text: Parthiba Ghosh1, Susmita Patra2, Susmita Roy1, Bipasha Mukherjee1, Pallab Kanti Haldar2 and Asis Bala1*
  1Division of Pharmacology, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F Nilgunj Road, Panihati, Kolkata-700114, West Bengal, India
  2Phytotherapy and Pharmacology Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata – 700032, West Bengal, India
  *Corresponding author: Asis Bala, Division of Pharmacology, West Bengal, India
  Submission: July 30, 2021;Published: August 05, 2021
  ISSN: 2576-9170 Volume3 Issue3
  The theory behind the madness of azithromycin for the treatment of COVID-19 is unclear as no significant evidences are available till date. The present study aimed to discuss about the comprehensive pharmacology of azithromycin and to explore the preclinical and clinical evidences repurposing for COVID-19. Here we reviewed briefly the current knowledge about COVID-19, considering the potential explanation for the repurpose of azithromycin for this pandemic disease condition and global crisis. Azithromycin alone or in combination with Hydroxychloroquine (HCQ) modulate the anti-inflammatory processes and decreases the susceptibility to secondary bacterial pneumonia. We highlighted potential approaches to address repurpose of azithromycin for COVID-19.
  Keywords: Azithromycin; Comprehensive pharmacology; Repurposing for COVID-19; Immunomodulatory activity; Combination therapy for COVID-19
  Azithromycin is a well-known broad-spectrum antibiotic amongst the macrolide group,
  primarily used for upper and lower respiratory tract infection . Recently it is repositioned
  for the treatment of covid-19 pandemic . However, some circumstantial scientific reports
  suggest that Azithromycin (AZ) in combination with hydroxychloroquine decrease the
  viral load in Covid patients . The open level non- randomized clinical trial carried out
  by Gautret and co-workers stated that the patients treated with hydroxychloroquine and
  azithromycin had 100% recovery rate after 5-6 days, compare to 57.1% of subjects treated
  with hydroxychloroquine only, and 12.5% of untreated individuals . There are some
  controversies about the use of AZ in Coronavirus disease (COVID-19) [3-4]. This article
  represents the research findings regarding the molecular pharmacology of AZ and how it is
  correlated for the treatment of COVID-19.
  The immunomodulatory and antiviral properties of AZ and other macrolides was
  previously being established . It is well known that coronavirus disease (COVID-19) is an
  infectious disease caused by a newly discovered noble coronavirus . Epithelial cells are the
  primary target of this virus and Infection is mediated by cellular expression of Angiotensin-
  Converting Enzyme 2 (ACE2), a carboxypeptidase that binds to the spike proteins of SARSCoV-
  2; ACE2 is expressed by the epithelium of the mouth, tongue and upper airways, thus
  enabling endocytosis of the virus . Severity and mortality of COVID- 19 are associated with
  host’s uncontrolled inflammatory response due to the hyper production of reactive oxygen
  species and cytokines .
  Macrolide antibiotics have promising activity against various respiratory viral disease
  reported in different studies. Azithromycin significantly reduced inflammatory cytokines such as cytokines IL-6 and IL-8 and so far, increase the production of IFN
  -gamma and IFN -gamma stimulated genes expression established
  in Human bronchial epithelial cells in an in vitro condition . AZ
  favouring tissue repair after inflammation by shifting helper T cell
  phenotype from type I to type II, reported by Murphy et al.  & .
  Several studies have been reported about the anti-inflammatory
  activities of AZ. AZ significantly reduced the production of proinflammatory
  cytokines IL-12 and IL-6, increased production of
  the anti-inflammatory cytokine IL-10 as shown in Figure 1; .
  Preclinical research found that AZ attenuated the accumulation of
  inflammatory cells in the lung tissue and significantly decreased
  the aggregation of macrophages, lymphocytes and neutrophils .
  Figure 1: The schematic representation of Azithromycin mechanism of action for inhibiting the viral translation and the possible way of explaining the immunomodulating role of Azithromycin.
  CD147 is a transmembrane receptor glycoprotein, present
  in host epithelial cell responsible for interaction with Covid-19
  spike protein. Thus, it mediates the viral entry inside the host cell
  . CD147 also present in RBC and inflammatory cells used as
  a receptor for parasite Plasmodium falciparum - protozoan that
  causes Malaria in humans and also regulates cytokine secretion
  and leukocytes chemotaxis. AZ interfere with the tight junction
  formation between spike protein and CD147 and prevents virus
  entry . Previously it was reported that Az blocks the invasion
  of Plasmodium falciparum in RBC. AZ reduces the expression
  of CD147 reported by other studies. CD147 known as inducer of
  extracellular matrix metalloproteinase, and CD147 functions as
  an upstream stimulator of Matrix Metalloproteinases (MMP’s). AZ
  exhibits reduced levels of MMP expression and activity, this may be
  associated to a reduced expression of CD147 in cells [12-14].
  COVID-19 considerably shows some higher mortality rate in
  geriatric patients as it was reported that the highest mortality rate
  was observed in patients aged ≥80 years. Patients aged >80 years
  had 60% higher risk of dead compared to patients with age 70 to79
  years . It was also seen that patients aged eighty and older on
  ventilators, the fatality rate was 90 percent [15,16]. This arise the
  question is to whether there is any correlation between ageing
  and COVID-19 infection. Cellular “senescence” defined as a state
  in which cells cease dividing and undergo distinctive phenotypic
  alterations, including profound chromatin and secretome
  changes, and tumor-suppressor activation . Senescence
  occurs throughout the lifespan including during embryogenesis
  and it plays very important role during development as well as
  wound healing [17,18]. There are certain kinds of biomarkers like
  CD26, ACE2 are express in senescent cell. Interestingly, these two
  receptors are used by COVID-19 for entering into the cell. Senescent
  cells produce large amounts of inflammatory cytokines, as a
  result of the senescence-associated secretory phenotype (SASP),
  including IL-6, increased protein synthesis, increased number of
  lysosomes. Corona virus uses the machinery of this cell which find as ideal cell for their replication . Azithromycin preferentially
  targets senescent cells, removing approximately 97% of them with
  great efficiency . AZ also acts as an anti-inflammatory agent and
  reduces SASP mediators such as IL-1 beta and IL-6. Interestingly Az
  inhibits the replication of other viruses, such as Zika and Ebola [18-
  21]. It can be predicted that senolytic agent can be useful for the
  treatment of COVID-19. In clinical trial Az shows its efficacy against
  Covid-19, combinely with Hydroxychloroquine may be due to its
  senolytic activity. Although clinical trials are needed to establish
  this hypothesis and repurposing efforts of Az against Covid-19
  There are some in vitro evidence that AZ may prevent replication
  of other viruses such as human influenza virus H1N1 and Zika virus.
  AZ and hydroxychloroquine combinedly inhibit the replication of
  SARS-CoVs 1 and 2 in in vitro, identified by Andreani et al. .
  It was reported previously that AZ prevents the replication and
  release of Rhinovirus (RV1B & RV16) [24,25].
  The review briefly explained the current knowledge about COVID-19, considering the potential explanation for the repurpose of azithromycin. Azithromycin modulates the antiinflammatory processes by modulating the Th1 and Th2 cytokine level as mentioned schematically in Figure 1. and decreases the susceptibility to secondary bacterial pneumonia.
  © 2021 Asis Bala. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and build upon your work non-commercially.