Running title: Effectiveness of Bromhexine in COVID-19
Prophylaxis
Milad Shirvaliloo1*, Roghayeh
Sheervalilou2
1Faculty of Medicine, Tabriz University of Medical
Sciences, Tabriz, Iran
2Cellular and Molecular Research Center, Resistant
Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan,
Iran
*Corresponding author :
Milad Shirvaliloo
Tabriz University of Medical Sciences
ORCID: https://orcid.org/0000-0001-5122-1274
Phone No: +989924567949
E-mail:
shirvaliloo@tbzmed.ac.ir
Postal code: 5166/15731
Dear Editor,
Since the early 2020, many countries around the world have become
afflicted with COVID-19, a respiratory infection caused by SARS-CoV-2,
that rapidly turned into an overwhelming pandemic, comparable to
devastating outbreaks such as the Spanish flu. As the well-funded
investigational efforts to develop preventive strategies and therapeutic
agents continues in the developed countries, new concerns regarding the
prospective waves of coronavirus infection arise in the developing
countries, which simply do not have access to effective treatments that
have been adopted in the modern world. However, based on the most recent
evidence regarding the pathogenesis of SARS-CoV-2, there is hope that
certain cost-effective medications, such as bromhexine hydrochloride,
might actually prove useful in containment of COVID-19, either as an
outpatient treatment or a prophylactic measure.
Shortly after the publicity of COVID-19 outbreak, numerous
investigations were conducted on almost every aspect of the novel
coronavirus, particularly the pathogenesis of SARS-CoV-2. A number of
studies reported that the virus made its entry into the cell by means of
Transmembrane Serine Protease 2 (TMPRSS2), among several other
receptors, most notably, Angiotensin Converting Enzyme 2 (ACE2)
(Hoffmann et al., 2020). This was mostly similar to the entry mechanism
adopted by SARS-CoV and MERS-CoV, as both strains were reported to have
interactions with TMPRSS2, which ultimately resulted in the entry of the
virus to the susceptible host cell, following the activation of Spike or
S protein of the virus (Shen, Mao, Wu, Tanaka, & Zhang, 2017). Similar
results involving TMPRSS2 have also been documented with VeroE6 cells,
as expression of TMPRSS2 in these cells rendered them highly susceptible
to SARS-CoV-2 infection (Matsuyama et al., 2020).
It is speculated that ACE2 and TMPRSS2 function together in favor of
SARS-CoV-2 cell entry, with the former binding to the S protein on the
virion, and the latter priming it, so that the virion can enter the
cell. During the priming, TMPRSS2 cleaves the S protein at the S1/S2
arginine-rich site of the viral protein. However, the action of TMPRSS2
does not seem to be solely restricted to processing of the S protein, as
it was indicated that this serine protease might also be involved in
regulation of the assembly of viral particles in the Golgi apparatus,
before the virions can be expelled from the cell (Hoffmann et al.,
2020). Investigations on the expression profile of TMPRSS2 and ACE2 in
the bronchial and alveolar tissue of the lung indicated that TMPRSS2 can
be found in both cell types, however, ACE2 is chiefly produced by
transient secretory cells located in the subsegmental bronchial
epithelium (Lukassen et al., 2020). Since it is more widely distributed
in the lung, TMPRSS2 can be regarded as a key factor involved in the
pathogenesis of SARS-CoV-2, which can be duly inhibited by specific
drugs that have been in use for a long time, particularly bromhexine
hydrochloride.
Most commonly recognized as an expectorant or cough syrup, bromhexine
hydrochloride is a mucolytic drug known to many communities since its
introduction back in 1963. As the drug class “mucolytic” might
suggest, bromhexine is often prescribed for treatment of illnesses
associated with excessive production of phlegm, as a result of
disturbances in normal mucous secretion by the secretory cells in the
epithelium of the bronchi. An investigation in 2014 on prostate cancer
metastasis revealed that bromhexine hydrochloride possessed certain
properties that made it a potent inhibitor of TMPRSS2, selectively
targeting the transmembrane serine protease 2 with an
IC50 of 0.75 μM (Lucas et al., 2014). This finding is of
crucial significance now, as TMPRSS2 is widely expressed in the lung,
and has been indicated to be involved in the cell entry of the novel
coronavirus (Lukassen et al., 2020).
As a mucolytic drug, bromhexine hydrochloride comes with several
important advantages. It is an over-the-counter (OTC) drug, that can be
purchased without a prescription. It is an affordable medication, that
is well tolerated by most of the patients, and has not been known to
cause any major adverse effects (Depfenhart, de Villiers, Lemperle,
Meyer, & Di Somma, 2020).
As Dr. Tedros Adhanom Ghebreyesus, World Health Organization (WHO)
Director-General, said “Pandemic is not a word to use lightly or
carelessly.” The COVID-19 pandemic has indeed posed a great challenge
to the entire world, but more importantly, the developing countries and
the less fortunate communities, that are struggling to contain the
insidious outbreak. Due to the scarcity of the recently developed
treatments and also the long-known expensive medications, it is totally
clear that cheaper and more affordable methods should be adopted by the
underdeveloped countries. With due attention to the safety of bromhexine
hydrochloride, it might be a reasonable strategy to adopt this
medication for outpatient management of patients with mild disease, or
even advise to use it as a prophylactic measure to communities that
might be in great risk. It must be clarified that despite the evidence
discussed in this paper, precise clinical trials are required to
appraise the effectiveness of this long-known mucolytic drug in
treatment of COVID-19, and potentially prophylaxis against it.
Keywords : Bromhexine, SARS-CoV-2, TMPRSS2, ACE2