Complementary Intervention for COVID-19

Since last December 2019, a syndrome of severe pneumonia associated with the coronavirus
disease 2019 (COVID-19) emerged in Wuhan, Hubei Province, China. It is highly contagious and
rapidly spread to many other parts of China and almost all countries all over the world,
representing one of the most aggressive pandemics ever reported.

To date, April 21, 2020, More than 2.5 million persons were infected and more than 171.000
deaths with more fears all over the world from the multiplication of the total deaths. This
huge no. of patients made a horrible pressure on health care facilities in all countries and
lots of patients were not able to receive the appropriate medical care in hospitals WHO
declared that to date, there is no specific medicine recommended to prevent or treat the
novel coronavirus. However, in China, historically, when the outbreak started, Traditional
Chinese medicine (TCM) approaches including oral administration of preventive herbal
formulae, wearing TCM sachets, indoor herbal medicine fumigation, etc. were recommended for
prevention and treatment.

For example, in 2003, TCM approaches were used to prevent and treat severe acute respiratory
syndrome (SARS) which was the most serious infectious disease outbreak in China prior to the
COVID-19. In 2009, during the pandemic of H1N1 influenza around the world, the National
Administration of Traditional Chinese Medicine of China issued a CM prevention program, which
included 4 Chinese herbal medicine (CHM) formulae for adults of different CM body
constitutions and one for children. The current outbreak of COVID-19 resulted in many
provinces in China issuing CM prevention and control programs, among which the prevention
programs are mainly oral CHM formulae.

Glycyrrhizin, a component of many formulae, has reported having anti-inflammatory, antiviral
and antioxidant properties. Also, Boswellia Gum Resin has many active components that have
many medicinal properties such as antimicrobial, antioxidant, antifungal, anti-inflammatory,
immuno-modulatory.

Efficacy:

1. The two agents have broad-spectrum antiviral effects in-vitro and in in-vivo in
preclinical and clinical studies:

A. There are clinical studies about the efficacy of licorice in severe acute respiratory
syndrome-related coronavirus, This can be of major importance in the coronavirus
infections, since immunodeficiency patients may be particularly at risk.

B. There are traditional use and clinical experience of Chinese traditional Medicine
containing licorice in the treatment of COVID 19.

2. The two agents have anti-inflammatory effects and blocking the production of cytokines
which are the main causes for the severity of diseases.

3. The two agents have antioxidant effects, prevent tissue damages in the lungs.

4. The two agents inhibit the airway mass hyperplasia so, they alleviate anoxia state and
improve clinical symptoms.

5. The two agents are used in the treatment of bronchial asthma and respiratory
inflammatory disorders.

6. Licorice has antithrombin and antiplatelet effects so, it alleviates the
hypercoagulation induced by COVID 19.

7. Licorice enhances the production of interferon-gamma that has high activity against the
replication of the virus.

Safety:

1. Licorice and Boswellia Gum Resin had been considered as a food supplement or nutritional
agents, so they have high safety margins in recommended doses, However, there is a
contraindication for the use of licorice in non controlled hypertensive patients.

2. Hypertensive patients and patients sensitive to hypokalemia are excluded from this
study. Regarding other patients, many studies documented that Hypertension may develop
as an adverse reaction after chronic use of large doses.

3. Excessive consumption of licorice for a long time (more than 2 mg/kg/day of pure
glycyrrhizinic acid, a licorice component) may result in adverse effects, such as
hypokalemia, increased blood pressure, and muscle weakness. People with previously
existing heart or kidney problems may be more susceptible to GZA and licorice poisoning.
It is important to monitor the amount of licorice consumed in order to prevent toxicity.

More interesting, It has been shown that monoammonium glycyrrhizinate injection or
glycyrrhizic acid exerts a protective influence on myocardial ischemic injury induced by
isoproterenol by inhibiting oxidative stress and regulating Ca2+ homeostasis, therefore, it
may be useful in the management of myocardial ischemic injury.

Isoliquiritigenin has reported having a significant anti-platelet action in vivo by
inhibiting cyclooxygenase and lipoxygenase or peroxidase activity in platelets.

Glycyrrhizin (GL) elicits effective antithrombotic action (prevent thrombosis), as it was
considered as an effective thrombin inhibitor.

However, the most important side effect is the induction of hypertension, and it can induce
what appears to be pseudohyperaldosteronism, due to glycyrrhetinic acid the main active
component of the root. Glycyrrhetinic acid and metabolites block the 11 beta-hydroxysteroid
dehydrogenase type 2 and also bind mineralocorticoid receptors directly, acting as agonists.

Boswellia serrate (B.serrata) is used traditionally to treat chronic inflammatory diseases
such as in acute systemic inflammation, accompanied liver dysfunction, and chronic
inflammatory diseases. Recent studies show that Boswellia serrate can improve the clinical
outcomes along with conventional therapies in ischaemic stroke. This action is due to the
anti-inflammatory properties of the main bioactive compounds Boswellic acids (BAs). It
inhibits the pro-inflammatory cytokines such as interleukin-1 β (IL-1 β), tumor necrosis
factor-α (TNF-α), interferon-gamma (IFN-γ), and inhibit 5-lipoxygenase (5-LOX) and therefore
shuts down mechanisms of leukotrienes, which are inflammatory mediators.

Many studies investigate the role of Boswellia serrata for the treatment of various
inflammatory conditions of respiratory disorders such as asthma, bronchitis, and laryngitis,
and cough. The anti-asthmatic potential of Boswellic acid which possesses significant
anti-inflammatory activities, the data suggest that the mechanism by which it effectively
treats bronchial asthma is based on reductions of Th2 cytokines via inhibition of a signal
transducer and activator of transcription (pSTAT6) and GATA-3 expression and inhibit
leukotriene biosynthesis which suppressed allergic airway inflammation. This treatment showed
improvement of disease as evidenced by the disappearance of physical symptoms and signs such
as dyspnea, rhonchi, number of attacks, as well as a decrease in the eosinophilic count.

The antiviral effect of Boswellia serrata and its components as boswellic acid was
investigated against HSV-1, Chikungunya virus (CHIKV) and vesicular stomatitis virus, the
mechanism of the effect of Boswellia acids against Herpes Simplex Virus (HSV) may through the
inhibition of nuclear factor - kappa B (NF-κB), essential for virus replication, and observed
significant down-regulation of NF-κB, and the mitogen-activated protein kinase (p38
MAP-kinase) activation, in addition, to reduce expression of tumor necrosis factor (TNF)-α,
Interleukin (IL)-1β and IL-6. Also, boswellic acid had been used in the outbreak of
Chikungunya virus (CHIKV) a broad antiviral agent by blocking of entry of CHIKV
Env-pseudotyped lentiviral vectors and inhibited CHIKV infection in vitro.

. Pharmacokinetic studies

Aim of the work:

To evaluate the therapeutic role of Licorice extract and Boswellia serrate gum as a
complementary intervention in addition to conventional therapy in Egyptian patients with
COVID-19.

All included patients will be diagnosed according to the Egyptian Ministry of Health and
population criteria for COVID-19 diagnosis:

Epidemiological history:

1. History of travel to or residence in communities where cases reported within 14 days
prior to the onset of the disease

2. In contact with viral RNA positive people within 14 days prior to disease onset.

3. In contact with patients who have a fever or respiratory symptoms from communities
confirmed cases reported within 14 days before disease onset Clinical features:

1. Fever and/or respiratory symptoms. 2. Imaging characteristics. 3. The white blood cell
count was normal or decreased, with lymphocyte decreased.

Diagnosis of any suspected patient should follow the following criteria:

1. Anyone of the epidemiological history with any of the clinical features. OR

2. All three clinical features. OR

3. Severe Acute Respiratory Infection (SARI) with no other obvious cause.

Confirmed Cases:

1. RT-PCR indicates positive for novel coronavirus RNA

2. Viral specific IgM and IgG are detectable in serum

3. Viral specific IgG is detectable from negative to positive, OR

4. Viral specific IgG antibody reaches a titration of at least 4-fold higher in the
recovery stage than in the acute stage.

All patients will have the following investigations:

1. X-ray chest/CT chest

2. CBC with differential count>, total blood picture

3. Arterial Blood Gas Test (ABG).

4. C-reactive protein (CRP)

5. D-Dimer.

6. Serum ferritin.

7. Triglycerides.

8. Fibrinogen.

9. Serum aspartate aminotransferase.

10. Renal functions.

11. Troponin T, Troponin I, if myocarditis is suspected. The study will be launched in at
least one center related to the Ministry of Health and following the protocol
recommended by the Scientific Committee and its dynamic changes that occur from time to
time.

The study population will be divided into two groups of patients:

A- Group 1: Will include patients who are receiving conventional therapy according to the MOH
protocol.

B- Group 2: Will include patients who will receive Licorice and Boswellia Serrata gum in
addition to conventional therapy.

Dosage form:

LICORICE CAPSULES; 250 mg standardized extract (25% Glycyrrhizin - 62.5 mg).

Dose:

One capsule, Two times daily, before meals For 10 days, with measuring blood pressure daily.

Boswellia serrata Gum Resin; B. serrate contains volatile oils (5-15%), pure resin (55-66%),
and mucus (12-23%). The resin contains terpenoids, phenolic compounds, flavonoids, and
phenylpropanoids. More than 12 different Boswellic acids have been identified, the amounts of
11-keto-β-boswellic acid KBA is 3-4.7% and acetyl-11-keto-β-boswellic acid(AKBA) is 2.2-2.9%,
Dose: 2 gm, 4 times daily For 15 days, Boswellia Gum Resin is administered by chewing for the
half-hour

Statistical analysis:

All data will be analyzed statistically by using Statistical Product and Service Solutions
(SPSS) version 18, to detect any statistically significant differences between the two groups
which include comparing the 2 groups in all clinical and laboratory variables and statistical
significance was considered when p-value <0.05, also will use univariate and multivariate
analysis to show if any differences in the 2 groups.