BENECIAL EFFECTS

OF ERDOSTEINE

Prof Heda Melinda N Nataprawira

Respirology Division-Department of Child Health-

Hasan Sadikin General Hospital-Universitas Padjadjaran

Presented in Bekasi Pediatric Update 2023. Symposium & Workshop. Bekasi, 6–7 May 2023
 Prof Dr. dr. Heda Melinda N Nataprawira, Sp.A(K), M.Kes

Staff of Department of Child Health-Hasan Sadikin General Hospital

Faculty of Medicine Universitas Padjadjaran
Previous, Current Position
Education
• Medical Doctor : - Pediatric Respirology Consultant

Faculty of Medicine Universitas Padjadjaran

Professor in Pediatric

• Pediatric Residence : iety - Secretary of Doctoral Program Faculty of Medicine Universitas

Faculty of Medicine Universitas Padjadjaran Padjadjaran-Bandung Indonesia (up to 2012)

• Fellow in Respirology : - Contributing Editor Paediatrica Indonesiana since 2004 up to now

- Author and Co-author International and National Publications
Nijmegen-Radboud University Nijmegen
(Academisch Ziekenhuis) The Netherland - Reviewer International and National Journal

• Health Magister - Faculty of Medicine Universitas Organization/Member

Padjadjaran - Indonesian Medical Association
• Doctoral Program - Faculty of Medicine Universitas - Indonesian Pediatric Association
Padjadjaran - Asian Pacific Society of Respirology (APSR)
- International Union Against Tuberculosis and Lung Disease
- European Respiratory Society (ERS) Slide Heda Melinda
 ERDOSTEINE
Erdosteine, N-(carboxymethylthioacetyl) homocysteine-thiolacetone is a prodrug molecule which is
characterized by the presence of two sulphure atoms, one of which is blocked in the aliphatic side chain and the
other enclosed in the heterocyclin ring (thiolacetone)

Thiol derivative: mucolytic and antioxidant activity

When passing to a more alkaline environment, the thiolactone

ring slowly opens, achieving in the bloodstream, the complete
transformation to I, N-thiodiglycolylhomocysteine, (met I)
which is the active metabolite of erdosteine owing to this
free thiol group capable of breaking the disulphide bonds of
mucins and thus improving mucociliary airway clearance
(MAC)
Cattò et al. Understanding the role of the antioxidant drug Erdosteine and its active metabolite on Staphylococcus aureus Methicillin Resistant Biofilm Formation. Antioxidants. 2021;10:1–18
Negro R, et al. Erdosteine: Drug exhibiting polypharmacy for the treatment of respiratory diseases. Pulm Pharmacol Ther. 2018;53:80-85. Slide Heda Melinda
Erdosteine Mechanism as Mucolytic Agent

ERDOSTEINE

Linssen RSN, et al. Rational use of mucoactive medications to treat pediatric airway disease. Pediatr Respir Rev. 2020;36:8–14. Slide Heda Melinda
Mucociliary Clearance System
• Mucociliary clearance (MCC) is the
primary innate defense mechanism of
the lung
• The functional components:
protective mucous layer,
airway surface liquid layer,
and the cilia on the surface of
ciliated cells.

Bustamante-Marin X, et al. Cilia and mucociliary clearance. Cold Spring Harb Perspect Biol .2017;9:1-9
Slide Heda Melinda
Bustamante-Marin X, et al. Cilia and mucociliary clearance. Cold Spring Harb Perspect Biol .2017;9:1-9 Slide Heda Melinda
 Mucociliary Clearance System

Downloaded from: https://www.youtube.com/watch?v=eehsgyvm0SQ&ab_channel=Medicurio Slide Heda Melinda

MUCOACTIVE AGENTS
Drugs that are designed to specifically alter the viscoelastic properties of mucus in
addition to promoting secretion clearance

MUCOLYTIC MUCOKINETIC

MUCOREGULATOR EXPECTORANT

Linssen RSN, et al. Rational use of mucoactive medications to treat pediatric airway disease. Paediatr Respir Rev.
2020;36:8–14.
Slide Heda Melinda
 WHEN DO WE USE MUCOLYTIC?
Mucolytics can be given to children over 2 years old
with an acute cough, and can be given combined with
antibiotics if indicated.

Acetylcysteine and carbocysteine may be useful in self-

limited disease (eg. acute cough, bronchitis) for children
over 2 years of age.

Guaifenesin or glyceryl guaiacolate, classified as mucolytics –

expectorants, have no effect compared to placebo in changing mucus
rheology in children over 12 years of age with acute respiratory
infections.

Chalumeau M, et al. Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic
broncho‐pulmonary disease. Cochrane Database Syst Rev. 2013;5:1-62
Slide Heda Melinda
• Acetylcysteine and carbocysteine are licensed for use for the treatment of acute upper and
lower RTIs in paediatric patients in many European countries children older than two years
of age and is not supported by any evidence in children under two years of age,
considering some important concerns about safety

• Mucolytic agents seem to have some benefits on frequency, intensity and duration of
symptoms, and appear to be safe in children older than two years.

• Regarding children younger than two years old, there are current strong concerns about
the safety of acetylcysteine and carbocysteine → These concerns led to the withdrawal of
their licence in this age group in France and Italy in 2010

Chalumeau M, et al. Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho‐pulmonary
disease. Cochrane Database Syst Rev. 2013;5:1-62 Slide Heda Melinda
Analysis of the French pharmacovigilance system
concerning adverse drug reactions (ADRs) to
acetylcysteine and carbocysteine
→ 59 children younger than six years (median
aged 5 mo, range 3 weeks–34 mo, 98% aged
<2 years old)
→ 30 children received carbocysteine, 28 received
acetylcysteine and one child received both
drugs at the same time.

Respiratory ADRs reported:

increased and/or prolonged cough, increased
bronchorrhoea, worsening of respiratory distress,
mucous vomiting, and dyspnoea
Slide Heda Melinda
 Mucolytic?
Mucoregulator?
Mukokinetic?
In non-asthmatic patients, SABA is not useful as
a treatment for acute cough in children

Corticosteroids can be used in a limited

condition in children with cough, such as asthma
attacks, croup, and in the long-term
management of asthma as controllers, allergic
rhinitis and rhinosinusitis

Becker LA, et al. Beta2‐agonists for acute cough or a clinical diagnosis of acute bronchitis. Cochrane Data- base Syst Rev. 2015;9:1-35.
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2022. Slide Heda Melinda
 -2 Agonist for Cough

Daily cough scores were no different between children given oral beta2-
agonists and children in the placebo control groups.

However, the results were mixed. Some trials show a benefit and some
show no benefit. This may be because some participants also had
wheezing or other signs of narrowed airways, in which case beta2-
agonists may be helpful only for them.

Slide Heda Melinda

 Daily Cough Score
• Acute cough defined as a cough lasting for 14 days with total clinical
cough score > 2.
• Cough score improvement was defined as a decrease in the total
clinical cough score, while no improvement was a persistence or
increase in the total cough score

Yenny Y, et al. Randomized controlled trial of erdosteine for acute cough in children with colds. Paediatr Indones. 2011;51:111-5.
Lai K, et al. Clinical practice guidelines for diagnosis and management of cough. J Thoracic Dis. 2018;10:6314.
Slide Heda Melinda
 Airway mucus → lining fluid that protects the
airway by entrapping and clearing inhaled
particulate matters, and prevents fluid loss from
the airway surface.

Approximately 95% water, with polymeric mucins

particularly MUC5B secreted from submucosal glands
AIRWAY MUCUS and MUC5AC secreted from mucous or goblet cells,
providing the gel structure

During infection and inflammation, airway

secretions also contain inflammatory and shed
epithelial cells, particulates, microorganisms,
secreted peptides and products of inflammation

This complex mix is called phlegm when it

is in the airway and sputum when
expectorated
Linssen RSN, et al. Rational use of mucoactive medications to treat pediatric airway disease. Paediatr Respir Rev. 2020;36:8–14.
Slide Heda Melinda
MUCOLYTIC
• Reduce sputum viscosity by disrupting polymer networks in the
secretion
• N-acetylcysteine, ambroxol, erdosteine

MUCOKINETIC
• Improve the effectiveness of ciliary propulsion or cough in
secretion clearance, either by increasing airflow or by altering the
sputum-epithelium interaction
• Bronchodilators, surfactants
Linssen RSN, et al. Rational use of mucoactive medications to treat pediatric airway disease. Paediatr Respir Rev. 2020;36:8–14.
Slide Heda Melinda
MUCOREGULATOR
• Decrease secretions by inhibiting mucus production or by decreasing
inflammation
• Anticholinergic agents, corticosteroid, macrolides

EXPECTORANT
• Increase the hydration of sputum either by the direct addition of
water or by stimulation of water secretion into the airway
• Guaifenesin, hypertonic saline

Linssen RSN, et al. Rational use of mucoactive medications to treat pediatric airway disease. Paediatr Respir Rev. 2020;36:8–14.
Slide Heda Melinda
 MECHANISMS OF
Erdosteine

ACTION

Linssen RSN, et al. Rational use of mucoactive medications to treat pediatric

airway disease. Paediatr Respir Rev. 2020;36:8–14.
Slide Heda Melinda
N-acetylcysteine
• A thiol-based drug with a free sulphydryl group (-SH), disrupts the structure of the
mucus
• Breaks the disulphide bonds (S–S) that connect mucin proteins by donating electrons to
the thiol groups of mucin monomer cysteine (Cys) residues
• Results in depolymerization of mucin oligomers, changes in the rheology of mucin-rich
secretions, and consequent reduction in the elasticity and viscosity of the mucus

Balsamo R, et al. Mucoactive drugs. Eur Respir Rev. 2010;19:127-33.

Slide Heda Melinda
Ambroxol
• Stimulate surfactant and mucus secretion, yet promote normalisation of mucus
viscosity in viscid secretions.
• Systematic review provides evidence of a generalised benefit using ambroxol for a
range of parameters, including secretolytic activity (promoting mucus
clearance), anti-inflammatory and antioxidant activity and exerts local
anaesthetic effect

Balsamo R, et al. Mucoactive drugs. Eur Respir Rev. 2010;19:127-33.

Slide Heda Melinda
Guaifenesin (glyceryl guaiacolate)
• No mucolytic action but may reduce bronchial sputum surface tension.
• No evidence is available to suggest antiseptic or anti-tussive effects.
• The main benefit: expectorant for the symptomatic treatment of coughs, producing small
quantities of thick viscous secretions.
• Stimulate the cholinergic pathway and increase mucus secretion from the airway submucosal
glands.

Bronchodilators
• Beta 2-adrenergic agonists: enhance mucocilliary clearance
• Recent reports: salmeterol could restore secretory functions in CF airway submucosal gland
serous cells, and that Beta 2-adrenergic agonists can enhance mucocilliary clearance in patients
with airway reversibility

Balsamo R, et al. Mucoactive drugs. Eur Respir Rev. 2010;19:127-33.

Slide Heda Melinda
BENECIAL EFFECTS OF ERDOSTEINE

Cazzola M, et al. Thiol-based drugs in pulmonary medicine: much more than mucolytics. Trends Pharmacol Sci. 2019;40(7):452-63. Slide Heda Melinda
Balsamo R, et al. Mucoactive drugs. Eur Respir Rev. 2010;19:127-33.
Slide Heda Melinda
 Erdosteine reduced
• frequency and severity of cough and sputum viscosity more
effectively than placebo
• more efficient in reducing sputum adhesion than ambroxol.

Although many mucolytics and mucoregulators have positive pharmacodynamic

effects against the mucus, only N-Acetylcysteine (NAC) and erdosteine have
shown a capacity to inhibit bacterial adhesion and therefore an action favoring the
antibacterial activity of the antibiotic when used in contemporary

Negro R, et al. Erdosteine: Drug exhibiting polypharmacy for the treatment of respiratory diseases. Pulm Pharmacol Ther. 2018;53:80-85.
Slide Heda Melinda
 Anti Inflammatory Effect of Erdosteine
Erdosteine is able to induce an anti-inflammatory activity (several in vitro and in vivo experimental
studies).
This effect could further explain the potentiating effect of erdosteine when given in combination with an
antibiotic therapy

In rat alveolar macrophage activated by lipopolysaccharide (LPS),

erdosteine was able to inhibit the synthesis of some cytokines
including tumor necrosis factor (TNF-α), IL- 1β and free radical
production.

Slide Heda Melinda

Erdosteine exerts its anti-inflammatory effects by inhibiting
NF-kB activation in LPS-stimulated mouse macrophages
Slide Heda Melinda
 Anti Adhesiveness Activity of Erdosteine
In vitro studies have highlighted an antibacterial activity of Met I, the active metabolite of
erdosteine, as it is able to reduce bacteria adhesiveness on eukaryotic host cells.

The postulated antibacterial activity is based on the

ability of Met I molecules bearing reducing SH groups,
to open the disulphide bonds present in pilins,
inducing stereochemical conformational changes that
interfere with the binding fimbriae to the receptors on
eukaryotic cells.

Simultaneous administration of Met I was able to increase

the effect of lower sub-MIC of clarithromycin to the same
level as that of higher sub-MIC of clarithromycin alone,
Thus, further prolonging inhibition of bacterial
adhesion to human mucosal cells for eight hours.

Slide Heda Melinda

Negro R, et al. Erdosteine: Drug exhibiting polypharmacy for the treatment of respiratory diseases. Pulm Pharmacol Ther. 2018;53:80-85.
Slide Heda Melinda
 Anti Adhesiveness Activity of Erdosteine
Erdosteine disrupts the pilin disulphide The adhesion ability of S. aureus bacteria (yellow
bonds in biofilms color) to human buccal cells (blue color)
Thereby, changing the morphology of the decreases after being given 2.5 μg/mL
bacteria erdosteine

Before After
Erdosteine Erdosteine
Before After
Erdosteine Erdosteine

Cattò et al. Understanding the role of the antioxidant drug Erdosteine and its active metabolite on Staphylococcus aureus Methicillin Resistant Biofilm Formation.
Antioxidants. 2021;10:1–18 Slide Heda Melinda
 Antibiotic Resistance
• Caused by irrational use of antibiotics and biofilm formation
• About 80% of chronic and recurrent microbial infections are caused by biofilms formation
• The goal of therapy is to increase antibiotic efficacy without increasing antibiotic resistance
• Erdosteine inhibits biofilm formation and causes biofilm disruption, thereby improving the
efficacy of antibiotic therapy

VS
Cattò et al. Understanding the role of the antioxidant drug Erdosteine and its active metabolite on Staphylococcus aureus Methicillin Resistant Biofilm Formation.
Antioxidants. 2021;10:1–18 Slide Heda Melinda
Both erdostein (Er) and active metabolite of Er (Met I) increased the number of adhered cells within
the biofilms and the effect was major upon Met I treatment in comparison to Er.
Additionally, study demonstrated that Met I is able to reduce bacterial virulence, beside increasing
the number of sessile cells during the drug treatment.
This effect is promising in enhancing the efficacy of antibiotics
treatments.
Slide Heda Melinda
Erdosteine alone does not affect MRSA or MSSA biofilm
formation or viability in vitro.
When erdosteine is combined with certain antibiotics,
there is a concentration-dependent reduction both in
biofilm formation and bacterial viability.
Slide Heda Melinda
Method
Multicentre, randomised, double-blind, parallel group
study
Erdosteine plus ampicillin vs ampicillin alone (100
mg/kg/day) for 5‒9 days
In 200 children with acute febrile lower RTI (acute
bronchitis, asthmatic bronchitis, trachea-bronchitis,
bronchoalveolitis).
Results
Combination of erdosteine plus
ampicillin allowed a more rapid
and definite amelioration of
symptoms (especially cough
[primary efficacy parameter])
compared with ampicillin alone
Slide Heda Melinda
Method
Multicentre, randomised, double-blind, placebo-
controlled study
Enrolled 158 children (aged 2‒12 years) with acute lower
RTI treated with amoxicillin alone or amoxicillin plus
erdosteine for mean duration of 7.28 days.
Results
Erdosteine in combination with
amoxicillin produced a more rapid
improvement in clinical symptoms
(cough, rales) than amoxicillin
alone.
Slide Heda Melinda
Method

Multicentre, randomised, double-blind,

placebo- controlled study
Enrolled 89 children or adults (aged 2‒65
years) with PCD treated with
azithromycin-placebo or erdosteine-
placebo or azithromycin-erdosteine for
12 months.

Results
Administration of erdosteine with azithromycin
for 12 months in adults and children was able
to significantly reduce the rate of acute
exacerbations compared to single erdosteine
and azithromycin groups.
Slide Heda Melinda
ERDOSTEINE

Slide Heda Melinda

 CONCLUSION
The anti-adhesive effect of erdosteine prevents bacterial adhesion to the
respiratory tract and synergizes with the antibiotic effects, influencing outcomes

Erdosteine is able to potentiate the activity of antibiotics facilitating their

penetration thus improving the benefits of the treatment

Several studies have highlighted that erdosteine does not interfere, but is able to
potentiate the effect of some antibiotics, thus improving the clinical outcome of the
therapy

Erdosteine inhibits biofilm formation and causes biofilm disruption, thereby,

improving the efficacy of antibiotic therapy

Slide Heda Melinda

Slide Heda Melinda
 Physiology of
Cough
• A cough reflex can be triggered by
several inflammatory or mechanical
changes in the airways.

• Inhalation of chemical and

mechanical irritants can trigger
cough reflex in the larynx, the
carina, and other points where the
proximal airways branch.

Chung, K. F., et al. Prevalence, pathogenesis, and causes of chronic cough. Lancet . 2008;371:1364–74.
Slide Heda Melinda
Physiology of Cough

Slide Heda Melinda

 Phase of Cough
The mechanical process of cough is divided into
three phases:
1) Inspiration phase: gas inhalation can be at
least 50% of tidal volume or as much as
50% of vital capacity needed for an effective
cough.
2) Compression phase: glottic closure
maintains intrathoracic pressures combined
with contraction of chest wall muscles,
diaphragm, and abdominal wall.
3) Expiration phase: glottis is opened,
producing expiration airflow and high cough
sound and compression on the large
respiratory tract. High airflow excretes
mucus and cleansed the respiratory tract.

Bakhtiar et al. Management Of Cough. J Respirasi, 2022;06:85–96. Slide Heda Melinda