Research International Journal of Endocrinology and Diabetes
Re Int Jou of end and dia
© 2020 MSD Publica ons. All rights reserved. 018
Volume 1 Issue 1 - 1005
Mini Review
Eff ects of Quadruple Therapy: Zinc, Quercetin, Bromelain
and Vitamin C on the Clinical Outcomes of Patients
Infected with COVID-19
Amr K. Ahmed1, Yousef S. Albalawi2, Hassan A. Shora3*, Hiba. K. Abdelseed4 and
Abdulla N. Al-Kattan5
1Tuberculosis Control Program, Mobile Team, Ministry of Health, Saudi Arabia.
2Medical Hospital Director, Elmam AbdelRahman lfaiasal Hospital, Saudi Arabia.
3Department of Biochemistry, Port-said University, Egypt.
4Tuberculosis Control Program Coordinator, Riaydh Ministry of Health, Saudi Arabia.
5Pharmacology Candidate, Ministry of Health, Saudi Arabia.
*Address for Correspondence: Hassan Shora, Senior Researcher, Port-Said University & Head of Medicine and Diabetes
Center, Ismailia General Hospital, Ismailia 064, Egypt. E mail: Hassanshora56@gmail.com
Received: 01 August 2020; Accepted: 28 August 2020; Published: 29 August 2020
Citation of this article: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy:
Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and
Diabe. 1(1): 018-021. DOI: 10.37179/rijed.000005.
Copyright: © 2020 Ahmed AK, et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction
A novel infectious disease, caused by severe acute respiratory
syndrome coronavirus 2 (SARS-Cov-2), was detected in Wuhan,
China, in December 2019. e disease (COVID-19) spread rapidly,
reaching epidemic proportions in China, and 27 other countries. No
speci c therapeutics are available, and current management includes
travel restrictions, patient isolation, and supportive medical care.
ere are several pharmaceuticals already being tested [1].
Coronavirus disease 2019 (COVID-19) is an acute respiratory
disease that can lead to respiratory failure and death. Patients with
chronic respiratory diseases, such as chronic obstructive pulmonary
disease (COPD) and asthma, would be anticipated to have an
increased risk of infection and a more severe disease [2].
ABSTRACT
COVID-19 emerged in Wuhan, China in December 2019, reached epidemic proportions and spread globally as a serious life-threatening
pandemic. SARS- Cov-2 is the causative virus that causes severe acute respiratory distress, pneumonia, respiratory failure, and septic shock
leading to increased mortality. High risk patients include those with chronic non-communicable diseases such as diabetes, hypertension,
coronary heart disease and cancers. No speciic treatment is available and supportive care all that could be done to rescue patients. Quadriple
therapy consisting of Zinc, Quercetin, Bromelain and Vitamin C showed promising results in improving clinical outcome among COVID-19
patients.
Keywords: COVID-19, Cytokines, zinc, Quercetin, Bromelain, Vitamin C.
Citation: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy: Zinc,
Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and Diabe.
1(1): 018-021. DOI: 10.37179/rijed.000005.
019
Volume 1 Issue 1 - 1005
Re Int Jou of end and dia
© 2020 MSD Publica ons. All rights reserved.
e pathogen, a novel coronavirus (SARS-CoV-2), was identi ed
by local hospitals using a surveillance mechanism for “pneumonia
of unknown etiology” that was established in the wake of the 2003
SARS outbreak with the aim of allowing timely identi cation of novel
pathogens [3].
e immune system plays a critical role in protecting the
human body from infectious diseases [4]. T-cell counts are reduced
signi cantly in COVID-19 patients, and the surviving T-cells appear
functionally exhausted. Non-ICU patients with total T cells counts
lower than 800/μ L may still require urgent intervention, even in
the immediate absence of more severe symptoms due to a high risk
for further deterioration in condition [5]. Further research on the
severity of comorbidities and all medication received by the patients
is mandatory to shed light on these associations [2] (Figure 1).
Vit c
Vitamin C exerts its antiviral properties by supporting lymphocyte
activity, increasing interferon-α production, modulating cytokines,
reducing in ammation, improving endothelial dysfunction, and
restoring mitochondrial function [9].
ere are also suggestions that vitamin C may be directly
viricidal. e in vitro e ects constitute a re ection of both the supra-
physiological concentrations of ascorbate and the interaction between
vitamin C and metal-containing culture media—both of which are
pro-oxidant, generating reactive oxygen species [10].
Quercetin (Que)
Quercetin (Que), (also known as 3,3’,4’5,7-pentahydroxy avone),
is a widely distributed plant avonoid, found in several vegetables,
leaves, seeds, and grains, where it is conjugated with residual sugars
to form Que glycosides. Studies suggest that Que supplementation
may promote antioxidant, anti-in ammatory, antiviral, and
immunoprotective e ects. Quercetin has been studied in various
types and models of viral infection due to its promising antiviral
e ects in inhibiting polymerases, proteases, reverse transcriptase,
suppressing DNA gyrase, and binding viral capsid proteins [11].
Recently, Que has been shown to inhibit in vitro production
of cyclooxygenase (COX) and lipoxygenase (LOX) which are
typically induced by in ammation. e anti-in ammatory e ect
has been supported by in vivo experiments as well. Examples of
Que’s inhibitory qualities include the signi cant blocking of pro
in ammatory cytokines in cultured broblasts. 10 𝜇M Que down
regulated the production of COX-2, the Nuclear Factor kappa B (NF-
𝜅B), and NO. 10–25 𝜇M Que inhibited the level of NO and TNF-𝛼.
Other properties of 50 and 100 𝜇M Que include reducing
the secretion of IL6 and TNF-𝛼 in LPS-stimulated RAW 264.7
microphages, while at 25 and 50 𝜇M it proved to be the most
e cient blocker of TNF-𝛼 secretion in macrophages. Finally, at
low concentrations, Que (less than 50 𝜇M) also stimulated anti-
in ammatory cytokine IL-10. Similarly, 25𝜇M Que blocked IL-1𝛽,
IL-6, IFN-𝛾, and TNF-𝛼 secretion in human whole blood induced by
LPS [12].
Quercetin can also inhibit pro in ammatory cytokines. A six-
week regiment of 150 milligrams of Que taken daily by human
subjects signi cantly lowered cytokine TNF-𝛼 serum concentrations
[12]. Quercetin e ectively inhibited LPS-induced DC activation by
reducing the production of proin ammatory cytokines/chemokines
and the expression levels of MHC class II and costimulatory
molecules. In addition, quercetin uniquely blocked endocytosis
by Dendritic Cells DCs and the LPS-induced DC migration was
diminished by quercetin treatment [13].
Quercetin has been shown clinically to block human mast cell
cytokine release, possibly inhibiting the clinical manifestation of
cytokine storm. Severe COVID-19 disease progression is associated
with increased levels of C-Reactive protein, D-Dimer, Ferritin, IL-
2, and IL-6. Quercetin has been shown in studies to reduce all these
markers [14].
Figure 1: Cytokine storm.
Discussion
The role of Zinc:
Since the discovery of the rst reported case with zinc-de ciency
in Iran by Prasad et al. in 1961 [6], we have learned a lot about Zinc,
and we have much more le to learn. Zinc is the second most abundant
common trace mineral in the human body, with vital biological
functions from cell growth and development to cell homeostasis and
immune response [7].
Mechanical ventilation is a necessary intervention to support
patients with lung injury and the acute respiratory distress syndrome
(ARDS) but can also exacerbate injury through mechanical stress-
activated signaling pathways. It is showed that stretch applied to
cultured human lung cells, and to mouse lungs in vivo, induces
robust expression of metallothionein, a potent antioxidant and
cyto-protective molecule critical for cellular zinc homeostasis.
Furthermore, genetic de ciency of murine metallothionein genes
exacerbated lung injury caused by injurious mechanical ventilation,
identifying an adaptive role for these genes in limiting lung injury.
Stretch induction of metallothionein required zinc and the zinc
binding transcription factor MTF-1. We further show that dietary
zinc-de ciency in mice potentiates ventilator-induced lung injury,
and that plasma zinc levels were signi cantly reduced in human
patients with ARDS compared to healthy and non-ARDS ICU
controls [8].
Citation: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy: Zinc,
Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and Diabe.
1(1): 018-021. DOI: 10.37179/rijed.000005.
020
Volume 1 Issue 1 - 1005
Re Int Jou of end and dia
© 2020 MSD Publica ons. All rights reserved.
Balancing systemic iron levels within narrow limits is critical
for maintaining human health. ere are no known pathways to
eliminate excess iron from the body and therefore iron homeostasis is
maintained by modifying dietary absorption so that it matches daily
obligatory losses. Several dietary factors can modify iron absorption.
Polyphenols are plentiful in human diet and many compounds,
including Que – the most abundant dietary polyphenol – are potent
iron chelators [15].
Quercetin is a zinc ionophore and could have similar antiviral
activity of chloroquine but described as safe choice in the treatment
of viral infections [16].
Bromelain
Bromelain activates the in ammatory mediators, including
interleukin (IL)-1β, IL-6, interferon (INF)-γ and tumor necrosis
factor (TNF)-α in mouse macrophage and human peripheral blood
mononuclear cells (PBMC) (Barth). ese results indicated that
bromelain potentially activates the healthy immune system in
association with the rapid response to cellular stress. Conversely,
bromelain reduces IL-1β, IL-6 and TNF-α secretion when immune
cells are already stimulated in the condition of in ammation-induced
over production of cytokines [17].
It was also found that bromelain upregulated p53 and Bax
with consequent activation of Caspase 3 and Caspase 9 with
concomitant decrease in BCL2. Marked inhibition of cyclooxygenase
2 (COX2) expression with inactivation of NF Kappa B by blocking
phosphorylation and degradation of IK B α were blocked by
bromelain. Furthermore, bromelain ameliorated extracellular signal
of regulated protein kinase ERK1/2, P38 mitogen activated protein
kinase MAPK and Akt activity. So, it modulated defective cellular
signaling cascades [18].
Bromelain prevents or minimizes the severity of angina pectoris
and transient ischemic attack (TIA). It is useful in the prevention and
treatment of thrombophlebitis. It may also break down cholesterol
plaques and exerts a potent brinolytic activity. A combination of
bromelain and other nutrients protect against ischemia / reperfusion
injury in skeletal muscle. Bromelain in uences blood coagulation by
increasing the serum brinolytic ability and by inhibiting the synthesis
of brin, a protein involved in blood clotting [19, 20] (Figure 2).
Conclusion
e dreadful pandemic caused by SARS-CoV2 led to extremely
high morbidity and mortality worldwide. ere is no speci c therapy
and only supportive treatment to rescue patients’ life is the only
available option. A novel Quadriple therapy consisting of Zinc,
Quercetin, Bromelain and Vitamin C shows a promising positive
therapeutic e ect. is mini review is the basis of our running clinical
controlled trial and results will be available nearly.
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Citation: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy: Zinc,
Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and Diabe.
1(1): 018-021. DOI: 10.37179/rijed.000005.
021
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© 2020 MSD Publica ons. All rights reserved.
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