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The potential role of Bromhexine in the management of COVID-19: Decipher and a real game-changer

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  • Al-Mustansiriyah University

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Primary infection of SARS-CoV-2 (novel coronavirus or 2019-nCoV), which leads to Covid-19, targets specific cells, such as nasal, bronchial epithelial and pneumocytes, through the viral structural spike (S) protein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor. Also, type 2 transmembrane serine protease (TMPRSS2) present in the host cell promotes viral uptake by cleaving ACE2 and triggering the SARS-CoV-2 S protein, which facilitates SARS-CoV-2 entry into host cells. One of the TMPRSS2 inhibitors with a greater distribution capacity into the lung tissue is bromhexine hydrochloride which attenuates the entry and proliferation of SARS-CoV-2. Bromhexine is an effective drug in the management and treatment of Covid-19 pneumonia via targeting ACE2/ TMPRSS2 pathway. However, prospective and controlled clinical trials are recommended to confirm this observation.
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Curr Med Drug Res, 2021, 5 (1), Article ID 212
Curr Med Drug Res, 2021, 5 (1), Article ID 212 Page 1
Concept note
The potential role of Bromhexine in the management of COVID-19: Decipher and a
real game-changer
Hayder M. Al-Kuraishy1,*, Marwa S. Al-Niemi2, Nawar R. Hussain2, Ali I. Al-Gareeb1 and Claire
Lugnier3,*
1Department of Clinical Pharmacology, Medicine and Therapeutics, College of Medicine, Al-Mustansiriya
University, P.O. Box 14132, Baghdad, Iraq
2Department of Pharmacology, College of Pharmacy, Al-Farahidi University, P.O. Box 14132, Baghdad, Iraq
3Unistra, Faculté de Médecine, Institut de Physiologie, EA 3072 Mitochondrie, stress oxydant et protection
musculaire, 4 Rue Kirschleger, 67085, Strasbourg Cedex, France
*Corresponding authors. E-mail: hayderm36@yahoo.com (HMA); claire.lugnier@unistra.fr (CL); Phone: +96-
407906230487
Article history
Received : December 06, 2020
Accepted : December 18, 2020
Keywords
Bromhexine
COVID-19
Novel coronavirus
SARSCoV2
TMPRSS2
ABSTRACT
Primary infection of SARSCoV2 (novel coronavirus or 2019nCoV), which leads to
Covid-19, targets specific cells, such as nasal, bronchial epithelial and pneumocytes,
through the viral structural spike (S) protein that binds to the angiotensin-converting
enzyme 2 (ACE2) receptor. Also, type 2 transmembrane serine protease (TMPRSS2)
present in the host cell promotes viral uptake by cleaving ACE2 and triggering the
SARS-CoV-2 S protein, which facilitates SARS-CoV-2 entry into host cells. One of the
TMPRSS2 inhibitors with a greater distribution capacity into the lung tissue is
bromhexine hydrochloride which attenuates the entry and proliferation of
SARSCoV2. Bromhexine is an effective drug in the management and treatment of
Covid-19 pneumonia via targeting ACE2/ TMPRSS2 pathway. However, prospective
and controlled clinical trials are recommended to confirm this observation.
© 2021 Global SciTech Ocean Publishing Co. All rights reserved. ISSN. 2581-5008
INTRODUCTION
The existing epidemic of the novel coronavirus
SARSCoV2 (coronavirus disease 2019; previously
2019nCoV), in Hubei Province of China, has
spread to numerous other countries and on 30
January 2020, the WHO Emergency Committee
declared a global health emergency based on
growing case notification rates at Chinese and
international locations (Al-Kuraishy et al., 2020a).
Coronaviruses are enveloped and positive
singlestranded large RNA viruses that infect
humans, and a varied range of animals.
SARSCoV2 belongs to the βcoronaviruses have
four structural genes encode the nucleocapsid
protein (N), the spike protein (S), a small
membrane protein (SM) and the membrane
glycoprotein (M) with an additional membrane
glycoprotein (HE). The SARSCoV2 is 96%
matching at the wholegenome level to a bat
coronavirus (Fig. 1) (Al-Kuraishy et al., 2020b;
Semwal et al., 2020)
Fig. 1. Structure of SARSCoV2
The primary infection of novel coronavirus
targets specific cells including nasal and bronchial
epithelial cells through the spike protein which
binds to the ACE2 receptor. Similarly, type 2
transmembrane serine protease (TMPRSS2),
present in the host cell promotes viral uptake by
cleaving ACE2 and triggering the SARS-CoV-2 S
protein, which facilitates SARS-CoV-2 entry into
host cells (Fig. 2) (Al-Kuraishy et al., 2020c).
Al-Kuraishy et al. [Potential role of Bromhexine in COVID-19]
Curr Med Drug Res, 2021, 5 (1), Article ID 212 Page 2
Fig. 2. SARS-CoV-2 binds to ACE2 receptor
ACE2 and TMPRSS2 are expressed in host
target cells, predominantly alveolar epithelial type
II cells. Furthermore, the viral inflammatory
response, consisting of both the innate and the
adaptive immune response blights lymphopoiesis
and increases lymphocyte apoptosis. Although up-
regulation of ACE2 receptors from ACE inhibitor
and angiotensin receptor blocker medications has
been hypothesized to increase susceptibility to
SARS-CoV-2 infection, large observational cohorts
have not found an association between these
medications and risk of infection or hospital
mortality due to Covid-19 (Al-Kuraishy et al.,
2020d).
ANTI-COVID-19 MEDICATIONS
Numerous dissimilar beneficial options like
anti-malaria, HIV medications, antivirals, and
steroids have been tried with limited results. The
most notable was the considerate use of
remedisivir in the scenery of Covid-19 infection.
The innovative data primarily fortified the FDA to
approve this medication for use in Covid-19
infections, but additional clinical trials have not
been able to support significant clinical benefit.
Presently, no therapeutic agents have been
established to be effective in plummeting the
mortality and treatment of patients with Covid-19.
There is some apprehension near the low
distribution of these drugs in the respiratory
system. One of TMPRSS2 inhibitors with a greater
distribution capacity into the lung tissue is
bromhexine hydrochloride (Hoffmann et al., 2020).
Bromhexine is planned to support the body's
mechanisms for clearing mucus from the respiratory
tract. It is secretolytic and increasing the
production of serous mucus in the respiratory tract,
which makes the phlegm thinner and less viscous
(Zanasi et al., 2017). This donates to secreto-
motoric effect, allowing the cilia to more easily
transport the phlegm out of the lungs. For this
reason, it is often added to cough syrups. It has
been shown to increase the proportion of serous
bronchial secretion, making it more easily
expectorated. It is indicated as secretolytic therapy
in bronchopulmonary diseases associated with
abnormal mucus secretion and impaired mucus
transport. Bromhexine is contained in various
formulations, high and low strength syrups
(8 mg/5 mL, 4 mg/5 mL), tablets and soluble tablets
(both with 8 mg bromhexine) and solution for oral
use (10 mg/5 mL), adapted to the need of the
patients. The posology varies with the age and
weight, but there are products for all age groups
from infant on. Bromhexine is well established and
tolerated (El-Sayed and Hashem, 2020).
ANTI-SARS-COV-2 EFFECTS OF BROMHEXINE
Blocking the non-endosomal pathway might be
an effective option to control Covid-19 infection.
The TMPRSS2 could be a good target to prevent
viral infection by blocking the fusion and priming
the processes of the virus (Li et al., 2020). There are
some medications such as camostat mesylate or
nafamostat, which are used in chronic pancreatitis
to inhibit the TMPRSS2 and eventually cell entry of
SARS-COV-2 (Depfenhart et al., 2020).
TMPRSS2 is a member of the type II
transmembrane serine protease (TTSP) family.
TTMPRS2 is expressed in the lungs, kidneys, and
prostate. It has been shown that the presence of
TMPRSS2 is very essential for the influenza virus
infection (Shrimp et al., 2020). TMPRSS2 cleaves the
surface glycoprotein hemagglutinin (HA) of the
influenza virus and ensures virus fusion and
propagation. The inhibition of TMPRSS2 by
bromhexine can prevent influenza infection (Fu et
al., 2020). As well to bromhexine, other synthetic
inhibitors of TMPRSS2 have been developed and
have demonstrated efficacy in preventing influenza
infection. However, these inhibitors also have
strong affinities for other proteases, such as
matriptase, making their precise therapeutic
mechanism unclear (Rosa and Santos, 2020).
TMPRSS2 expression in the prostate is driven by
androgen receptor signalling. TMPRSS2 mRNA
expression is upregulated and remains elevated in
androgen-stimulated prostate cancer. The admin-
istration of bromhexine hydrochloride, an inhibitor
of TMPRSS2, was able to suppress distant
metastasis to the liver and lungs sites in mice
models via modulating of ERG oncogene (Song et
al., 2020). This link between androgen receptor
signalling and TMPRSS2 expression could explain
the higher prevalence and severity of coronavirus
in males as compared to females (Kron et al., 2017).
Bromhexine is a potent inhibitor of TMPRSS2, a
key protease in the infection and transmission of
novel coronavirus SARS-CoV-2, bromhexine has
the advantage of low price and greater safety
(Sagawa et al., 2020). Also, bromhexine and its
Al-Kuraishy et al. [Potential role of Bromhexine in COVID-19]
Curr Med Drug Res, 2021, 5 (1), Article ID 212 Page 3
metabolites can competitively bind to cellular
receptor angiotensin-converting enzyme 2 (ACE2).
This strongly inhibits the key M proteases of novel
coronavirus SARS-Cov-2, promotes the release of
endogenous active substances in the lungs,
maintains alveolar function, and promotes sputum
excretion (Sanders et al., 2020).
Related studies have pointed out that effective
drugs to prevent novel coronavirus infection must
contain either TMPRSS2 inhibitors or competitive
ACE2 binding inhibitors, and it is particularly
recommended that bromhexine, a specific
TMPRSS2 inhibitor, be used to prevent and treat
Covid-19 (Fig. 3) (Azimi, 2020). In addition, several
university and institutional experts have jointly
published articles to evaluate the importance of
TMPRSS2 for respiratory virus infection and
introduce the therapeutic potential of bromhexine
as a TMPRSS2 inhibitor for Covid-19 (Barzegar et
al., 2021).
Fig. 3. Bromhexine blocks TMPRSS2 during SARS-
CoV-2 invasion
A combination of bromhexine and amoxicillin
in lower respiratory tract infection enhance clinical
effectiveness. Additionally, patients in the group of
bromhexine had a significantly greater reduction of
their symptom scores for symptoms of cough
discomfort, cough frequency, ease of expectoration
and sputum volume. The patients taking
bromhexine had treated rapidly of pneumonia
(Azimi, 2020). The role of the mucociliary system in
the development of immunity and protection
against microorganisms is very important.
Bromhexine is also used to treat coughs caused by
bronchitis, chronic obstructive pulmonary disease
(COPD) or cystic fibrosis (Al-Kuraishy et al.,
2020e). Accordingly, the effect of bromhexine
metabolites in children with respiratory disorders,
the positive effect of this drug was observed in the
treatment of sputum caused by respiratory
infections. Hence is likely to be beneficial for the
treatment of Covid-19 to prevent viral entry, the
drug should be an ACE2 (angiotensin-converting
enzyme 2)-binding inhibitor or TMPRSS2-specific
inhibitor. It is of great importance to conduct some
trials on the efficacy of bromhexine as a
prophylactic or curative agent in Covid-19 patients
(Al-Kuraishy et al., 2020f).
The mechanism of bromhexine is inhibition of
TMPRSS2, since this pathway showed its effect in
patients with the Middle East respiratory syndrome
(MERS) and severe acute respiratory syndrome
(SARS) some years ago (Al-Kuraishy, 2021). In an
ongoing trial, bromhexine hydrochloride is given
to Covid-19 patients as a mucolytic agent to
suppress cough in patients with suspected Covid-
19 in China which shows the effectiveness of this
drug to suppress cough (AI-Kuraishy and AI-
Gareeb, 2020). Also, bromhexine may have a main
role in the prevention of Covid-19. There is no
absolute contraindication reported for bromhexine,
except for rare allergy reactions to bromhexine.
Meanwhile, only a few adverse effects of
bromhexine are reported such as nausea, vomiting,
diarrhoea and fever. For these reasons,
bromhexine is a safe drug. It should be noted that,
by preventing the progress of Covid-19 by using
bromhexine, the renal involvement by SARS-CoV-2
may be indirectly prevented or ameliorated, while
acute kidney injury is frequently observed in
severe Covid-19 patient (Al-Niemi et al., 2021).
Moreover, the use of bromhexine as a prophylactic
and in a favourable combination with hydroxyl
chloroquine as an effective endosomal protease
inhibitor for the treatment of moderate to severe
COVID-19 cases (Al-Kuraishy et al., 2020g).
CONCLUSION
Bromhexine is an effective drug in the
management and treatment of Covid-19 pneumonia
via targeting ACE2/ TMPRSS2 pathway. However,
prospective and controlled clinical trials are
recommended to confirm this observation.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
DECLARATION
The contents of this paper are published after
receiving a signed copyright agreement from the
corresponding author declaring that the contents of
this paper are original. In case of any dispute
related to the originality of the contents, editors,
reviewers and publisher will remain neutral.
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How to cite this article?
Al-Kuraishy HM, Al-Niemi MS, Hussain NR, Al-Gareeb AI,
Lugnier C (2021). The potential role of Bromhexine in the
management of COVID-19: Decipher and a real game-
changer. Current Medical and Drug Research, 5 (1),
Article ID 212.
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