive bronchitis were treated with ampicillin, and randomised to erdosteine or placebo for 5-9 days.
In both study populations, erdosteine confirmed to be an effective treatment in association with antibiotics. There was a significant difference in improvements in cough and rales between patients treated with erdosteine and those treated with antibiotics alone. The reduction of cough was by 60% vs. 37% in the younger children, and by 57% vs. 32% in 5-10 yrs. old children (p<0.01).
The tolerability profile of erdosteine was excellent in both age-range groups.
These findings confirm the efficacy profile of erdosteine already demonstrated in adults, with a better and more rapid improvement of symptoms in patients treated with the combination of antibiotics and erdosteine. The improvement in efficacy is not offset by any increase in side effects.
A recent multinational, multicenter, double-blind, controlled trial in 158 children, aged from 2 to 12 years, with a diagnosis of acute lower respiratory tract infections to be treated with antibiotics, gives same evidence for the synergic effect of erdosteine with antibiotics in children. Patients received erdosteine or placebo (both in association with amoxicillin). The duration of the treatment was from 3 to 9 days.
The results of the study have shown that erdosteine in combination with amoxicillin produced a more rapid improvement in the clinical symptoms compared to the antibiotic therapy alone. The severity of cough decreased significantly more in children treated with erdosteine compared to placebo, as well as other secondary efficacy parameters such as rhonchi and rales. The tolerability of erdosteine was very good.
The results observed for the association erdosteine plus amoxicillin compared to association amoxicillin plus placebo were not only statistically significant but also clinically relevant. In fact, cough (especially at night) is a very disturbing symptom of respiratory tract infections and has a negative impact on the quality of life of both children and parents.
1.4 Tolerability
Erdosteine is characterised by an excellent safety profile, with an observed incidence of adverse events comparable to that of placebo.
In clinical studies, more than 2,000 patients have been treated with erdosteine at doses ranging from 600 mg/day to a maximum of 1,200 mg/day, with an exposure ranging from short-term 7-10 days to long-term 8 months.
The frequency of adverse events in patients treated with erdosteine, placebo and reference drugs (i.e. other mucolytics) was 13.4%, 19.8% and 23.9%, respectively.
There were no differences between erdosteine and placebo in the rate of any of the adverse event categories: gastrointestinal, cardiovascular, cutaneous and general reactions.
In particular, the incidence of gastrointestinal side effects in patients treated with erdosteine was comparable to that in the placebo-treated patients, and about 3-fold lower than in patients treated with other mucolytics.
About 7.2% of patients treated with erdosteine reported GI disturbances, more frequently gastralgia (1.7%) and nausea (1.1%). Respective figures were 10.5% of patients reporting GI adverse events in the placebo groups, and 17.2% in the reference drug groups.
All adverse events were of mild/moderate intensity, and no severe adverse reactions were reported.
A dedicated study performed in patients undergoing gastroscopy for pre-existing gastric complaints showed that erdosteine did not cause any worsening of symptoms not occurrence of new symptoms or new histological findings.
The favourable tolerability profile of erdosteine is likely to be explained by the presence of blocked sulphydryl groups released only after metabolisation of erdosteine to metabolite I, that occur not in the stomach but when passing into the bowel or after absorption. These characteristics mark the difference with other compounds of the same therapeutic class, such as NAC.
Compounds containing free SH groups often present an unpleasant smell and may frequently cause, after intake, reflux phenomena.
The more favourable profile of erdosteine in this respect represents a plus of particular importance in terms of patient compliance.
Erdosteine has been administered in association with systemic antibiotic therapy (e.g. ampicillin, amoxicillin, bacampicillin, ciprofloxacin, cotrimoxazol) without any increase of adverse event incidence. Moreover, no untoward drug interactions have been observed when erdosteine was administered with theophylline and ß2-mimetics.
This feature of erdosteine is particularly advantageous in view of a chronic use in COPD patients (elderly and likely to present multiple significant co-morbidities), since minimal impact with a possibly complex set of interacting diseases and drugs should be expected.
Specific studies conducted in elderly subjects and in patients with mild renal or hepatic failure did not show any increase of untoward PK and safety findings. It is however suggested, to halve the erdosteine dose in patients affected by severe hepatic impairment, and the drug is not recommended in patients with a creatinine clearance less than 25 ml/min.
(catatan: untuk yang tidak lancar berbahasa inggris silahkan translate dengan google)
The collective term COPD encompasses two previously used diagnoses, i.e. chronic bronchitis and emphysema and, according to current pathogenetic theories, is considered to be sustained by chronic lung inflammation and remodelling associated to persistent airflow obstruction not fully reversible with inhaled bronchodilators.
Chronic bronchitis (CB) is one of the most common health problems in the industrialised world. Epidemiological studies have reported incidences of chronic bronchitis of about 20% in the adult population. The term “chronic bronchitis” may be attributed to clinical conditions of different aetiology, incidence and severity. However, common features are represented by mucus hypersecretion, mucus retention in small peripheral and larger central airways, mucus-enriched exudates partially occluding small airways, associated to varying degrees of poorly reversible airway obstruction.
The most commonly recognized risk factor for CB/COPD is cigarette smoking (and/or other environmental pollution factors) initiating and maintaining a cascade of events responsible for the clinical manifestations of the disease:
- impaired mucociliary clearance
- bacterial colonisation
- oxidative stress
- inflammation
Figure 1. Cole & Wilson theory of the development of COPD
Smoking cessation is the single most effective preventative measure to reduce exposure to CB/COPD risk factors, being however a difficult measure to implement.
Hence, the strong need for medications that can effectively break the vicious circle and prevent disease progression. So far, none of the existing medications for COPD have been shown to modify the progressive lung function decline and the systemic complications that are the hallmarks of the disease.
Pharmacologic therapy for COPD is used to decrease symptoms and/or complications, and to improve patients’ quality of life. Antibiotics are effective in the acute bacterial exacerbations but have no role in the long-term prevention of exacerbations.
Although improving symptoms, anti-oxidants/mucolytics have not yet demonstrated their efficacy in the preemptive management of the infections and in delaying lung function deterioration.
Any new drug being able to act on the above mentioned pathogenetic mechanisms will be ideal candidate to fill the gap in the presently available medical armamentarium.
Erdosteine, thanks to its multiple mechanisms of action, has the potential to be a good candidate in this respect.
Erdosteine Profile
1.1. ChemistryErdosteine, chemically N-(carboxymethylthioacetyl) homocysteine thiolactone, is a pro-drug characterised by the presence of two blocked thiol groups. The thiolactone ring, which is relatively weak and stable only in dry or acidic conditions (such as in the stomach), in a more alkaline environment opens achieving a complete transformation to active species owing to the presence of a free thiol group available for pharmacological activity.
N-thiodiglycolylhomocysteine (Met I) is the active metabolite of erdosteine, reaching peak plasma concentrations within two hours, that are 3 to 4 times higher compared to those of intact erdosteine.
1.1.1. Dosage forms
The following pharmaceutical forms have been developed and already registered in several countries:
- 150 mg and 300 mg capsules
- 225 mg and 300 mg sachets
- 3.5% dry-syrup (powder for suspension)
Erdosteine is an original compound, developed by Edmond Pharma – Milan, Italy – and covered by the European Patent No. 0061386, which has been extended in several other countries.
Supplementary Protection Certificate (SPC) were obtained in a few countries, extending the patent protection up to 2006.
A novel manufacturing process was patented on June 1993.
A European Patent on the bacterial anti-adhesion activity has been granted in December 2004.
1.1.3. Marketing Authorisation
Marketing Authorisation for Erdosteine has been granted in 43 countries worldwide (18 in Europe).
1.2. Mechanisms of action
As previously described, four inter-related etiopathogenetic events link risk factors (e.g. cigarette smoking, pollution, etc.) to disease progression to irreversible deterioration of lung function, and erdosteine has been extensively proved to be effective on all of these events, thanks to multiple pharmacological properties:
- Muco-modulatory activity
- Antibacterial activity
- Anti-oxidative activity
- Anti-inflammatory activity
Erdosteine has been shown to be an effective muco-modulatory agent that can:
- Improve mucus rheological characteristics in terms of viscosity, elasticity, and biochemical composition
- Improve mucociliary clearance
- Reduce mucus hypersecretion and the expectoration volume.
It has been demonstrated in a placebo-controlled trial in patients with CB exacerbation that erdosteine significantly decreases mucus viscosity and elasticity.
A second placebo-controlled study in patients with stable CB has shown that erdosteine provides a statistically significant decrease in the viscosity and glycoprotein content of mucus.
Erdosteine improves mucociliary clearance indirectly through its effect on mucus rheological properties and directly acting on ciliary movement.
In a double-blind study, patients with CB were randomised to either placebo or erdosteine for 8 days. Mucociliary transport (MCT), assessed by a modified bronchofiberscopic technique at the start and at the end of treatment, demonstrated a significant improvement of the rapidity of MCT by 57% and reached a MCT rate comparable to that of healthy non-smokers in 37.5% of treated patients.
Erdosteine reduces the volume of expectorations.
In a placebo-controlled trial in patients with CB exacerbations, a significant fluidifying action on bronchial secretions was exerted by erdosteine, with an early increase of expectorations (day 2) but a net volume decrease at the end of treatment4.
These results have been confirmed by another placebo-controlled trial involving 100 patients with stable CB5.
1.2.2 Antibacterial activity
Infective acute exacerbations represent an important cause of morbidity in CB/COPD patients and significantly contribute to the poor outcome of the disease. About 70% of these exacerbations are caused by bacterial infections.
Bacterial colonisation requires bacterial adhesion which occurs through the formation of bonds between cell receptors, adhesions and bacterial filament structures (fimbriae).
1. Direct effects on bacterial adhesion
Erdosteine has proved to have important anti-adhesive activity. The anti-adhesive effects are exerted through an interfering mechanism at the level of bacterial fimbriae. Incubation of bacteria with erdosteine metabolite Met I - at concentrations that can be attained in bronchial mucus after oral administration of therapeutic doses - led to a significant reduction in bacterial adhesion to human mucosa epithelial cells. No reduction in bacterial adhesion was obtained with N-acetylcysteine.
2. Increase in sputum concentration of antibiotics
A double-blind, placebo-controlled trial in patients with acute CB exacerbations has shown that erdosteine can increase antibiotic (amoxycillin) concentrations in the sputum and enhance pathogen clearance. Mean serum amoxycillin concentrations did not differ between the two groups at the end of the study, however sputum amoxycillin concentrations were significantly higher in patients treated with amoxycillin plus erdosteine, and persisted for a longer period.
This effect is thought to be related to the reduction in the viscosity of the bronchial secretions and to an improvement in the mucociliary transport. As a consequence, amoxycillin penetrates better into the mucus from either the bloodstream or the bronchial mucosa. Thus, higher local antibiotic concentrations are achieved and bacteria are more effectively suppressed.
These findings were confirmed in an international, multicentre, double-blind, parallel-group trial was conducted in 237 CB/COPD patients during acute exacerbation8. The addition of erdosteine to amoxycillin improved the outcome of infective exacerbations, by resolving symptoms earlier without increasing the incidence of adverse effects.
1.2.3 Anti-oxidant / anti-inflammatory activity
Reactive oxygen species (ROS) are associated to a direct toxicity to key lung structures and/or mediate a variety of processes implicated in the progression of COPD, in particular:
- the increase of activated neutrophils and other phagocytosis cells, starting and self-maintaining inflammation
- the activation of proteases such as collagenases
- the inactivation of anti-proteases, like a1-antitrypsin
- the shifting of the protease-antiprotease balance towards an increased proteolysis (leading to alveolar destruction)
- a chronic lung inflammation caused by oxidative stress and ultimately leading to lung fibrosis and remodelling
Erdosteine has a marked direct scavenging activity on free radicals and increases the endogenous levels of anti-oxidants.
In addition, erdosteine has been shown to exert a consistent local anti-inflammatory activity, and could therefore provide clinical benefit in controlling symptoms, preventing exacerbations and, possibly, slowing the progression of the disease.
The antioxidant / anti-inflammatory effects of erdosteine have been demonstrated in several studies, both in vitro and in vivo.
1. Decrease in ROS production
In several in vitro experiments erdosteine has shown a strong scavenging activity against the most important ROS, such as hypochlorous acid, hydrogen peroxideand superoxide anion and was able to significantly decrease superoxide and peroxynitrite production.
As an example, the respiratory burst by human activated neutrophils was significantly inhibited by Met I, while other tested compounds, including N-acetylcysteine and ambroxol, were found to be inactive at similar concentrations.
2. Protective effects on tissue injuries mediated by products of oxidative stress
Several in vivo animal experiments have confirmed the efficacy of erdosteine in preventing or reducing free-radical oxidant-induced organ damage.
As an example, in a mouse model of acute lung injury induced by hypochlorous acid (ROS produced by activated neutrophils), erdosteine could significantly prevent tissue injury, while other tested mucoactive compounds (ambroxol and carboxy-methyl-cysteine) had little effect.
Furthermore, erdosteine has been shown to significantly reduce the organ damage induced by cisplatin, doxorubicin and bleomycin; tissue injury induced by sepsis and hemorrhagic shock in the lung; the nicotine-induced apoptosis of pulmonary and cardiac cells; the ischemia-reperfusion injury in rat kidney and rabbit spinal cord; the liver fibrosis in an experimental model of biliary obstruction; the acute colonic inflammation induced by the contact-sensitizing allergen TNBS through an excessive ROS production.
3. Increase of glutathione (GSH) levels in plasma and broncho-alveolar lavage (BAL) fluid
A study has compared the effects of erdosteine and N-acetylcysteine on plasma/BAL concentrations of GSH.
The results have shown a significantly higher increase in plasma and BAL fluid levels of GSH with erdosteine as compared with N-acetylcysteine.
4. Protection against smoke-induced a1-antitrypsin inactivation
Smoking reduces a1-antitrypsin activity in inhibiting the elastase-induced alveolar destruction.
A four-week double-blind placebo-controlled study was performed to evaluate the effect of erdosteine on a1-antitrypsin.
The study confirmed that cigarette smoke causes functional impairment of lung a1-antitrypsin activity, and that erdosteine, administered for at least 1 month, effectively reduces a1-antitrypsin inactivation.
5. Protective activity against smoke-induced peripheral neutrophil dysfunction
Neutrophils play a primary role in host defence against acute infections and their chemotactic activity is essential to their recruitment at the site of infection. Polymorphonuclear leukocytes (PMN) from peripheral blood of smokers exhibit depressed chemotaxis when compared with non-smokers.
The protective effect of erdosteine on smoke-induced peripheral neutrophil dysfunction has been assessed both in healthy subjects exposed to smoke and in smokers with bronchitis.
A 2-week treatment with erdosteine could restore the reduced chemotactic responsiveness of PMN cells from both healthy and CB subjects.
6. Reduction of markers of bronchial inflammation
A placebo-controlled study in patients with clinically stable CB/COPD has shown the effects of erdosteine on bronchial inflammation markers. The concentrations of some markers of bronchial inflammation (e.g. albumin, IgG and DNA) decreased after 2 weeks of treatment while the IgA/albumin, lactoferrin/albumin and lysozyme/albumin ratios significantly increased. No important changes were observed in the placebo group. These results suggest a reduction of the inflammatory process and an enhancement of the defence mechanisms.
7. Effects of Erdosteine on ROS production, e-NO, pro-inflammatory cytokines and lipid peroxidation in current smoker COPD patients
In a first pilot study conducted in ten patients treated with erdosteine for 10 days, a significant decrease of ROS and eNO was observed starting from day 4, accompanied by a decrease of pro-inflammatory cytokines, such as IL-6, IL-8 and TNFa.
A subsequent, double-blind, placebo-controlled study conducted in 20 patients with the same characteristics of the pilot phase, the significant reduction compared to placebo was confirmed for ROS and IL-8. In this study, erdosteine could significantly reduce in bronchial secretions 8-isoprostane, an indicator of lipid peroxidation. The difference vs. placebo became significant at day 10 of treatment.
A third placebo- and active-controlled study conducted in patient with the same clinical characteristics have demonstrated that a difference in the pharmacological profile of erdosteine compared to N-acetylcysteine. In fact, NAC significantly reduced ROS in a comparable manner, however, differently from erdosteine, NAC was ineffective on lipid peroxidation, since it induced only a transient decrease of 8-isoprostane on Day 4 that became negligible six days later.
8. Enhancement of FEV1 response to salbutamol in current smoker COPD patients.
In the above mentioned placebo- and active-controlled study, erdosteine was also shown to improve the reversibility to short-acting ß2-agonists. Oxidative stress is supposed to impair ß2-adrenoceptor function and this contributes to airway obstruction.
The results of the study show that erdosteine restores short-term reversibility in these COPD patients, previously poorly responsive to ß2 adrenergics. This activity of erdosteine does not seem to be related to the ROS scavenging effects, since NAC (which proved equal on ROS) was not effective on this parameter. Rather, it could be linked to the inhibiting effects exerted by erdosteine on lipoperoxidation.
1.3. Clinical Efficacy
The clinical efficacy of erdosteine has been evaluated in more than 30 clinical studies involving about 3,500 patients in a range of disease conditions, including acute CB/COPD exacerbations, stable COPD, E.N.T. hypersecretory diseases and lower respiratory tract infections in children.
Several of these studies were controlled trials comparing erdosteine with other mucolytics (N-acetylcysteine, ambroxol, sobrerol).
Overall, the results of the studies indicate that erdosteine, administered orally, is an effective treatment in patients with respiratory diseases characterized by mucus hypersecretion.
Erdosteine results in fast symptom amelioration (sometimes faster than active comparators), can positively influence respiratory function parameters, and has a protective effect against acute exacerbations.
In the treatment of acute CB/COPD exacerbations, erdosteine has been shown a synergistic activity with antibiotics, improving the outcome of the acute episodes.
1.3.1 Efficacy in stable CB/COPD
The efficacy of erdosteine in the treatment of chronic obstructive bronchial diseases in stable hypersecretive phase was evaluated in a crossover, double-blind, placebo-controlled study performed in 100 patients treated with erdosteine or placebo for 4 weeks.
The results of the study showed that erdosteine:
is an effective therapy for stable CB/COPD: The global efficacy score (combined score for dyspnoea, cough quality and frequency, quality of sputum and apparent viscosity of sputum, assessed on a four-point scale) evolved significantly in favour of erdosteine, while no significant changes occurred during the placebo period.
significantly improves some spirometric parameters (FEV11 and Tiffeneau index)
allows a significant reduction in the use of “rescue” ß2-agonists
shows a side-effect profile comparable to placebo.
A randomized, double-blind, placebo-controlled, parallel group study has been performed to evaluate the efficacy of erdosteine versus placebo for 21 days in 170 patients with stable hypersecretory CB/COPD.
The results of the study confirmed that erdosteine:
is an effective and well tolerated therapy for stable CB/COPD: The global efficacy index (combined score for frequency and severity of cough, chest discomfort and dyspnoea, assessed on a five-point scale) was significantly lower (i.e. an improvement) in the erdosteine group compared to placebo at day 21 despite a not negligible placebo effect.
significantly ameliorates sputum viscosity (already from the first days of treatment).
1.3.2 Long-term treatment of CB/COPD: Prevention of seasonal exacerbations
A double-blind, placebo-controlled study was carried out in order to evaluate the potential of erdosteine administered for 6 months in 184 patients with CB/COPD to prevent seasonal exacerbations.
The findings of this study demonstrated that a long-term treatment with erdosteine:
significantly reduces the incidence of acute exacerbations compared to placebo
when exacerbations occurred, symptoms (relating to mucus characteristics, cough and difficulty of expectoration) were significantly less severe in patients taking erdosteine
the number of days off work was found to be considerably lower in patients receiving erdosteine
the excellent tolerability of erdosteine was confirmed.
In conclusion, there is evidence that a long-term treatment with erdosteine can exert a protective effect in patients with CB/COPD, significantly reducing the number of exacerbations and, when they occur, significantly decreasing their severity.
A long term randomized, double-blind multicentre study has been carried out in 155 patients in order to investigated the effect of 8 months treatment with erdosteine compared with placebo in stable COPD patients. Patients continued to receive their regular COPD treatment with the addition of erdosteine or placebo The primary endpoint of the study was to assess the effect of erdosteine on exacerbation rate, quality of life and disease costs over 8 months of treatment.
The study has shown that:
patients treated with erdosteine long-term have significantly fewer exacerbations and spend less days in hospital that did patients receiving placebo
in patients treated with erdosteine, there is a clinically and statistically significant improvement of Quality of Life, as assessed through the St. George’s Respiratory Questionnaire (for each domain and for the total scores)
at the end of the 8-month treatment, there was a better performance in the 6MWT and a better lung function (FEV1) in patients treated with erdosteine.
lower mean total costs (direct medical, direct non-medical and workdays lost) per patient receiving erdosteine compared to placebo treatment were calculated (decreased by 30%).
1.3.3 Treatment of acute COPD exacerbations: Synergism with the antibiotic therapy
An international, multicentre, randomised, double-blind, parallel-group study was conducted with the aim of demonstrating that erdosteine can improve the efficacy of amoxicillin in the treatment of patients during acute infective exacerbations without negatively affecting tolerability.
Two hundred thirty seven patients were enrolled; all were treated with amoxicillin and randomly allocated to receive erdosteine or placebo for 7-10 days, while maintained on their standard COPD regimen.
The primary efficacy endpoint was the global clinical assessment (CGA), the sum of the scores for six parameters (sputum appearance, sputum viscosity, difficulty at expectoration, auscultation, cough and dyspnea), each scored on a scale of 0 to 3 with 3 being worst.
Clinical improvement was experienced by patients in both treatment groups, as expected due to the concomitant antibiotic therapy; however, the erdosteine-treated patients showed a significantly greater reduction in the GCA compared to placebo. The reduction of GCA was 31% at day 3 and 60% at day 7 in the erdosteine group compared to 22% and 41%, respectively, for the placebo-treated patients. Each of the individual components of the GCA also showed a significant improvement.
Moreover the overall physician judgement of efficacy was significantly in favour of the combination.
The safety profile of erdosteine in association with amoxicillin was comparable to that of amoxicillin alone.
The results of the study indicate that the outcome of infective exacerbations is modified earlier and to a deeper degree by the synergistic activity of erdosteine and the antibiotic without a risk of increased side effects.
A multicentre, randomised, double-blind clinical study versus placebo was conducted in 200 patients with acute exacerbations of chronic bronchitis (cough with difficult expectoration, mucopurulent and viscous sputum, fever >38ºC, and ciprofloxacin-sensitive bacteria on culture). All patients received ciprofloxacin and were randomized to erdosteine or placebo for 7 days.
The primary efficacy assessment was a Global Efficacy Index consisting of the scores of six parameters (sputum viscosity and appearance, difficulty in expectoration, abnormalities at auscultation, cough and dyspnea), each evaluated on a range from 0 to 3 with 3 being the worst.
The treatment with erdosteine in association to ciprofloxacin resulted in significantly greater reduction in the Global Efficacy Index (a decrease indicating clinical improvement) at day 3 and day 7 compared to ciprofloxacin alone (plus placebo). Erdosteine also significantly reduced the 24-hour sputum volume, a secondary efficacy outcome.
1.3.4 Comparison with ambroxol
Mucolytic agents, such as the expectorant ambroxol, are commonly used to improve sputum characteristics in respiratory disorders.
A randomised, single-blind study has compared the efficacy of erdosteine and ambroxol in patients with COPD exacerbations treated for 5 days.
The results of the study show that:
erdosteine is significantly more effective than ambroxol for cough severity, and signs of catarrhal encumbrance at auscultation
erdosteine show a faster and more consistent reduction of expectoration difficulty (by 59.3% at day 2 and 88.9% at day 5) than ambroxol (28.1% and 56.3%)
the reduction of sputum viscoadhesiveness is numerically in favour of erdosteine (by 37.5% at day 2 and 52.5% at day 5) compared to ambroxol (by 15.8% and 36.8%)
A second randomised, single-blind study has evaluated the efficacy of erdosteine compared to ambroxol in hospitalised patients with acute infective exacerbations, all under antibiotic treatment.
The results of the study show that:
patients receiving erdosteine have a more rapid improvement of cough frequency (p<0.01) and cough severity (p<0.05) at day 3 compared to ambroxol-treated patients.
mucociliary transport (likely linked to sputum adhesiveness and ciliary function) was improved by both treatments, however a numerical difference in favour of erdosteine was observed (improvement of 74.6% vs. 57.5%)
treatment with erdosteine was associated with a more favourable evolution of the spirometric index FEV1 than ambroxol.
In a third study comparing erdosteine and ambroxol in patients with acute exacerbations, there were no significant differences in the clinical efficacy criteria, although the improvement was sometimes numerically greater in erdosteine- than in ambroxol- treated patients.
Overall, these findings suggest that erdosteine has a superior therapeutic efficacy compared to ambroxol, especially regarding the onset of effects.
1.3.5 Comparison with N-acetylcysteine (NAC)
A commonly used drug in the treatment of chronic bronchopneumopathies is N-acetylcysteine, a drug showing similar mucolytic properties, but often associated to GI side effects and unpleasant taste. The tolerability of erdosteine may be better, since it is a prodrug stable at acidic pH, and its SH groups become available only after metabolization.
Four studies have compared erdosteine and NAC in patients with acute CB exacerbations.
A randomised study performed in 50 patients treated for 7-10 days showed that both treatments significantly improved the efficacy parameters of cough and sputum appearance, viscosity and volume by treatment end, however:
erdosteine was significantly faster than NAC in improving sputum viscosity and cough frequency (at day 2 and 4)
a significantly greater reduction of sputum volume was obtained by erdosteine from day 6 onwards
a statistically significant increase of FVC in comparison to baseline values was achieved only in the erdosteine group
erdosteine had a more favourable safety profile than NAC. No side effects were reported in the erdosteine group, while patients treated with NAC reported nausea (2 cases), pyrosis (4 cases) and halitosis (7 patients).
In the other studies, consistent results were observed, in particular:
while clinical and spirometric criteria improved with both treatments, the volume of expectoration decreased more significantly with erdosteine
a more rapid resolution of symptoms was observed with erdosteine
a significant increase of FEV1 (by 14%) was only observed in erdosteine-treated patients
erdosteine was better tolerated than NAC.
1.3.6 E.N.T. (rhynopharyingitis, sinusitis)
Two studies conducted in patients with acute and chronic exacerbated infections of upper respiratory airways have shown that erdosteine ameliorates clinical symptoms to a similar extent than NAC, but is better tolerated.
1.3.7 Acute lower respiratory tract diseases in children
Due to its favourable pharmacological properties, the synergistic activity with antibiotics, and the good tolerability profile, the efficacy of erdosteine was evaluated on special populations, such as children suffering from lower respiratory tract diseases.
In a first double-blind study, 100 children (aged 2-4 yrs) and 100 (aged 5-10 yrs) suffering from acute hypersecretive bronchitis were treated with ampicillin, and randomised to erdosteine or placebo for 5-9 days.
In both study populations, erdosteine confirmed to be an effective treatment in association with antibiotics. There was a significant difference in improvements in cough and rales between patients treated with erdosteine and those treated with antibiotics alone. The reduction of cough was by 60% vs. 37% in the younger children, and by 57% vs. 32% in 5-10 yrs. old children (p<0.01).
The tolerability profile of erdosteine was excellent in both age-range groups.
These findings confirm the efficacy profile of erdosteine already demonstrated in adults, with a better and more rapid improvement of symptoms in patients treated with the combination of antibiotics and erdosteine. The improvement in efficacy is not offset by any increase in side effects.
A recent multinational, multicenter, double-blind, controlled trial in 158 children, aged from 2 to 12 years, with a diagnosis of acute lower respiratory tract infections to be treated with antibiotics, gives same evidence for the synergic effect of erdosteine with antibiotics in children. Patients received erdosteine or placebo (both in association with amoxicillin). The duration of the treatment was from 3 to 9 days.
The results of the study have shown that erdosteine in combination with amoxicillin produced a more rapid improvement in the clinical symptoms compared to the antibiotic therapy alone. The severity of cough decreased significantly more in children treated with erdosteine compared to placebo, as well as other secondary efficacy parameters such as rhonchi and rales. The tolerability of erdosteine was very good.
The results observed for the association erdosteine plus amoxicillin compared to association amoxicillin plus placebo were not only statistically significant but also clinically relevant. In fact, cough (especially at night) is a very disturbing symptom of respiratory tract infections and has a negative impact on the quality of life of both children and parents.
1.4 Tolerability
Erdosteine is characterised by an excellent safety profile, with an observed incidence of adverse events comparable to that of placebo.
In clinical studies, more than 2,000 patients have been treated with erdosteine at doses ranging from 600 mg/day to a maximum of 1,200 mg/day, with an exposure ranging from short-term 7-10 days to long-term 8 months.
The frequency of adverse events in patients treated with erdosteine, placebo and reference drugs (i.e. other mucolytics) was 13.4%, 19.8% and 23.9%, respectively.
There were no differences between erdosteine and placebo in the rate of any of the adverse event categories: gastrointestinal, cardiovascular, cutaneous and general reactions.
In particular, the incidence of gastrointestinal side effects in patients treated with erdosteine was comparable to that in the placebo-treated patients, and about 3-fold lower than in patients treated with other mucolytics.
About 7.2% of patients treated with erdosteine reported GI disturbances, more frequently gastralgia (1.7%) and nausea (1.1%). Respective figures were 10.5% of patients reporting GI adverse events in the placebo groups, and 17.2% in the reference drug groups.
All adverse events were of mild/moderate intensity, and no severe adverse reactions were reported.
A dedicated study performed in patients undergoing gastroscopy for pre-existing gastric complaints showed that erdosteine did not cause any worsening of symptoms not occurrence of new symptoms or new histological findings.
The favourable tolerability profile of erdosteine is likely to be explained by the presence of blocked sulphydryl groups released only after metabolisation of erdosteine to metabolite I, that occur not in the stomach but when passing into the bowel or after absorption. These characteristics mark the difference with other compounds of the same therapeutic class, such as NAC.
Compounds containing free SH groups often present an unpleasant smell and may frequently cause, after intake, reflux phenomena.
The more favourable profile of erdosteine in this respect represents a plus of particular importance in terms of patient compliance.
Erdosteine has been administered in association with systemic antibiotic therapy (e.g. ampicillin, amoxicillin, bacampicillin, ciprofloxacin, cotrimoxazol) without any increase of adverse event incidence. Moreover, no untoward drug interactions have been observed when erdosteine was administered with theophylline and ß2-mimetics.
This feature of erdosteine is particularly advantageous in view of a chronic use in COPD patients (elderly and likely to present multiple significant co-morbidities), since minimal impact with a possibly complex set of interacting diseases and drugs should be expected.
Specific studies conducted in elderly subjects and in patients with mild renal or hepatic failure did not show any increase of untoward PK and safety findings. It is however suggested, to halve the erdosteine dose in patients affected by severe hepatic impairment, and the drug is not recommended in patients with a creatinine clearance less than 25 ml/min.
Key Claims
- Multifactorial mechanism of action that may favourably impact on the progression of CB/COPD from milder to more severe conditions
- Anti-bacterial adhesiveness activity that acts synergistically with antibiotics
- Strong anti-oxidant activity
- Consistent local anti-inflammatory activity
- Excellent overall efficacy
- Proved amelioration of CB/COPD symptoms both in the stable phase and during acute exacerbations, with a faster onset of effects compared to other mucolytics
- Significant protective effects against acute exacerbation episodes in COPD patients
- Significant reduction of number of hospitalisations in COPD patients, and favourable pharmaco-economy impact.
- Positive benefits in terms of lung function parameters and physical performances
- Good (placebo-like) safety profile
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