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Erdosteine is a molecule with
mucolytic Mucoactive agents are a class of chemical agents that aid in the clearance of mucus or sputum from the upper and lower airways, including the lungs, bronchi, and trachea. Mucoactive drugs include expectorants, mucolytics, mucoregulators, and muco ...
activity. Structurally it is a
thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...
derivative characterized by the presence of two thiol groups. These two functional
sulfhydryl In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...
groups contained in the molecule are released following
first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...
with the conversion of erdosteine into its pharmacologically active metabolite Met-I. The molecule has been discovered and developed in Italy by Edmond Pharma, today it is prescribed for chronic and acute respiratory disorders in more than 40 countries worldwide. The drug is sold under several commercial names (Esteclin, Erdomed, Erdos, Erdotin etc.), as hard capsules 300 mg, dispersible tablets 300 mg, granulates for oral suspension 225 mg and powder for oral suspension 175 mg/5ml.


Pharmacodynamics

Erdosteine is an oral mucoactive
anti-oxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants, ...
molecule, characterized by a multi-faceted pharmacological profile that may positively interfere in more than one of the pathological processes ongoing in all respiratory disorders characterized by thickened or increased mucus production, increased
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...
and chronic
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
. Moreover, an important feature of the pharmacological profile of erdosteine is represented by its synergy with
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
s. *
Anti-oxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants, ...
and
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as op ...
activity Erdosteine exerts its role as anti-oxidant and anti-inflammatory thanks to the free sulphydrylc groups of its active metabolite Met I, which has a direct scavenging effect (particularly on reactive oxygen species, ROS), and it is able to bind the
free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spo ...
preventing tissue damage.    Erdosteine exerts a protective role against
lipid peroxidation Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chai ...
(smokers, COPD patients) by increasing the availability of endogenous antioxidants, such as glutathione, in plasma and bronco-alveolar lavage. * Antiadhesive activity Erdosteine is able to interfere with bacterial adhesion. In fact, Met I can affect the integrity of the natural intrachain disulphide bonds of pilin; the opening of this bond can induce a morphological change that interferes with the binding of bacterial adhesin (fimbriae) to receptor. The bacterial adhesion reduction is reached by Met I ad concentration similar to the plasmatic peak obtained after a single 300 mg oral administration of erdosteine. Erdosteine showed in vivo and in vitro synergistic activity with antibiotics, against bacterial adhesiveness, in patients with
respiratory infections Respiratory tract infections (RTIs) are infectious diseases involving the respiratory tract. An infection of this type usually is further classified as an upper respiratory tract infection (URI or URTI) or a lower respiratory tract infection (LRI ...
. Several clinical studies underline that, when given in combination with antibiotics, erdosteine does not interfere with their activity but improve their effects, causing an increase in therapeutic efficacy. *
Mucolytic Mucoactive agents are a class of chemical agents that aid in the clearance of mucus or sputum from the upper and lower airways, including the lungs, bronchi, and trachea. Mucoactive drugs include expectorants, mucolytics, mucoregulators, and muco ...
activity Erdosteine shows an important muco-regulatory activity (it increases mucus production and makes it more fluid and much less thick), and positively influences the mucociliary clearance. Several studies show that erdosteine results more active compared to other muco-regulatory drugs (such as N-acetylcysteina, sobrerol and ambroxol). *
Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce m ...
Evidence obtained in patients with stable chronic bronchitis/COPD with mucus hypersecretion show that erdosteine can bring therapeutic advantages during long-term administration.   A long-term treatment with erdosteine (6–8 months) can significantly decrease the risk of
exacerbation An exacerbation, in medicine, is the worsening of a disease or an increase in its symptoms. Examples includes an acute exacerbation of chronic obstructive pulmonary disease An acute exacerbation of chronic obstructive pulmonary disease, or acute ...
s and hospitalizations and improve patients' quality of life. These data are in agreement with recent indications from the international literature, that support the use of mucoactive agents in patients with hypersecreting chronic pulmonary diseases, especially during winter months. A metanalysis conducted on 1278 patients demonstrated that erdosteine brings to symptoms improvement and reduces the risk of exacerbations of chronic bronchitis and COPD. Furthermore, erdosteine demonstrated to reduce the exacerbation duration and the hospitalization risk due to COPD. The RESTORE study (Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD) was a multinational, randomized,
double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...
,
placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can aff ...
-controlled study to evaluate the efficacy and safety of erdosteine 300 mg/bid added to usual maintenance therapy vs. placebo over 12-months, a period long enough to avoid bias due to seasonal variability in exacerbation frequency. During the study 467 patients with moderate-to-severe stable COPD were randomized and treated in 47 hospital-based pulmonary clinics in 10 European countries. After 1 year of treatment there was a 1.4% reduction in the exacerbation rate with erdosteine treatment; this result was mainly driven by the reduction in the rate of mid exacerbations equal to 57.1%. Furthermore, erdosteine treatment was associated with a 24.6% decrease in all exacerbation duration compared to placebo. Both for exacerbation rate and duration, no significant differences among inhaled corticosteroids taking and non-taking patients has been registered. A RESTORE sub-analysis demonstrated that adding erdosteine to the maintenance therapy reduces the number of mild exacerbations and the duration of all exacerbations in patients with moderate COPD. A metanalysis conducted on 2753 patients with moderate COPD shows that the efficacy and safety profile of erdosteine is superior to that of other muco-regulatory drugs (carbocysteine and N-acetylcysteine). Furthermore, erdosteine was the only mucolytic able to reduce the risk of hospitalization due to COPD exacerbations. * Other activities Several studies demonstrate the efficacy of erdosteine in the treatment of bronchiectasis in terms of facility of expectoration. In several Countries in the world erdosteine is approved for the bronchiectasis treatment. Erdosteine has shown benefits also in the treatment of chronic
rhinosinusitis Rhinosinusitis is a simultaneous infection of the nasal mucosa ( rhinitis) and an infection of the mucosa of the paranasal sinuses (sinusitis). A distinction is made between acute rhinosinusitis and chronic rhinosinusitis. Background Because si ...
with
nasal polyp Nasal polyps (NP) are noncancerous growths within the nose or sinuses. Symptoms include trouble breathing through the nose, loss of smell, decreased taste, post nasal drip, and a runny nose. The growths are sac-like, movable, and nontender, t ...
osis and Otitis Media Secretorica. * Pediatric population Erdosteine was tested in pediatric patients with lower tract respiratory disorders, in association with
ampicillin Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It may also be used to prevent group B strepto ...
, demonstrating a high symptoms reduction. In pediatric population with acute bronchitis, tracheobronchitis and
pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
, erdosteine showed a significantly high reduction in cough intensity and improvement of clinical symptoms, with very good tolerability.


Pharmacokinetics

Erdosteine, administered in single doses from 150 mg to 1200 mg to adult volunteers, shows a linear kinetic, with Met I serum concentration approximately 4-fold higher than those of erdosteine. The
pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
parameters of erdosteine and Met I are fully comparable after single and multiple doses, therefore there is no accumulation or metabolic activation after repeated administrations. Food does not significantly affect the absorption of erdosteine. After oral administration, erdosteine is rapidly absorbed in the gastro-intestinal tract and the plasmatic peak concentration (Cmax) is reached after 30–60 minutes (Tmax) from consumption. The molecule is rapidly transformed through a first-pass metabolism to the biologically active metabolite Met I. The drug bioavailability by oral route is very good. The half-life is 3 hours and the plasma binding protein is 65%. With respect to pharmacokinetics in special populations, a study in 12 health volunteers (mean age 70 years) confirmed that pharmacokinetic parameters for both erdosteine and Met I were similar to those observed in younger adults (mean age 31 years). Moderate renal dysfunction in elder volunteers did not affect erdosteine and Met I pharmacokinetics.


Toxicity

The LD50 in rats is very high, between 3.500 and 5.000 mg/kg.


Clinical uses

Clinical studies in more than 4.000 patients demonstrated that erdosteine is effective is the treatment of acute and chronic affections of upper and lower respiratory tract with mucus hypersecretion. It modules the sputum viscosity in the respiratory tract, making it more fluid and less thick, bringing to an increase of mucociliary rate which allows the mucus removal from respiratory tract. Erdosteine is used as mucolytic and fluidifying agent in upper and lower respiratory disorders. It modules the sputum viscosity. Erdosteine efficacy is significant in reducing symptoms associated with Chronic Obstructive Pulmonary Disease. A multicentric, multinational study on more than 450 patients with COPD demonstrated that erdosteine is able to reduce both the frequency and the duration of symptomatic exacerbations, typical of this disease. The GOLD (
Global Initiative for Chronic Obstructive Lung Disease The Global Initiative for Chronic Obstructive Lung Disease (GOLD) is a non-profit organization started by the World Health Organization and the US National Heart, Lung, and Blood Institute in 1997 to improve care for chronic obstructive pulmonary di ...
) International Guidelines indicate that a regular treatment with a mucolytic like erdosteine can reduce exacerbations and improve the health status of patients with COPD. In some countries erdosteine in approved for the treatment of bronchiectasis.


Safety profile

Data from post marketing surveillance confirm that erdosteine is well tolerated, with an excellent safety profile. Frequency and severity of adverse effects in clinical studies (more than 2300 patients in more than 70 clinical studies) was very low and comparable to placebo. Erdosteine is stable to
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis i ...
in acid environment, so it does not have any direct effect on gastric mucus, which implies a very good safety profile. Less than 1 patient in 1.000 is expected to have gastrointestinal undesirable effects. Very rare (<1/10.000) adverse events are
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result of ...
,
dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
, taste alterations,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis ...
,
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
,
epigastric pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...
.


Contraindications

The drug is contraindicated in subjects with hypersensitivity to the active substance or to any of the
excipient An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...
s. It is contraindicated in subjects with active peptic ulcer. Because of a possible interference of the product with methionine metabolism, the drug is contraindicated in patients with
hepatic cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
and deficiency of the cystathionine-synthetase
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
.


Interaction with other medicinal products

No harmful interactions with other drugs have been reported and the product can therefore be administered together with antibiotics and
bronchodilator A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lung ...
s (such as beta2-mimetics and cough sedatives).


References

{{Cough and cold preparations Carboxylic acids Thioethers Thiolactones Carboxamides Expectorants