WO2021205196A1

WO2021205196A1 - Compositions and prevention and intervention methods for covid-19 with divine ayats' fitra30 covid-19 protocol

Info

Publication number: WO2021205196A1
Application number: PCT/IB2020/001140
Authority: WO
Inventors: Taliah MUHAMMAD
Original assignee: Muhammad Taliah
Priority date: 2020-12-30
Filing date: 2020-12-30
Publication date: 2021-10-14
Also published as: WO2021205196A4

Abstract

"Fitra30 COVID-19 Protocol" consists of treatments that stimulate healing mechanisms which are intrinsic to the host. This protocol consists of the features: 1) The Milhu Shamsi Herbal Formulation (MSHF), 2) Induction of autophagy, and 3) Divine Ayat's Spiritual, Mental, and Emotional Rejuvenation Program, wherein the Milhu Shamsi Herbal Formulation (MSHF) consists of 14 herbs which include Nigella saliva (Black Seed), Sassurea lappa (Indian Costus), Astragalus membranaceus (Astragalus), Paeonia lactiflora (Peony Root), Nelumbo nucifera (Lotus Seed), Panax ginseng (Ginseng), Radix Bupleuri (Bupleuri Powder), Artemisia vulgaris (Mugwort), Angelica archangelica (Angelica Root Powder), Ocimum tenuiflorum (Holy Basil), Citrus sinensis (Orange Peel Powder), Zingiber officinale (Ginger Powder), Rosa canina (Rosehip Powder), and Glycyrrhiza glabra (Licorice Root Powder).

Description

Compositions and Prevention and Intervention Methods for

COVID-19 with Divine Ayats’ Fitra30 COVID-19 Protocol

“Fitra30 COVID-19 Protocol” is a method comprising:

□ Identifying a human subject with COVID-19 and;

□ Establishing a regime for administering a composition to the subject;

□ The composition is formulated to restore stasis in all bodily systems and rid the body of COVID-19 compromising of Nigella sativa (Black Seed) and Sassurea lappa (Indian Costus) which are main active ingredients and;

□ At least one supplemental herb selected from the group consisting of; Astragalus membranaceus (Astragalus), Paeonia lactiflora (Peony Root), Nelumbo nucifera (Lotus Seed), Pan ax ginseng (Ginseng), Radix Bupleuri (Bupleuri Powder), Artemisia vulgaris (Mugwort), Angelica archangelica (Angelica Root Powder), Ocimum tenuiflorum (Holy Basil), Citrus sinensis (Orange Ped Powder), Zingiber officinale (Ginger Powder), Rosa canina (Rosehip Powder), and Glycyrrhiza glabra (Licorice Root Powder) collectively referred to as Milhu Shamsi “Sun Salt”™.

□ Intermittent fasting protocol based npnn Islamic Medicine designed to induce autophagy and increase antimicrobial peptides which includes a herbal formula entitled; “Autophagy Jump Start” consisting of the following herbs;

□ Vaccinium angustifolium (Wild Blueberry Powder), Andrographis paniculata

(Kalmegh Powder), Polygonum cuspidatum root (Japanese Knotweed Powder), and Glycyrrhiza glabra (Licorice Root Powder).

□ Divine Ayats’ Spiritual. Mental. and Emotional Rejuvenation (SMER) Program (Optional)

This is an optional therapy using methods of Islamic Medicine which consists of a 30 Day Guided Meditation online program and Journaling.

Nontypeable Haemophilus Influenzae (NTHI). a catalvst for COVID-19?

According to research on emerging pathogens published by the National Institutes of Health in 2015, Nontypeable Haemophilus Influenzae (NTHI) is a major cause of invasive disease worldwide (1). It is believed that this emergence may be partly due to increased NTHi colonization in children which might contribute to increased transmission to persons susceptible to developing invasive NTHi disease. Over the last 25 years in the U.S., the elderly have accounted for 89% of all invasive NTHI infections. Much like SARS-CoV-2, pre-existing diseases such as COPD, cancer, chronic renal failure, and diabetes place people at greater risk for contracting invasive NTHI (10, 203). However, it has been found that NTHI infections are not just found in persons with immunocompromising conditions or co-existing conditions but in almost half the cases in persons who were otherwise in good health (203).

Viral infections in patients colonized with NTHI may be atrisk for futureexacerbations asspecific viruses, like SAR-CoV-2. on top of a bacterial infection may significantly enhance the risk for excessive inflammation In a 2015 study, it was found that Nontypeable Haemophilus influenzae (NTHI) can enhance expression of the cellular receptor intercellular adhesion molecule 1 (ICAM-1) on airway epithelial cells, which in turn increases the binding of major group human rhinoviruses (HRVs) for attachment (9). Major group human rhinoviruses or HRVs are members of the Picomaviridae family. Like Coronaviruses or CoVs, they are a large family of single stranded RNA viruses. These viruses can cross species barriers and can cause, in humans, illness ranging from the common cold to more severe diseases such as MERS and SARS (8).

Many COVID-19 patients experience symptoms that are similar to symptoms presented by those who have COPD including frequent coughing, excess phlegm, shortness of breath, and trouble breathing (24). Recent studies have focused on the role of viral and bacterial coinfection in patients with COPD. This coinfection is associated with incidences of intensified respiratory disease and more inflammation (11). The most common co-infection is with rhinovirus (RV) and NTHI in COPD (12-13). NTHI also has significant and scientifically noted high morbidity risks for patients who smoke, or have Bronchiectasis, Cystic Fibrosis, Pneumonia, and Intestinal Lung Disease (14). These factors and diseases are also associated with increased risk of severe complications from COVID-19 (10).

NTHI is a very common gram-negative coccobacillus that colonizes the nasopharyngeal region in up to 80% of humans (5). It is present in the nose and throat of 50% of all children and is usually harmless until it moves to the middle ear or the lungs where it can cause the most damage. NTHI is a frequent cause of otitis media (chronic middle ear infections) (2) in children and acute bronchitis and pneumonia in patients with chronic obstructive pulmonary disease (3). Non-typeable Haemophilus influenzae (NTHI) has been associated with early pregnancy loss and in a 2020 report it was deemed an emerging neonatal and maternal pathogen (4).

This bacterium needs an iron rich environment to survive. Once NTHI has moved into the lungs and middle ear, heme iron is sequestered as part of the body’s immune response. Instead of (tying, the bacterium is kept alive by using clever hacks of the host's immune response (6).

Scientists Kevin M. Mason, PhD and Sheryl S. Justice, PhD, principal investigators in the Center for Microbial Pathogenesis figured out how NTHI was able to maintain a relatively low profile amongst clinicians with respiratory/pulmonary backgrounds and not be considered an important pathogenic bacterium. Their research shows that NTHI uses the body’s own immune system to its advantage. Once the immune system is alerted of a bacterial invasion in the lungs, middle ear, and other parts of the body, the immune system cuts off access to nutrients the bacteria need to survive- including heme iron. This process is known as nutritional immunity. This immune response triggers a series of additional immune defenses to include inflammation, which involves the release of chemicals that are designed to find and sequester NTHI and bring in white blood cells to the site of infection to destroy the invading bacterium

(6).

The scientist developed a lab experiment designed to imitate the immune response to NTHI infection in the middle ear and to further observe how NTHI responds to the body’s immune responses. The research results showed that in the body's immune response a serum designed to carry disease fighting chemicals and white blood cells to the site of the infection includes heme-iron. They further observed that when NTHI was re-exposed to heme-iron the bacteria underwent structural changes that allowed it to divide much more slowly and become elongated and spaghetti-like in appearance. As a result, the NTHI was ignored by the disease fighting white blood cells as they usually target rapidly dividing shorter cells. Thus, NTHI was left alone to replicate and thrive. “This clearly shows that NTHI is changing to become more fit in the host,” says Dr. Justice, who also is an assistant professor of pediatrics and urology at the Ohio State University College of Medicine (7).

Much like NTHI, SARS-Co-V-2 also has the abihty to block the host innate immune response through its links to the function of structural and non-structural proteins (202) which makes co-infection with invasive NTHI and SARS-Co-V-2 a severe threat to host morbidity.

Could Unregulated ICAM-1 in COVID-19 Patients Come from NTHI + SARS-CoV-2

To date it is believed that SARS-CoV-2 via its surface spike glycoprotein interacts with Angiotensin-converting enzyme 2 (ACE2) and invades host cells. ACE2 is expressed in human vascular endothelium, respiratory epithelium, and other cell types (182). Endothelial cells play an important role in virtually every system in the body. These cells form the inner lining of the cardiovascular and lymphatic systems. They make up the inner layer of blood and lymphatic vessels and organs including the brain, lungs, skin and heart (22). Epithelial cells provide biochemical barriers by synthesizing and secreting substances meant to trap or destroy bacteria like NTHI (15). However, NTHI is able to allow its binding to epithelial cells. There is also evidence that NTHI may thrive in the respiratory tract by surviving inside of epithelial cells (16).

Though ACE2 is thought to be the main point of cellular entry for SARS-CoV-2, it is well known that viruses often use a variety of mechanisms for attachment. The most common cell adhesion molecules are CAMs which are routinely exploited by viruses to gain cellular entry (187). A retrospective study of COVID-19 patients in China found that serum levels of fractalkine, vascular cell adhesion molecule- 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein- 1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase (188).

Much like Human herpesvirus 8 (HHV-8), HIV, and AIDS, NTHI can inhibit epithelial host defense proteins (18,19, 80,81). Once compromised, airway epithelial cells respond to the invasion of NTHI by secreting inflammatory acute-phase reactants such as IL-6, IL-8, and

(18-19).

NTHI then increases the expression of ICAM-1 by airway epithelial cells which increases the susceptibility of viruses binding to the cells (20).

ICAM-1 or Intercellular Adhesion Molecule 1, also known as CD54 (Cluster of Differentiation) is a protein that in humans is encrypted by the ICAM-1 gene. The ICAM-1 gene is coded by a cell surface glycoprotein which is expressed on endothelial cells and cells of the immune system (21). An NTHI and SARS-CoV-2 co-infection that originates from the middle ear might allow these pathogens cellular access to the respiratory system as scientists have discovered that there is a similar allergic inflammation in the middle ear and the upper airway suggesting the middle ear may be a part of the united airways concept (17). The major leading cause of death in patients with COVID-19 is respiratory failure from acute respiratory distress syndrome (ARDS) (204). Can we compare Pathophysiology of COVID-19 to that of HIV/AIDS for better understanding of the disease and to develop treatments ?

Many receptors for cytokines/chemokines have recently been identified by a group of scientists as upregulated in COVID-19 patients including; C-C chemokine receptor (CCR) 1 (CCR1), CCR2, and CCR5. These same scientists claim; “our work highlights opportunities for clinical trials with existing or under development CCR5 drugs to treat high risk or severe COVID-19 cases” (86). ICAM-1 and CCR5 upregulation are both implicated in the pathogenesis and progression of HIV (82, 189).

It has been previously established that HIV’s replication is facilitated by ICAM-1 which is believed to increase infection of CD4 T-cells (99). Plasma biomarkers of endothelial injury such as higher levels of cICAM-1, lower levels of cICAM2, an increase in cB2 microglobulin levels, and the decrease in CD4 T-cell counts are well established predictive biomarkers in HIV 1 -infected patients used to determine disease progression and prognosis for AIDS progression (82). These same markers may be useful in determining disease progression and prognosis in asymptomatic COVID-19 patients and further identifying potential therapeutic candidates.

Due to the similarities between COVID-19 and HIV disease infection and progression, a closer look at the mechanisms of HIV infection is warranted. HIV gains entry into the cells via gpl20 and CD4. This allows for binding to the chemokine receptors CCR5 or CXCR4, which act as coreceptors for the virus for which CD4 antibodies have been identified as effective therapeutic targets (84). It is important to note that a 2008 research study found that HIV transfer between CD4 T-cells did not require LFA-1 binding to ICAM- 1 and is governed by the interaction of HIV envelope glycoprotein with CD4. The researchers discovered that HIV transmission between infected and uninfected primary CD4 T-cells was stopped by inhibitors of gpl20 binding to CD4 by not blocking LFA-1 binding to ICAM- 1 or I CAM-3. Further, it was noted that LFA-1 and ICAM-3 monoclonal antibodies (MoAb) actually enhanced HIV transfer (85). Recent research noted that CCR5 receptor and chromosome 3 gene clusters contribute to susceptibility to COVID-19 and the development of severe complications.

allele , a polymorphism in CCR5 that regulates its expression has been identified as a partial to full protection against HIV infection and acts as a foundational basis for gene deletion studies aimed at achieving a permanent cure to HIV (88-89). It should be noted that a positive correlation between COVID-19 mortality rate and

allele ( n African population was found (86).

Further, there is a correlation between the progression of HIV and invasive NTHI infections. A study designed to evaluate increases in invasive NTHI infection from 2017-2018 among homosexual HIV infected men in Atlanta, Georgia found the incidence of invasive NTHI infection increased signigicantly from 2017-2018 compared with 2008-2016. Additionally, two unique but genetically connected strains were observed and associated with septic arthritis among homosexual black men who lived in geographic proximity (83). Theoretical Proposition: COVID-19 Pathophysiology is much like HIV/AIDS

Like HIV, SARS-CoV-2 gains cellular entry via CD4 T-cells. However, different mechanisms lead to SARS-CoV-2 infection.

Asymptomatic people are super spreaders due to high levels of NTHI. SARS-CoV-2 not cause serious disease in these populations yet causes severe disease progression in others. This may be due to the condition of the innate immune system- several groups have found that the binding of IgM to the bacterial surface might play a role in the innate defense against NTHI infections. Another study found that patients with hyper-IgM syndrome were less susceptible to NTHI colonization, a finding that emphasizes the role of IgM in the immune system defense against NTHI. The percentages of IgM-producing CD27+ memory B cells in the peripheral blood of children are low but increases to almost 20% in adults and declines again in the elderly. This might address the question of whether a diminished protective immunoglobulin level in the elderly contributes to susceptibility to invasive NTHI disease.

The COVID-19 Model

1. A person with increased NTHI colonization becomes infected with SARS-CoV-2

2. Due to a weakened immune system (lower IgM levels) the body pushes harder against the co-infection through mounting an excessive inflammatory response.

3. ICAM-1 becomes upregulated

4. ICAM-1 acts as a ligand to LFA-1

5. LFA- 1 becomes activated on CD4 T-cells

6. LFA- 1 activation on target and infected CD4 T-cells enhance SARS-CoV-2 infectivity and transmission by promoting virus binding and cell to cell spread via the CCR5 coreceptor.

7. LFA- 1 also increases the cell susceptibility to bacterial toxin LtxA that preferentially targets active LFA- 1. https : //journals.plos.org/plosone/article?id= 10,1371/joumal.pone.0023202#:~-:text=LFA% 2D1%20activation%20on%20target.preferentially%20targets %20active%20LFA% 2D1. a. Leukotoxin (LtxA; Leukothera), a protein toxin secreted by the oral bacterium Aggregatibacter actinomycetemcomitans, specifically kills white blood cells (WBCs). LtxA binds to the receptor known as lymphocyte function associated antigen- 1 (LFA-1), a β2 integrin expressed only on the surface of WBCs. https://www.ncbi.nlm.nih.gov/nmc/articles/PMC4219105/ b. NTHI and Aggregatibacter actinomycetemcomitans are two species under genus Pasteurellaceae thus closely related. https://www.ncbi.nlm nih.gov/pmc/articles/PMC.3993099/ c. A. actinomycetemcomitans is associated with gum disease.

8. LtxA binds preferentially to the active form of LFA- 1 and minimally affects cells that express resting-state LFA-1 (DiFranco et al., 2012; Hioe et al., 2011; Stenderup et al., 2011). The mechanism of cellular killing by LtxA has been studied in several cell types. Studies indicate that in HL-60 monocytes, LtxA causes necrosis at high doses by forming pores in the host cell membrane, while at low doses LtxA induces apoptosis (Korostoff et al., 1998, 2000).

9. Persons with increased NTHI colonization and Aggregatibacter actinomycetemcomitans colonization are at higher risk from severe complications of COVID-19 as NTHI increases the host's susceptibility to viral infections, while A. actinomycetemcomitans kill white blood cells designed to clear the body of the invading pathogens (NTHI and SARS-CoV-2) leaving the host completely vulnerable to COVID-19.

Intestinal Disease as a Marker for COVID-19 Disease Progression Cytokine induced changes in mucin expression and 0-glycosylation are likely involved in the pathogenesis and progression of inflammatory bowel diseases (IBD) such as ulcerative cohtis and Crohn's disease. Disrupted gut barrier integrity is at the heart of all inflammatory bowel diseases (29,30).

A recent study performed by researchers Giron, Dweep and others revealed severe COVID-19 is fueled by disrupted gut barrier Integrity These researchers found that hospitalized COVID-19 patients had higher plasma levels of zonulin, (the only known physiological conciliator of tight junction permeability in the digestive tract), and were more likely to die. This progression of disease was due to the ability of microbes to enter into the bloodstream causing systemic inflammation. The researchers also pointed that systemic inflammation caused by a lung infection can lead to a disruption of the gut barrier integrity leading to microbial translocation. Upon examining plasma glycomes, their research uncovered that translocation of glycan-degrading enzymes alter extraintestinal circulating high-mannose glycoform (HM-ICAM-1) (31). Further, in the inflamed gut of Crohn’s Disease and Ulcerative Colitis patients, lCAM-1 is enhanced. Research points to HM-ICAM-1, ICAM-1 as a key therapeutic target for controlling leukocyte trafficking and endothelial inflammation (32,144).

Some bacteria in the normal intestinal microbiome are opportunistic. Opportunistic bacteria like Candida albicans can overgrow due to prolonged treatment with broad-spectrum antibiotics (33). Broad-spectrum antibiotics are often prescribed to target pathogens sensitive to antimicrobial agents. However, other organisms such as Candida albicans that are resistant to the therapeutic intervention invate the unoccupied space and multiply rapidly. This occurrence is called Candidiasis or superinfection (34). In 2019 the CDC listed drug resistant Candida species in its Antimicrobial Resistance Threats Report, stating that many are resistant to antifimgals used to treat them (35).

When Candida albicans overgrowth and the normal lining of the intestinal tract is damaged, the body can absorb yeast cells, particles of yeast, and various toxins (36). Candida accounts for 70-90% of all invasive fungal infections in hospitalized patients and is a leading cause for sepsis in critically ill patients. Additionally, administration of broad-spectrum antibiotics, central vascular catheters, diabetes mellitus, parenteral nutrition, mechanical ventilation, renal insufficiency, hemodialysis, colonization, antifungal prophylaxis, surgery, pancreatitis, and treatment with corticosteroids and chemotherapy were the most frequently identified risk factors for sepsis in patients with Candidiasis (37). Researchers have increasingly become aware of COVID-19 fungal co-infections. The main fungal pathogens for fungal co-infections in severe COVID-19 patients are Aspergillus and Candida (225).

On April 24, 2020 a 67 year old COVID-19 patient presented oral mucosal lesions resembling late state herpetic recurrent oral lesions associated with candidiasis. He was admitted to the ICU for supplemental oxygen therapy. The patient's symptoms worsened and doctors suspected pneumonia. The patient was placed on antibiotic regimens. On the twenty fourth day of hospitalization, dentists discovered white patches on the patient's tongue. He was prescribed antifungal medications and the patches cleared up. The patient was released from ICU two weeks later and was discharged from the hospital after forty-four days.

It should be noted that Acute Acquired Haemolytic Anaemia has been associated with Herpes Simplex Infection (39). Hemolytic anemia is a blood disorder that occurs when your red blood cells are destroyed faster than they can be replaced. Severe hemolytic anemia can cause fever, chills, back pain, shock, irregular heartbeat, and cardiomyopathy in which the heart grows larger than normal (40).

Intestinal Disease &Inflammation: Making Sence of MIS in Children

Inflammation can modify the glycosylation pattern of glycolipids and glycoproteins. It is well known that the glycosylation of acute-phase proteins is subjected to marked changes during acute and chronic inflammation (27). The inflammatory response caused by ICAM- 1 Upregulation and COVID-19 can lead to increased levels of pro-inflammatory cytokines in response to pathogens lead to a constant NF-KB activation resulting in an increased synthesis of pro-inflammatory cytokines, which contributes the vicious inflammatory cycle seen in patients with Kawasaki disease and other systemic inflammation presentations (28-29).

NTHi strains cause mucosal infections, including otitis media, conjunctivitis, sinusitis, bronchitis, and pneumonia. Less commonly, these strains cause invasive disease in children but account for half of the invasive infections in adults which may explain why children are less likely to become severely ill from COVID-19 (41).

On August 7, 2020 a report on Multisystem Inflammatory Syndrome in Children (MIS-C) was released by the U.S. Department of Health and Human Services and the CDC. Clinical symptoms of patients included in this report included; fever, rash, conjunctivitis, peripheral edema, gastrointestinal symptoms, shock, and elevated markers of inflammation and cardiac damage.

This report found that of the 570 children with COVID-19 related MIS-C, 25% of them were obese. 90% of them experienced gastrointestinal symptoms including abdominal pain, vomiting, and diarrhea. About 71% of them experienced dermatologic and mucocutaneous presentations including rash (55.3%) and mucocutaneous lesions (35.3%). Furthermore, 60.4% of these children had Elevated D-dimer levels indicating significant formation and breakdown of blood clots in the body. Researchers further found that it is often difficult to distinguish MIS-C from other conditions like severe COVID-19 and Kawasaki disease. Hispanic and Black children made up 73% of this study (29).

Discussions:

1. Male children who are more prone to chronic ear infections may be more likely to be the asymptomatic superspreaders of COVID-19.

2. High COVID-19 morbidity rates among men may be explained by a lifetime overuse of antibiotics (for chronic ear infections and other diseases) which may have led to imbalance in gut flora specifically Candida albicans infection, and a disrupted gut barrier. Generally, Men are underdiagnosed for Candida albicans infection. Men become more susceptible to this infection by using testosterone containing products as research strongly suggests that testosterone plays an important role in decreasing resistance to systemic C. albicans infection (42).

3. Published national and state data shows that persons of color might might be more likely to become infected with SARS-CoV-2, the virus that causes COVID-19, experience more severe COVID- 19-associated illness, including that requiring hospitalization, and have higher risk for death from COVID-19 (43) and pre-existing anemia may be a contributing factor.

In a 2013 study, it was found that Blacks have moderate to severe anemia almost 3 times more Than whites and hispanics (44).

Pre-existing anemias, can worsen the symptoms of NTHI/COVID-19 Infections during the nutritional immunity stage. During this stage iron is sequestered as a first line defense strategy. However, iron is reintroduced to NTHI which causes sharp rises and falls in iron levels which can have severe clinical implications for those who suffer with iron deficient blood. Furthermore, acquired haemolytic anemia may develop after treatment with drugs such as quinine, sulphonamides, para-amino-salicylic acid, or it may follow infections caused by bacteria or viruses (39). In the case of a patient with pre-existing anemias getting infected with NTHI/COVID-19 could be deadly especially when the aforementioned treatments are used.

4. Discussion of Current therapies: a. Oxygen therapy. Doctors have reported that after NIV respiratory therapy, there is a sudden, unexpected worsening of symptoms in some patients. This often leads to intubation and invasive mechanical ventilation (8).

Nontype able Haemophilus bacteria is an anaerobe. These pathogens die quickly when exposed to oxygen. The rapid decline in patients' health after NTV may be explained by the Herxheimer Reaction or “die off effect” of the NTHi bacteria (tying quickly. b. Antibiotics are not appropriate therapies. Infections caused by NTHI are chronic and similar to other bacterial infections that are difficult to treat (7).

_C. Antibiotics further strengthen bacterial resistant microbes which in turns further disrupts the gut barrier integrity. "In essence, antibiotics progress COVID-19 disease manifestations leaving moderate to severe patients open to re-infection. In severe patients, antibiotic therapies can lead to death as in the case of Penicillin. Penicillin is known to cause hemolytic anemia which can lead to hemorrhaging, blood clots, heart failure, and stroke” (45).

1. Consider Antiviral therapies using iminosugar derivatives. Since ADCC is thought to play a role in protecting against initial infection and controlling progression of infection in HIV, 2G12 dimmers may be a possible therapy (92). 2G12 is a neutralising human monoclonal antibody that has 3 possible combining sites. It has been identified as a possible antiviral therapy for various viruses (93). Studies also suggest that “ 2G12 competitively inhibits interactions between gp 120's V3 loop and the tyrosine sulfate-containing CCR5 amino terminus, thereby reducing assembly of complexes that catalyze entry (94). 2. Cleanse Patient Gut - consider using enema treatments with antisense oligonucleotides as a short term remedy to reduce intestinal inflammation and downregulate ICAM- 1 (130,142,143). A holistic approach using herbs and lifestyle modifications will be necessary to prevent symptom relapse after therapy.

3. Consider Replenishing Gut Flora via exaggerated probiotic therapy.

4. Consider available therapies using iminosugar derivatives for Candida Albicans overgrowth;

5. Enlist Resident Nutritionists with backgrounds in Vitamin Therapy, microbiology, biochemistry etc to help formulate the appropriate (and available) therapies given the considerations outlined in this research.

Divine Aval’s Fitra30 COVID-19 Protocol

RNA viruses, COVID-19 in particular, are highly mutagenic- up to a million times higher than that of their hosts therefore, it is essential to build host resilience and defence mechanisms to ward off entry of this disease into the body. The Fitra30 COVID-19 Protocol consists of natural treatments that stimulate and strengthen defence and healing mechanisms which are intrinsic to the host These treatments are designed to specifically target COVID-19 by 1) blocking of pathways to SARS-CoV2 cellular entry and 2) Riding the body of COVID-19. Divine Ayats’ Fitra30 COVID-19 Protocol is useful for individuals who desire effective natural treatments to prevent and treat COVID-19 as opposed to (or in conjunction with) vaccines and standard treatments.

This protocol consists of three features:

1) The Milhu Shamsi Herbal Formulation (MSHF) MSHF is designed to prevent and treat COVID-19 by targeting internal mechanisms which act as conduits for COVID-19 infection such as ICAM- 1 and CCR5.

2) Induction of autophagy The Fitra30 COVID-19 Protocol is holistic in the sense that it aids the body in inducing autophagy, an essential internal process for disease prevention and eradication. Interventions include Autophagy Jumpstart Herbal Blend (AJHB) and lifestyle modifications (i.e., proper diet, exercise, and sleep recommendations).

3) Divine Ayat’s Spiritual. Emotional, and Mental Rejuvenation Program (SEM-RP) . The presence COVID-19 has caused stress, anxiety, and other mental health crises with people around the world. Consequently, it is essential to address this disease via Physical, Spiritual, Emotional, and Mental mechanisms. SEM-RP is an optional therapy using methods of Islamic Medicine which consists of a 30 Day Guided Meditation program (online) and Journaling.

These components will now be discussed in detail as well as the specific therapeutic targets.

1) Divine Avats’ “Milhu Shamsi” Herbal Formulation

U.S. Patent Application No.: 63113935

Divine Ayats’ Milhu Shamsi Herbal Formulation is a multi-compound herbal formulation inspired by Islamic Medicine (Tibb An-Nawawi or Medicine of The Prophet

Traditional Chinese Medicine (TCM), and Traditional Japanese Medicine (Kampo). The composition is formulated to restore stasis in all bodily systems and rid the body of COVID-19. Milhu Shamsi was scientifically developed to act as an immunomodulator drug with exemplary additive and synergistic effects. Immunomodulators are effective treatments for inflammatory and immune system diseases (71). Specific therapeutic targets include of the Milhu Shamsi formulation include; 1) Downregulation of ICAM-12) Enhance the function/increase number of CD4 T-cells 3) Interference with SARS-CoV2/CD4 interaction, 4) Downregulation of CCR5 5) Preventing and treating Systemic Inflammation and Microbial Infection.

A brief summary of scientific relevance is discussed below. Downregulation of ICAM-1. CCR5. Interference with SARS-CoV2/CD4 Interaction:

Currently, ACE2 is believed to be the main glycoprotein utilized by SARS-CoV2 for cellular entry (182). However, many other receptors have been identified as facilitating SARS-CoV2 including; CD209L (L-SIGN), CD209 (DC-SIGN) (183), Neuropilin receptors (NRPs) which allows for viral entry into the central nervous system (184-185), and CD147/Basigin (186). It is well known that viruses may use a variety of mechanisms for attachment The most common cell adhesion molecules are CAMs which are routinely exploited by viruses to gain cellular entry (187). A retrospective study of COVID-19 patients in China found Serum levels of fractalkine, vascular cell adhesion molecule- 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein- 1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase (188). Additionally, many receptors for cytokines/chemokines have recently been identified by a group of scientists as upregulated in COVID-19 patients including; C-C chemokine receptor (CCR) 1 (CCR1), CCR2, and CCR5. These same scientists claim; “our work highlights opportunities for clinical trials with existing or under development CCR5 drugs to treat high risk or severe COVID- 19 cases” (86). ICAM- 1 and CCR5 upregulation are both implicated in the pathogenesis and progression of HIV (82, 189).

Due to the similarities between COVID-19 and HIV disease contraction and progression, a look at the mechanisms of HIV infection is warranted. HIV gains entry into the cells via gpl20 and CD4. This allows for binding to the chemokine receptors CCR5 or CXCR4, which act as coreceptors for the virus for which CD4 antibodies have been identified as effective therapeutic targets (84). It is important to note that a 2008 research study found that HIV transfer between CD4 T-cells did not require LFA-1 binding to ICAM-1 and is governed by the interaction of HIV envelope glycoprotein with CD4. The researchers discovered that HIV transmission between infected and uninfected primary CD4 T-cells was stopped by inhibitors of gpl20 binding to CD4 by not blocking LFA-1 binding to ICAM-1 or I CAM-3. Further, it was noted that LFA-1 and ICAM-3 monoclonal antibodies (MoAb) actually enhanced HIV transfer (85). As aforementioned, recent research on chemokine receptor gene polymorphisms and COVID-19 identified CCR5 as a therapeutic target for COVID-19. The research noted that CCR5 receptor and chromosome 3 gene clusters contribute to susceptibility to COVID-19 and the development of severe complications.

allele ( n African population was found (86).

Prevention and Treatment of Systemic Inflammation / Microbial Infection which can lead to Sensis

A recent study performed by researchers Giron, Dweep and others revealed severe COVID-19 is fueled by disrupted gut barrier Integrity These researchers found that hospitalized COVID-19 patients had higher plasma levels of zonulin, (the only known physiological conciliator of tight junction permeability in the digestive tract), and were more likely to die. This progression of disease was due to the ability of microbes such as Candida albicans and other bacteria to enter into the bloodstream causing systemic inflammation and sepsis. Bacteria can also enter the bloodstream as a complication of pneumonia and standard treatments to include; catheters, injections, and other medical devices used when treating COVID-19 patients. All these factors put the patient at increased risk for sepsis and death (31, 196). The researchers also pointed that systemic inflammation caused by a lung infection can lead to a disruption of the gut barrier integrity leading to microbial translocation. Upon examining plasma glycomes, their research uncovered that translocation of glycan-degrading enzymes alter extraintestinal circulating high-mannose glycoform (HM-ICAM-1) (31). Further, in the inflamed gut of Crohn’s Disease and Ulcerative Colitis patients, ICAM-1 is enhanced. Research points to HM-ICAM-1, ICAM-1 as a key therapeutic target for controlling leukocyte trafficking and endothelial inflammation (32,144).

Accordingly, primary therapeutic targets of Divine Ayat’s Milhu Shamsi Herbal Formulation include; downregulation of ICAM-1 and CCR5, increasing the fimction and number of CD4 T-cells, and preventing and treating Systemic Inflammation and Microbial Infection. Divine Ayat’s Milhu Sham si Herbal For mula c onsists 14 H erbs wh ich include:

1. Nigella sativa (Black Seed),

2. Sassurea lappa (Indian Costus),

3. Astragalus membranaceus (Astragalus),

4. Panax ginseng (Ginseng),

5. Radix Bupleuri (Bupleuri Powder),

6. Angelica archangelica (Angelica Root Powder),

7. Citrus sinensis (Orange Peel Powder),

8. Zingiber officinale (Ginger Powder),

9. Glycyrrhiza glabra (Licorice Root Powder),

10. Paeonia lactiflora (Peony Root),

11. Nelumbo nucifera (Lotus Seed),

12. Artemisia vulgaris (Mugwort),

13. Ocimum sanctum (Tulsi) and;

14. Rosa canina (Rosehip Powder)

For Muslims, Islam is a complete way of life that promotes homeostasis in the Spiritual, Physical, Mental, and Emotional domains of wellness. COVID-19 has thrust this generation into a very precarious time where understanding and exploring Islamic pathways to wellness is obviously more relevant now than ever during our time. For example key principles to promote wellness during COVID-19 include social distancing; including refraining from handshaking, an emphasis on physical cleanliness through frequent handwashing, and covering the face and hands, are all fundamental acts performed daily by billions of Muslims worldwide as religious obligations.

Two main herbs in the Milhu Shamsi formulation are Nigella sativa and Sassurea lappa. Over 1400 years ago, Prophet Muhammad (peace and blessings of Allaah be upon him) informed us about how to treat over 30 ailments and specifically 61 differenent herbs. Two of the most potent herbs he, (peace and blessings of Allaah be upon him), mentioned were Nigella sativa, commonly known as Black Seed and Sassurea lappa which is commonly known as Indian Costus (46-47). It was narrated by a nobel companion, Abu Hurairah

that Prophet Muhamamd (peace and blessings of Allaah be upon him) said; “In black seed there is healing for every disease, except death.” (50). It was also reported that The Prophet (peace and blessings of Allaah be upon him) also informed us to use Indian Costus as it contains “seven cures" including a cure for pleurisy (51). Much scientific research has been done about the benefits of both herbs which has proved their efficacy in treating diseases including cancer, diabetes, hypertension, and more (48-49).

A concoction of 60% Nigella sativa and 40% honey induced sustained seroreversion in an adult HIV patient. The patient visited a Herbal Medicine Practitioner and was recommended the Nigella sativa concoction at a dose of lOmls twice daily for 6 months. The patient was monitored daily. The patient reported that fever, diarrhoea, and multiple pruritic lesions disappeared on day 5, 7, and 20 respectively. Although the patients CD4 counts decreased to 160 cells/mm3 there was a significant reduction in viral load by Day 30 (≤1000 copies/ml). It should be noted that the patient was not on highly active anti-retroviral therapy (HAART) before, during, or after the Nigella sativa concoction therapy (90).

There is growing evidence to support the effectiveness of treating COVID-19 with Nigella sativa. Bioactive constituents of Nigella sativa seed, in particular thymoquinone, a-hederin, and nigeUidine, have been identified as alternative and promising herbal therapies to combat COVID-19 (90). Thymoquinone, thymohydroquinone, and nigeUidine, aU have proven antihistamine effects. NigeUa sativa seeds have also shown significant immuno-potentiating effects in human T cells in vitro. Additionally, these constituents are believed to reduce inflammation, oxidative stress, cardiovascular disorder, hypertension, and induce autophagy (91).

The second main herb used in Divine Ayats’ Milhu Shamsi formula is Sassurea lappa. This herb has been widely studied and documented for its anti-inflammatory, anticancer/tumor, hepatoprotective, immunomodulating, antimicrobial, and antiparasitic benefits (101). Costunolide is a sesquiterpene lactone isolated from Sassurea lappa which stops the endothelial cell proliferation instigated by vascular endothelial growth factor or VEGF. which increases expression of ICAM-1. Costunolide was also found to inhibit the VEGF induced movement of human umbilical vein endothelial cells (HUVECs) thus proving that Sassurea lappa might prevent angiogenesis (the formation of new blood vessels) by blocking the angiogenic factor signaling pathway. Further, costunolide and dehydrocostus lactones found in Saussurea lappa inhibit hepatocyte growth factor which in turn downregulates ICAM-1 (102, 103, 104). Molecules that reduce cholesterol or disrupt viral entry points is believed to reduce the severity of COVID-19 in obese patients (107). Sassurea lappa has hypolipidemic action which proves useful when treating obsese COVID-19 patients presenting high cholesterol levels (101). Additionally, the significance of Sassurea lappa as a potential treatment of COVID-19 has risen in the medical community. Researchers are encouraging exploration of this beneficial herbal medicine through clinical trials (110).

Svnereistic Herbs in the Milhu Shamsi Formulation:

Japanese herbal formulations date back more than 1500 years. The word “Kampo” which literally means “method from the Han period (206 BC to 220 AD) of ancient China”, refers to its origin from ancient China (56). In fact, many Japanese herbal formulations are variations of formulations found in TCM with different names. Consequently, Traditional Chinese Medicine (TCM) has an even longer history dating 3000 years starting from the early Zhou Dynasty of China. According to researchers TCM could date back even earlier as the oldest medical writings on herbs were found in Classic of Changes (Yi Jing) and Classic of Poetry (Shi Jing) (57).

Along with Nigella sativa and Sassurea lappa, herbs in Divine Ayat’s Milhu Shamsi formulation include some herbs that are used in a Kampo formulation entitled; “Hochuekkito”. Herbs in the Hochuekkito consist of 10 component herbs;

1. Astragalus membranaceus (Astragalus)

2. Panax ginseng (Ginseng)

3. Atractylodis macrocephalae Rhizoma

4. Jujubae Fructus

5. Citri reticulatae Pericarpium

6. Bupleuri Radix

7. Angelicae sinensis Radix

8. Cimicifiigae Rhizoma

9. Glycyrrhizae Radix

10. Zingiberis Rhizoma

Hochuekkito (HET) has been traditionally used by Kampo practitioners to treat fatigue, poor appetite, spontaneous sweating, loose stools, frequent colds and infections, hemorrhage, male infertility, and sexual dysfunction. Research points to Hochuekkito’s effectiveness in clinical settings with strengthening the immune system, improving systemic inflammation in patients with COPD, modulating the immune function, in Intestinal Peyer’s Patches and Epithelial cells (59-66). In a 2017 study, researchers discovered that Hochuekkito restores metabolic homeostasis between mitochondrial and glycolytic pathways impaired by Influenza A Virus Infection (68).

A 2010 research study found that orally administered Hochuekkito, may partly contribute to enhancement of IgA immune response against intestinal antigens and strengthen immune defense systems against various pathogens and food antigens in the intestinal tract A spray-dried extract preparation of HET in the following composition was used; a mixture of Astragali Radix (4 g, roots of Astragalus membranaceus Bunge), Atractylodis lance ae Rhizoma (4 g, rhizomes of Atractylodes lancea DC.), Ginseng Radix (4 g, roots of Panax ginseng C.A. Meyer), Angelicae Radix (3 g, roots of Angelica acutiloba Kitagawa), Bupleuri Radix (2 g, roots of Bupleurum falcatum L), Zizyphi Fructus (2 g, fruits of Zizyphus jujuba Miller var. inermis Rehder), Aurantii Bobilis Pericarpium (2 g, pericarps of ripe fruits of Citrus unshu Markovich), Glycyrrhizae Radix (1.5 g, roots of Glycyrrhiza uralensis Fisch et DC.), Cimicifiigae Rhizoma (1 g, rhizomes of Cimicifuga simplex Wormskjord) and Zingiberis Rhizoma (0.5 g, rhizomes of Zingiber officinale Roscoe) was added to water and extracted at 100°C for 1 h. The extracted solution was filtered and spray-dried to obtain dry extract powder (5 g) which was chosen to be the 1 day dosage. To investigate HET potentials on mucosal IgA immune response, mice were orally immunized with ovalbumin (OVA)-entrapped biodegradable microparticles (OVA-microparticles) as an antigen for 3 days. HET or water was then administered via gavage from through the 7th -27th day after the onset of immunization. Data showed that OVA-specific IgA titers in intestinal washes were greatly amplified by oral administration of HET. Further, upon investigating cytokine production in the lymphocytes from the spleen, peripheral blood, and Peyer's patch cells revealed that the IFN-y secretion from the lymphocytes was increased by the administration of HET (69). In Traditional Chinese Medicine (TCM), “Hochuekkito” is called“Hochueklti”. Hochuekki contains the exact same 10 component herbs as its Japanese successor. In 2009 a group of researchers reviewed 59 research studies of in vitro and in vivo models (both animals and humans) studying the effect of Traditional Chinese Medicine formulations on cytokine activity. There research showed that in vivo aqueous Hocheukki formulations administered at 1000mg/kg QD, PO for 2-21 days had an effect on cytokines;

Divine Ayats’ Milhu Shamsi Herbal formulation contains 6 of the 10 herbs in the Hochuekkito/Hochuekki formulations to include;

1. Astragalus membranaceus (Astragalus)

2. Panax ginseng (Ginseng)

3. Bupleuri Radix

4. Angelicae sinensis Radix

5. Glycyrrhizae Radix

6. Zingiberis Rhizoma

Recent research performed by David Lee from Bio-Organic and Natural Research Laboratory, McLean Hospital, Harvard Medical School, and Belmont has shown that herbs commonly used in TCM formulations along with cutting edge science and technology may be effective in treating COVID-19.

The primary goal of this research was based upon their theory of treating COVID-19 by expelling toxic moisture from the upper respiratory system while improving intestinal obstruction. These researchers believe that the goal of TCM in the treatment of COVID-19 is to promote and restore balance between the lung and intestine. This study examined TCM relating to treating COVID-19 that is registered on www. ClinicalTrails. gov. The study found that trials in Wuhan showed 89% to 92% effectiveness of TCM therapies in the 692 studies registered. Further, an examination of the pharmacological basis of the Chinese herbs used the most frequently in the clinical trials was performed (67). Of those frequently used herbs, there are 3 that are used in the Milhu Shamsi formulation which include;

1. Astragalus membranaceus (Astragalus)- a 2020 study on the effects of this herb on cytokine storms producing systemic inflammatory was promising. Astragalus impeded the activation of MAPK/NF-B signaling pathway, promoted the down regulation of of IL-6, IL-8, TNF-a levels, activated the PI3K/Akt/mTOR signaling pathway, promoted the upregulation of superoxide dismutase (SOD), promoted the detoxification of flee radicals (67).

2. Glvcvrrhizae Radix- a 2014 study showed that this herb inhibited the replication of FFM-1 and FFM-2 viruses. A water extract also had anti-herpes simplex virus (HSV-1) activity possibly due to its anti-adhesion activity which disallowed the attachment process of the HSV-1 virus (67). Additionally, Glycyrrhizae Radix has been identified as a highly beneficial treatment for COVID-19 patients (111).

3. Bupleuri Radix- in a 2015 study this herb reduced fever in dry yeast-induced rats. It also increased arginine vasopressin in rat plasma (67). Finally, six additional herbs were chosen to be a part of the Milhu Shamsi formulation. After careful study and research, it was determined that the follow herbs would add balance and synergistic effects to the overall formulation making it more effective in the treatment of COVID-19:

1. Citrus sinensis (Orange Peel Powder);

2. Paeonia lactiflora (Peony Root);

3. Nelumbo nucifera (Lotus Seeds);

4. Artemisia vulgaris (Mugwort);

5. Ocimum sanctum (Tulsi); and

6. Rosa canina (Rosehip Powder)

Below we will discuss in detail each herb in Divine Ayats; Milhu Shamsi formula to include; a description of the active ingredient, a description of its physical characteristics, indications, specific mechanisms of actions for treating COVID-19, pharmacokinetic, and toxicology data. Note: the dosage form for the Milhu Shamsi composition is an aqueous extract which may be delivered bv mouth or feeding tube.

In true Islamic Medicine (Tibb an-Nawawi) alcohol extractions are not permissible;

In Saheeh Muslim it is narrated from Taariq ibn Suwayd al-Ju’fi that he asked the Prophet (peace and blessings of Allaah be upon him) about alcohol and he forbade him or told him not to make it He said: "But I make it as a remedy.” He said: “It is not a remedy, it is a disease.”

Further, some herbs in this formulation may not be suitable for every patient The mix of synergistic herbs with corresponding functions is a build in measure that serves two purposes: 1) to enhance the therapeutic effectiveness of this drug and 2) ensure the overall therapeutic effect (preventing and eradicating COVID-19 from the body) if the main herbs; Nigella sativa and Sassurea lappa in addition to at least one synergistic herb is present in the formulation.

2)a Divine Ayats’ Intermittent Fasting & Eating Therapy Based upon Islamic Medicine

Weakening of the body’s defense mechanisms may result in infectious microorganisms being transported in the blood (bacteremia) to infect other organs or even multiplying in the blood (sepsis) (226).

A recent study performed by researchers Giron, Dweep and others revealed severe COVID-19 is fueled by disrupted gut barrier Integrity. These researchers found that hospitalized COVID-19 patients had higher plasma levels of zonulin, (the only known physiological conciliator of tight junction permeability in the digestive tract), and were more likely to die. This progression of disease was due to the ability of microbes to enter into the bloodstream causing systemic inflammation. The researchers also pointed that systemic inflammation caused by a lung infection can lead to a disruption of the gut barrier integrity leading to microbial translocation. Further, their research uncovered that translocation of glycan-degrading enzymes alter extraintestinal circulating high-mannose gly coform (HM-ICAM-1) (31).

Candida albicans is the most common cause of fungal infections in humans (226). In 2019 the CDC listed drug resistant Candida species in its Antimicrobial Resistance Threats Report, stating that many are resistant to antifungals used to treat them (35). When Candida albicans overgrowth and the normal lining of the intestinal tract is damaged, the body can absorb yeast cells, particles of yeast, and various toxins leading to a condition called Candidiasis (36). Candidiasis accounts for 70-90% of all invasive fungal infections in hospitalized patients and is a leading cause for sepsis in critically ill patients (37) and almost 90% of people with AIDS have Candida at least one time during the disease (226). Researchers have increasingly become aware of COVID-19 fungal co-infections. In fact, recent research has discovered that the main fungal pathogens for fungal co-infections in severe COVID-19 patients are Aspergillus and Candida (225).

Helping the Body Heal Itself Through Autophagy

The term “autophagy” is Greek, meaning “eating of self’. It is a sophisticated way by which the body rids itself of harmful pathogens (bacteria, viral particles, etc.) on a cellular level to restore homeostasis (225). In disease recovery, autophagy can be thought as the body’s desperate, self-destructive attempt at survival. Autophagy may in fact be the last immune defense against infectious pathogens that penetrate intracellularly (229). SARS-CoV-2 infection suppresses autophagy (227).

Divine Ayat’s COVID-19 Protocol- Intermittent Fasting for Autophagy Induction

A proven way of inducing autophagy is by food restriction (fasting), which upregulates autophagy in many organs (231).

Fasting plays an important role in Islamic Medicine. Once per year Muslims are obliged to participate in Ramadan in which they fast from sunrise to sundown. Outside of Ramadan, it is encouraged for Muslims to fast at least 11 days during the month, to include; Mondays, Thursdays, and the 13, 14, and 15th of each month (according to the Islamic Calendar). Eating in moderation outside of these times is encouraged and recommended foods include (but are not limited to) the Prophetic Foods;

• Honey

• Pomegranates

• Mushrooms

• Bananas

• Dates

• Meat

• Bread

• Vegetables

• Water

Divine Ayats’ Intermittent Fasting to Induce Autophagy Recommendation includes fasting at least 3 days per week; Monday, Thursday, and Saturday for 30 days. Additionally, participants should eat in moderation from the foods they desire outside of fasting days, preferably including Prophetic Foods listed above.

What Prophet Muhammad said about food in moderation:

Miqdam ibn Ma’d reported: The Messenger of Allah, peace and blessings be upon him, said, “The son of Adam cannot fill a vessel worse than his stomach, as it is enough for him to take a few bites to straighten his back. If he cannot do it, then he may fill it with a third of his food, a third of his drink, and a third of his breath.” Sunan al-Tirmidhl 2380.

2b) Divine Ayats’ “Autophapy Jumpstart ” Herbal Formula

Pharmacological agents that induce autophagy may have antiviral effects against SARS-CoV-2 (228).

Divine Ayats’ Autophapy Jumpstart” Herbal Formula consists nf four herbs including·

1. Andrographis paniculate (Kalmegh Powder),

2. Vaccinium angustifolium (Wild Blueberry Powder),

3. Polygonum cuspidatum root (Japanese Knotweed Powder), and

4. Glycyrrhiza glabra (Licorice Root Powder)

Dosage form & Duration: Capsules or Aqueous Extracts which may be delivered by mouth or feeding tube for a period of 30 days.

3) Divine Ayats’ Spiritual, Mental, and Emotional Rejuvenation (SMER) Program

(Optional). This is an optional therapy using methods of Islamic Medicine which consists of a 30 Day Guided Meditation online program and Journaling.

COVID-19 Treatment Calls for a “Holistic” Approach

The Islamic approach to medicine is “holistic” as it puts forth that Spiritual, Physical (to include the use of whole plant medicine), Mental, and Emotional causes of disease must be identified and properly treated in order to open the pathway for a complete cure. Treating symptoms is an approach that may slow one dis-ease progression while acting as a catalyst for another. This can be exemplified in the case of the overprescription of antibiotics for diseases like STDs. The overprescription of antibiotics for diseases like STDs led to antibiotic resistant bacteria suchs NTHI and Candida albicans. This can also be seen the decrease in the incidence of invasive Hib diseases due to widespread use of the Hib vaccine, giving way to the NTHi strains taking the lead in becoming the most common cause of invasive disease in all age groups with routine Hib vaccination (41).

Prophet Muhammad

(may the peace and blessings of Allah be upon him) told us the reasons why we would experience new diseases like COVID-19;

“...Iffomification should become widespread, you should realize that this has never happened without new diseases befalling the people which their forebears never suffered. ” (52).

We are indeed living in a time where fornication has become widespread and deemed morally acceptable by a majority. Results from a 2002 U.S. survey revealed that by age 20, 75% of all respondents had premarital sex. It further revealed that by age 44, 95% of respondents (94% of women, 96% of men, and 97% of those who had ever had sex) had had premarital sex The conclusions of this survey by the National Survey of Famiy Growth indicated that almost all Americans have sex before marrying (53).

According to a 2019 Pew Research Study, 62% of respondents in the U.S. said casual sex between consenting adults who aren’t in a committed relationship is acceptable at least sometimes (54).

Another survey conducted by The Pew Research Center in 2014 compared global views of premarital sex found that respondents in predominantly Muslim countries like Indonesia, Jordan, Turkey and Egypt overwhelmingly agreed that premarital sex is morally wrong. Western countries such as Europe mainly found premarital sex morally acceptable (55).

Why Divine Aval’s SMER Program is important·

COVID-19 has greatly affected many lives around the world. The combination of uncertainty and quarantining is causing depression, anxiety, sleep problems, and psychological distress (236).

Divine Ayat’s SMER Program is a 30-day guided meditation program designed to reduce stress. In a previous study, after 3 weeks of meditation students reported feeling less anxious, stressed, and displayed greater improvements in attentional control (237).

Title; Compositions and Methods for Treating COVID-19 with Divine Ayats’ Fitra30 COVID-19 Protocol

Phase of Development: Phase 2

Study Overview:

This is a single center, double-blind, placebo-controlled, randomized, incomplete block, 3 period crossover trial. 100 subjects are planned. Each subject will be administered a single dose of study drug daily, for thirty days, consisting each time of various doses of active or placebo. Each subject will receive three of the five experimental treatments. Subjects will be assigned to the treatments in random order. Evaluations will be taken at baseline and every 2 hours after the daily administration of each dosage. Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion criteria and none of the exclusion criteria will be entered into the study.

The following treatment regimens will be used:

Arm 1;

Experimental treatment Milhu Shamsi dosage to be formulated based upon the participants weight. and;

• Placebo or Comparator: Standard of Care

Total duration of subject participation will be 30 days. Total duration of the study is expected to be 10 weeks.

Vs.

• Placebo or Comparator: Standard of Care

Arm 2:

• Experimental treatment Intermittent Fasting & Autophagy Jumpstart Formula at doses of

2000, 2200, 2500, and 2700 mg per day. and;

Placebo or Comparator: Standard of Care Total duration of subject participation will be 30 days. Total duration of the study is expected to be 10 weeks.

Vs.

• Placebo or Comparator: Standard of Care

Arm 3:

Experimental treatment Intermittent Fasting & Autophagy Jumpstart Formula at doses of 2000, 2200, 2500, and 2700 mg per day.

Vs.

• Placebo or Comparator: Standard of Care

Primary Efficacv Endooint

To restore stasis in all bodily systems and rid the body of COVID-19 as evidenced by a negative COVID-19 test at the end of treatment.

Secondary Efficacy Endopoints

To induce autophagy and increase antimicrobial peptide secretion as evidenced by the conversion of LC31 to LC311 and enhanced protein expression of human B-defensin-1 (hBD-1).

Increase in CD4 T-cell counts, Decrease inflammation and oxidative stress as evidenced by a decrease in CRP and MDA levels. Stimulation of the immune system as evidenced by an increase in serum IgM, IgE, and cyclic AMP concentrations. Effect reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) evaluated by flow cytometry. Subject Population: a. Inclusion criteria:

• 18 years of age or older;

• Moderate to severe COVID-19;

• COVID-19 & Bacterial/fungal Co-Infections - particularly NTHI and Candida albicans; b. Exclusion criteria:

• Pregnant;

• Breastfeeding;

• Allergies/contraindications corresponding to any of the herbs in the Milhu Shamsi and Autophagy Jumpstart formulas;

• Recent or upcoming surgical procedures;

• Under 18 years of age;

• Blood Disorders - on blood clotting / anticoagulant / antiplatelet medications;

STUDY TREATMENTS a. Method of Assigning Subjects to Treatment Groups Describe the randomization scheme and any randomization procedures.

100 eligible patients will be randomly assigned to XXX or placebo treatment groups in a 1:1 ratio using a SAS-based computer-generated randomization scheme developed by the study data management provider. The investigator or designee will complete a randomization worksheet (at Visit 1). b. Blinding

Due to the objectives of the study, the identity of test and control treatments will not be known to investigators, research staff, or patients. The following study procedures will be in place to ensure double-blind administration of study treatments;

• Access to the randomization code will be strictly controlled.

• A taste-matching agent.

• Packaging and labeling of test and control treatments will be identical to maintain the blind.

The study blind will be broken on completion of the clinical study and after the study database has been locked. Investigators will be made aware of their subjects treatment assignments immediately upon administration of last dosages.

During the study, the blind may be broken only in emergencies when knowledge of the patient’s treatment group is necessary for further patient management When possible, the Investigator should discuss the emergency with the Medical Monitor prior to unblinding. c. Formulation of Test Products

Test products include “Milhu Shamsi Herbal Formulation” and “Autophagy Jumpstart” manufactured by Divine Ayat, LLC. Herbs in each formula will be identified, cleansed, powdered, formulated for each participant, and made into capsules or aqueous extracts. d. Packaging and Labeling

Milhu Shamsi and Autophagy Jumpstart Aqueous Extracts shall be supplied daily in enteral feeding pump bags for each participant. Each bag of Milhu Shamsi will be labeled with the required FDA warning statement, the protocol number, a treatment number, the name of the sponsors, and directions for patient use and storage.

Autophagy Jumpstart Capsules shall be supplied in 100 cc white HDPE plastic pill packer bottles. Each bottle will be labeled with the required FDA warning statement, the protocol number, a treatment number, the name of the sponsors, and directions for patient use and storage. e. Supply of Study Drug at the Site

Divine Ayat, LLC. will deliver aqueous extracts of Study Drugs daily to the investigational sites. The initial study drug shipment will be shipped after site activation (i.e., all required regulatory documentation has been received by the Sponsor and a contract has been executed) and once participants have been selected. The Milhu Shamsi and Autophagy Jumpstart Aqueous extracts will be made daily for each subject and delivered to the site. The Autophagy Jumpstart Blend (capsules only) will be shipped to the site directly after site activation. Subsequent study drug shipments (in the case of replacements of subjects) will be made after site request for resupply. f. Dosage/Dosage Regimen

The Milhu Shamsi Formula may be administered three (3) times per day by mouth or enteral feeding tube. Optimal timing between doses is 4-6 hours. Formulation is based upon the participants weight.

The Autophagy Jumpstart Formula shall be studied in dosages of 2000, 2200, 2500, and 2700 mg per day. Once dose per day, preferably in the morning, and taken with meals is ideal.

Intermittent fasting schedule is as follows: Fasting Mondays, Thursdays, and Saturdays. Limited food/water intake (without minimal interference with Standard of Care treatments). g. Dispensing

Dispensing shall be done by the Investigator under the supervision of a licensed Pharmacist. h. Administration Instructions Aqueous extracts may be administered by mouth or enteral feeding tube. If feeding by mouth, extracts poured into a cup, warmed, and sweeteners (preferably honey) added to enhance the taste.

If aqueous extracts should be administered by enteral feeding tube, it should be done by administering ½ of the formula every 4-6 hours.

Administration of Autophagy Jumpstart Capsules should be done by giving the participant water or juice. i. Storage

Crude herbs and study drugs shall be stored at a Divine Ayat, LLC. secure facility located within 5 miles of the study site. Crude herbs should be stored at room temperature, away from tight, in glass containers free of moisture. j. Study Drug Accountability

An accurate and current accounting of the dispensing and return of study drug for each subject will be maintained on an ongoing basis by a member of the study site staff. The number of study drug dispensed and returned by the subject will be recorded on the Investigational Drug Accountability Record. The study monitor will verify these documents throughout the course of the study. k.

Nurses and Doctors will be asked to keep a patient diary noting the day and date the patients take their study drug and any adverse events.

Prior to conducting any study-related activities, written informed consent and the Health Insurance Portability and Accountability Act (HIPAA) authorization must be signed and dated by the subject or subject’s legal representative. a. Clinical Assessments b. Concomitant Medications

All concomitant medication and concurrent therapies will be documented at Baseline/Screening, once per day during study, and at early termination when applicable. Dose, route, unit frequency of administration, and indication for administration and dates of medication will be captured. c. Demographics

Demographic information (date of birth, gender, race) will be recorded at Screening. d. Medical History

Relevant medical history, including history of current disease, other pertinent respiratory history, and information regarding underlying diseases will be recorded at Screening. e. Physical Examination

A complete physical examination will be performed by either the investigator or a subinvestigator who is a physician at Visit #1. Qualified staff (MD, NP, RN, and PA) may complete the abbreviated physical exam at all other visits. New abnormal physical exam findings must be documented and will be followed by a physician or other qualified staff at the next scheduled visit f. Vital Signs

Body temperature, blood pressure, pulse and respirations will be performed after resting for 5 minutes during daily visits. g. Oximetry

Oximetry will be measured on room air with the subject at rest during daily visits. h. Spirometry

Spirometry will be performed during daily visits and in accordance with the current American Thoracic Society recommendations for the performance and interpretation of tests. i. COVID-19 Test

To be performed during screening and within 1 week of administration of the last dose. j. NTHI Test k. Disrupted Gut Barrier Testing Plasma biomarkers of endothelial injury include; high levels of ICAM- 1, cICAM2 , an of increase in CB2 microglobulin levels, decrease in CD4-T cells.

1. Candida a lbicans and Microbial Translocation Testing

Presence of bacterial blood infections including Candida albicans. m. Autophagic Proteins bv Western blot analysis n. Hematology

Blood will be obtained and sent to each site’s clinical hematology lab for CRP, INF Gamma, MDA Levels, Serum IgM, Serum IgE, Cyclic AMP Concentration, Reactive oxygen species (ROS), Mitochondrial Membrane Potential (MMP), a complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell differential, and platelet count), erythrocyte sedimentation rate (ESR), and serum C-reactive protein (CRP) determinations for assessment of systemic evidence for infection and/or inflammation. Performed weekly. o. Blood Chemistry Profile

Blood will be obtained and sent to each site’s clinical chemistry lab for determination of serum sodium, potassium, chloride, bicarbonate, random glucose, BUN, creatinine, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase, total bilirubin, direct bilirubin, gamma-glutamyl transferase (GGT), albumin and LDH. p. Pregnancy Test

A urine or serum pregnancy test will be obtained from female subjects who are of childbearing age prior to their participation in the study. q. Urinalysis

Urine will be obtained and sent to each site’s clinical laboratory for determination of color, specific gravity, pH, protein, glucose, ketones, and blood.

EVALUATIONS BY VISIT a. Visit 1

1. Review the study with the subject (subject’s legal representative) and obtain written informed consent and HIPAA authorization and assent, if appropriate.

2. Assign the subject a unique screening number.

3. Record demographics data.

4. Record medical history, including a history of obesity, anemia, HIV/AIDS, Chronic Yeast Infections, use of Full Spectrum Antibiotics, Chronic Ear Infections (OME), IBS or other inflammatory bowel disorders, blood clotting disorders, heart disease, severe allergies, gum disease, diagnosis date (s), and any prior treatments.

5. Record concomitant medications.

6. Perform a complete physical examination.

7. Perform and record vital signs.

8. Perform and record oximetry.

9. Perform and record results of blood pressure testing.

10. Collect blood for clinical laboratory tests (chemistry, hematology, prothrombin time, pregnancy test, methemoglobin, and serum nitrate).

11. Perform and record spirometry.

12. Collect sputum for culture.

13. Obtain an echocardiogram.

14. Obtain a chest x-ray.

15. Schedule subject for Visit 2 in 1 day.

16. List all additional procedures, such as Randomize subject, Dispense study drug, Initiate subject diary, etc. b. Visits 2-30

1. Record any Adverse Experiences and/or Review subject diary for adverse experiences and dosing compliance.

2. Concomitant medications review.

3. Perform abbreviated physical examination.

4. Perform and record vital signs. 5. Perform and record oximetry.

6. Perform and record spirometry.

7. List all additional procedures.

8. Record changes to concomitant medications.

9. Weekly: Collect blood sample for clinical laboratory tests: Chemistry, Hematology, Urinalysis, Pregnancy (urine or serum). c. Visit 31 (to be performed one week after administration of last dose).

1. Record any Adverse Experiences and/or Review subject diary for adverse experiences and exclusionary medication use.

2. Record changes to concomitant medications.

3. Perform complete physical examination.

4. Perform and record vital signs.

5. Perform and record oximetry.

6. Collect blood for clinical laboratory tests: Chemistry, Hematology, Urinalysis, Pregnancy (urine or serum).

7. Perform and record spirometry. d. Early Withdrawal Visit

1. Record ary Adverse Experiences and/or Review subject diary for adverse experiences and exclusionary medication use.

2. Record changes to concomitant medications.

3. Perform complete physical examination.

4. Perform and record vital signs.

5. Perform and record oximetry.

7. Perform and record spirometry. a. Adverse Events:

ICH E6 defines an AE as ary untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product regardless of its causal relationship to the study treatment. FDA defines an AE as ary untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.

An AE can therefore be ary unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of medicinal (investigational) product The occurrence of an AE may come to the attention of study personnel during study visits and interviews of a study recipient presenting for medical care, or upon review by a study monitor.

All AEs, including solicited local (injection site) and systemic (subjective and quantitative) reactions, will be captured on the appropriate data collection form and eCRF. Information to be collected for AEs includes event description, date of onset, assessment of severity, relationship to study product and alternate etiology (assessed only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as an investigator), date of resolution, seriousness and outcome. AEs occurring during the trial collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution.

Αny medical condition that is present at the time that the subject is screened will be considered as baseline and not reported as an AE. However, if the severity of any pre-existing medical condition increases, it should be recorded as an AE.

If an event meets both the criteria of a study endpoint and an adverse event, the event will be reported either as a study endpoint or as an adverse event (not both).

Safety oversight will be conducted by a DSMB that is an independent group with expertise to interpret data from this study and will monitor subject safety and advise DMID. The DSMB members will be separate and independent of study personnel participating in this study and should not have scientific, financial or other conflict of interest related to this study. DSMBs must consist of at least three voting members, including a biostatistician experienced in statistical methods for clinical trials and a clinician with relevant expertise.

The DSMB will operate under the rules of a DMID-approved charter that defines the data elements to be assessed and the procedures for data reviews and will be written at the organizational meeting of the DSMB. Procedures for DSMB reviews/meetings will be defined in the charter. Reports may include enrollment and demographic information, medical history, concomitant medications, physical assessments, clinical laboratory values, dosing compliance, and solicited and unsolicited AE/SAEs. The DSMB will review SAEs on a regular basis and ad hoc during this trial. The DMID Medical Monitor and the ISM (as deemed necessary) will be responsible for reviewing SAEs in real time.

As defined in the charter, the DSMB will review data at specified times during the course of the study for subject and overall study progress, and will conduct ad hoc reviews as appropriate when a halting rule is met or for immediate concerns regarding observations during this study. b. Adverse Events Granding:

All AEs (laboratory and clinical symptoms) will be graded for severity and assessed for relationship to study product (see definitions). AEs characterized as intermittent require documentation of onset and duration of each episode. The start and stop date of each reported AE will be recorded on the appropriate data collection form and eCRF. Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each level of intensity.

Severity of Event:

AEs will be assessed by the investigator using a protocol-defined grading system (toxicity table included as an appendix). For events not included in the protocol-defined grading system, the following guidelines will be used to quantify severity: • Mild (Grade 1): Events that are usually transient and may require only minimal or no treatment or therapeutic intervention and generally do not interfere with the subject’s usual activities of daily living.

• Moderate (Grade 2): Events that are usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant.

• Severe (Grade 3): Events interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating.

Relationship to Study Product: The assessment of the AE’s relationship to study product will be done by the licensed study physician indicated on the Form FDA 1572 and the assessment will be part of the documentation process. Whether the AE is related or not, is not a factor in determining what is or is not reported in this trial. If there is any doubt as to whether a clinical observation is an AE, the event should be reported.

In a clinical trial, the study product must always be suspect. The relationship to study product will be assessed for AEs using the terms related or not related:

• Related - There is a reasonable possibility that the study product caused the AE. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the AE.

• Not Related - There is not a reasonable possibility that the administration of the study product caused the event c. Serious Adverse Events;

An AE or suspected adverse reaction is considered a serious adverse event (SAE) if, in the view of either the site principal investigator or sponsor, it results in any of the following outcomes:

• Death,

• a life-threatening adverse eventl,

• inpatient hospitalization or prolongation of existing hospitalization,

• a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or

• a congenital anomaly/birth defect.

• Important medical events that may not result in death, be life-threatening, or require hospitalizations may be considered serious when, based upon appropriate medical judgment they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

1 Life-threatening adverse event. An AE is considered “life-threatening” if, in the view of either the site principal investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an AE that, had it occurred in a more severe form, might have caused death.

SAEs will be: • Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 or by the Institution as the site Principal Investigator or Sub-Investigator.

• Recorded on the appropriate SAE data collection form and eCRF.

• Followed through resolution by a licensed study physician (for IND studies, a physician listed on the Form FDA 1572 as the site Principal Investigator or Sub-Investigator).

• Reviewed and evaluated by DMID, an Independent Safety Monitor (ISM) (as deemed necessary), the DSMB or SMC (periodic review unless related), and the IRB/IEC. d. Specification of Safety Parameters:

Safety will be assessed by the severity of COVID-19.

Discontinuation and Replacement of Subjects: a. Early Discontinuation of Study Drug

A subject may be discontinued from study treatment at any time if the subject, the investigator, or the Sponsor feels that it is not in the subject’s best interest to continue. The following is a list of possible reasons for study treatment discontinuation:

• Subject withdrawal of consent (or assent)

• Subject is not compliant with study procedures

• Adverse event that in the opinion of the investigator would be in the best interest of the subject to discontinue study treatment

• Protocol violation requiring discontinuation of study treatment

• Lost to follow-up

• Sponsor request for early termination of study

• Positive pregnancy test (females)

If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized.

All subjects who discontinue study treatment should come in for an early discontinuation visit as soon as possible and then should be encouraged to complete all remaining scheduled visits and procedures.

All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified, and without prejudice.

Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals. The reason for the subject’s withdrawal from the study will be specified in the subject’s source documents Refer to Section 10 for early termination procedures. b. Withdrawal of Subjects from the Study

A subject may be withdrawn from the study at any time if the subject, the investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.

Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals. The reason for the subject’s withdrawal from the study will be specified in the subject’s source documents. As noted above, subjects who discontinue study treatment early (i.e., they withdraw prior to Visit X) should have an early discontinuation visit. Refer to Section 10 for early termination procedures. Subjects who withdraw after Visit X but prior to Visit X should be encouraged to come in for a final visit (and the procedures to be followed would include those for their next scheduled visit). c. Replacement of Subjects

Subjects who withdraw from the study treatment will be replaced.

PROTOCOL VIOLATIONS

A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to significant protocol requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria. Protocol violations for this study include, but are not limited to, the following:

• Failure to meet inclusion/exclusion criteria

Use of a prohibited concomitant medication

Include other specific examples as appropriate for the study (non-compliance with study drug regimen, etc.)

Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol violation. The Sponsor will determine if a protocol violation will result in withdrawal of a subject.

When a protocol violation occurs, it will be discussed with the investigator and a Protocol Violation Form detailing the violation will be generated. This form will be signed by a Sponsor representative and the Investigator. A copy of the form will be filed in the site’s regulatory binder and in the Sponsor’s files.

STATISTICAL METHODS AND CONSIDERATIONS

Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be written describing all analyses that will be performed. The SAP will contain ary modifications to the analysis plan described below. a. Data Sets Analyzed

All eligible patients who are randomized into the study and receive at least one dose of the study drug (the Safety Population) will be included in the safety analysis. b. Demographic and Baseline Characteristics

The following demographic variables at screening will be summarized by dose level: race, gender, age, height and weight.

DATA COLLECTION. RETENTION AND MONITORING a. Data Collection Instruments

The Investigator will prepare and maintain adequate and accurate source documents designed to record all observations and other pertinent data for each subject treated with the study drug.

Study personnel at each site will enter data from source documents corresponding to a subject’s visit into the protocol-specific electronic Case Report Form (eCRF) OR paper CRF when the information corresponding to that visit is available. Subjects will not be identified by name in the study database or on arty study documents to be collected by the Sponsor (or designee), but will be identified by a site number, subject number and initials.

For eCRFs: If a correction is required for an eCRF, the time and date stamps track the person entering or updating eCRF data and creates an electronic audit trail. For paper CRFs: If a correction is made on a CRF, the study staff member will line through the incorrect data, write in the correct data and initial and date the change.

The Investigator is responsible for all information collected on subjects enrolled in this study. All data collected during the course of this study must be reviewed and verified for completeness and accuracy by the Investigator. A copy of the CRF will remain at the Investigator’s site at the completion of the study. b. Data Management Procedures

The data will be entered into a validated database. The Data Management group will be responsible for data processing, in accordance with procedural documentation. Database lock will occur once quality assurance procedures have been completed.

All procedures for the handling and analysis of data will be conducted using good computing practices meeting FDA guidelines for the handling and analysis of data for clinical trials.

C. Data Quality Control and Reporting

After data have been entered into the study database, a system of computerized data validation checks will be implemented and applied to the database on a regular basis. For EDC studies: Queries are entered, tracked, and resolved through the EDC system directly. For paper studies: Query reports (Data Clarification Requests) pertaining to data omissions and discrepancies will be forwarded to the Investigators and shirty monitors for resolution. The study database will be updated in accordance with the resolved queries. All changes to the study database will be documented. d. Archival of Data

The database is safeguarded against unauthorized access by established security procedures; appropriate backup copies of the database and related software files will be maintained. Databases are backed up by the database administrator in conjunction with any updates or changes to the database.

At critical junctures of the protocol (e.g., production of interim reports and final reports), data for analysis is locked and cleaned per established procedures. e. Availability and Retention of Investigational Records The Investigator must make study data accessible to the monitor, other authorized representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request A file for each subject must be maintained that includes the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all source documentation related to that subject The Investigator must ensure the reliability and availability of source documents from which the information on the CRF was derived. All study documents (patient files, signed informed consent forms, copies of CRFs, Study File Notebook, etc.) must be kept secured for a period of two years following marketing of the investigational product or for two years after centers have been notified that the IND has been discontinued. There may be other circumstances for which the Sponsor is required to maintain study records and, therefore, the Sponsor should be contacted prior to removing study records for any reason. f. Monitoring

Monitoring visits will be conducted by representatives of the Sponsor according to the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the Investigator grants permission to the Sponsor (or designee), and appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate study documentation. g. Subject Confidentiality

In order to maintain subject confidentiality, only a site number, subject number and subject initials will identify all study subjects on CRFs and other documentation submitted to the Sponsor. Additional subject confidentiality issues (if applicable) are covered in the Clinical Study Agreement

ADMINISTRATIVE. ETHICAL. REGULATORY CONSIDERATIONS

The study will be conducted according to the Declaration of Helsinki, Protection of Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical Investigators (21 CFR 312).

To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records will be identified by a coded number and initials only. All study records will be kept in a locked file cabinet and code sheets linking a patient’s name to a patient identification number will be stored separately in another locked file cabinet. Clinical information will not be released without written permission of the subject, except as necessary for monitoring by the FDA. The Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). a. Protocol Amendments

Any amendment to the protocol will be written by the Sponsor. Protocol amendments cannot be implemented without prior written IRB/IEC approval except as necessary to eliminate immediate safety hazards to patients. A protocol amendment intended to eliminate an apparent immediate hazard to patients may be implemented immediately, provided the IRBs are notified within five working days. b. Institutional Review Boards and Independent Ethics Committees The protocol and consent form will be reviewed and approved by the IRB/IEC of each participating center prior to study initiation. Serious adverse experiences regardless of causality will be reported to the IRB/IEC in accordance with the standard operating procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of the study. The Investigator will obtain assurance of IRB/IEC compliance with regulations.

Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, payment or compensation procedures, or other pertinent information) will be submitted to the IRB/IEC. The IRB/IECs written unconditional approval of the study protocol and the informed consent form will be in the possession of the Investigator before the study is initiated. The IRB/IECs unconditional approval statement will be transmitted by the Investigator to the Sponsor or designee prior to the shipment of study supplies to the site. This approval must refer to the study by exact protocol title and number and should identify the documents reviewed and the date of review.

Protocol and/or informed consent modifications or changes may not be initiated without prior written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients or when the change(s) involves only logistical or administrative aspects of the study. Such modifications will be submitted to the IRB/IEC and written verification that the modification was submitted and subsequently approved should be obtained.

The IRB/IEC must be informed of revisions to other documents originally submitted for review; serious and/or unexpected adverse experiences occurring during the study in accordance with the standard operating procedures and policies of the IRB; new information that may affect adversely the safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and when the study has been completed. c. Informed Consent Form

Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), and local regulations.

The Investigator will prepare the informed consent form, assent and HIPAA authorization and provide the documents to the Sponsor or designee for approval prior to submission to the IRB/IEC. The consent form generated by the Investigator must be acceptable to the Sponsor and be approved by the IRB/IEC. The written consent document will embody the elements of informed consent as described in the International Conference on Harmonisation and will also comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for the study file.

A properly executed, written, informed consent will be obtained from each subject prior to entering the subject into the trial. Information should be given in both oral and written form and subjects (or their legal representatives) must be given ample opportunity to inquire about details of the study. If appropriate and required by the local IRB/IEC, assent from the subject will also be obtained. If a subject is unable to sign the informed consent form (ICF) and the HIPAA authorization, a legal representative may sign for the subject A copy of the signed consent form (and assent) will be given to the subject or legal representative of the subject and the original will be maintained with the subject’s records. d. Publications

The preparation and submittal for publication of manuscripts containing the study results shall be in accordance with a process determined by mutual written agreement among the study Sponsor and participating institutions. The publication or presentation of any study results shall comply with all applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability Act of 1996. Bibliography

1. Langereis JD, de Jonge MI. Invasive Disease Caused by Nontypeable Haemophilus influenzae. Emerg Infect Dis. 2015:21(10) 1711-1718. httns://dx doi.ore/10.3201/eid2110.150004

2. Bluestone, C. D. Otitis media in children: to treat or not to treat? N. Engl. J. Med. 306:1399-1404. PubMed.

3. Murphy, T. E, and M. A. Apicella. Nontypeable Haemophilus influenzae: a review of clinical aspects, surface antigens and the human response to infection. Rev. Infect Dis. 9: 1-15, https.//pubmed ncbi.nlm mh.gov/3547567/.

4. Cevik M, Moncayo-Nieto OL, Evans MJ. Non-typeable Haemophilus influenzae-associated early pregnancy loss: an emerging neonatal and maternal pathogen. Infection. 2020 Apr;48(2):285-288. doi: 10.1007/sl5010-019-01359-6. Epub 2019 Sep 23. PMID: 31549360; PMCID: PMC7292808.

5. Turk DC. The pathogenicity of Haemophilus influenzae. J Med Microbiol. 1984 Aug; 18(1): 1-16. doi: 10.1099/00222615-18-1-1. PMID: 6146721.

6. Szelestey, Blake R., et al. "Haemophilus Responses to Nutritional Immunity: Epigenetic and Morphological Contribution to Biofilm Architecture, Invasion, Persistence, and Disease Severity.” PLoS Pathogens, vol. 9, no. 10, 2003. DOI: 10.1371/joumal.ppat.1003709.

7. Nationwide Children's Hospital. "Why some ear, respiratory infections become chronic." ScienceDaily. ScienceDaily, 22 November 2013.

<www.sciencedaily.com/releases/2013/11/131122103934.htm>.

8. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus. 2020 Oct 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. PMID: 32150360. Originally accessed April 23, 2020.

9. Gulraiz, Fahad, et al. Haemophilus influenzae increases the susceptibility and inflammatory response of airway epithelia cells to viral infections.” The FASEB Journal, no. 29, 2015, pp. 849-858, www.fasebj.org. Accessed 23 April 2020.

10. Centers for Disease Control. “People with Certain Medical Conditions.” CDC, 1 December

2020, https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditi ons.html. Accessed 5 December 2020.

11. Wedzicha, J. A. “Rose of viruses in exacerbations of chronic obstructive pulmonary disease.” Proceedings of the American Thoracic Society, vol. 1, no. 2, 2006, pp. 115- 120.

12. Wilkinson, T M A., et al. "Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD.” Chest, vol. 129, no. 2, 2006, pp. 317-324.

13. Papi, A., et al. “Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations.” American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 10, 2006, pp. 1114-1121.

14. King, Paul T, and Roleen Sharma. “The Lung Immune Response to Nontypeable Haemophilus influenzae.” Hindawi Publishing Corporation, no. 706376, 2015, p. 14. http://dx.doi.org/10.1155/2015/706376. Accessed 21 April 2020.

15. McCance, Kathryn L, et al. Pathophysiology The Biologic Basis for Disease in Adults and Children. Seventh ed., St. Louis, Elsevier Mosby, 2014. P. 192 16. Clementi, C. F, and T. F Murphy. “Non-typeable Haemophilus influenzae invasion and persistence in the human respiratory tract” Frontiers in Cellular and Infection Microbiology, vol. 1, no. 1, 2011.

17. Nguyen, Lily R, et al. “Similar allergic inflammation in the middle ear and the upper airway: Evidence linking otitis media with effusion to the united airways concept” American Academy of Allergy, Asthma, and Immunology, 2004. doi:10.1016/j.jaci.2004.07.061.

18. Jono, H., and T. Shuto. “Transforming growth factor B-Smad signaling pathway cooperates with NF-kB to mediate nontypeable Haemophilus influenzae-induced MUC2 mucin transcription.” Journal of Biological Chemistry,, vol. 277, no. 47, 2002, pp. 44547-45557.

19. Khair, O. A., et al. “Bacterial induced release of inflammatory mediators by bronchial epithelial cells.” European Respiratory Journal, vol. 9, no. 9, 1996, pp. 1913-1922.

20. Sajjjan, U. S., et al. “H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression.” FASEB J., vol. 20, 2006, pp. 2121-2123.

21. NCBI. “Entrez Gene: intercellular adhesion molecule 1.” https://www.ncbi .nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=3383#bibliography

22. Bailey, Regina. “Types of Cells in the Human Body.” ThoughtCo., https.//www.thoughtco.com/types-of-cefls-in-the-bodv-373388?nrint-

23. Lei, J., et al. “Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein.” Antiviral Res., vol. 149, 2018, pp. 58-74.

24. Cascella M, Rajnik M, Cuomo A, et al. Features, Evaluation, and Treatment of Coronavirus. [Updated 2020 Oct 4], In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nhn.nih.gov/books/NBK554776/

25. Song W, Gui M, Wang X, Xiang Y. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog. 2018 Aug

13; 14(8):e 1007236. doi: 10.1371/joumal.ppat.1007236. PMID: 30102747; PMCID: PMC6107290.

26. Abraham, G, and R J Colonno. “Marty rhinovirus serotypes share the same cellular receptor.” Journal of virology vol. 51,2 (1984): 340-5. doi: 10.1128/JVI.51.2.340-345.1984

27. Van Dijk W, Mackiewicz A. Interleukin-6-type cytokine-induced changes in acute phase protein glycosylation. AnnN YAcad Sci. 1995 Jul 21;762:319-30. doi:

10.1111/j.1749-6632.1995.tb32336.x. PMID: 7545370.

28. Dewald, Justine H et al. “Role of Cytokine-Induced Glycosylation Changes in Regulating Cell Interactions and Cell Signaling in Inflammatory Diseases and Cancer.” Cells vol. 5,443. 29 Nov. 2016, doi: 10.3390/cells5040043

29. Godfred-Cato S, Bryant B, Leung J, et al. COVID- 19-Associated Multisystem Inflammatory Syndrome in Children — United States, March-July 2020. MMWR Morb Mortal Wkly Rep 2020;69:1074-1080. DOI: http://dx.doi.org/10.15585/mmwr.mm6932e2external icon

30. Antoni, Lena et al. “Intestinal barrier in inflammatory bowel disease.” World journal of gastroenterology vol. 20,5 (2014): 1165-79. doi: 10.3748/wjg.v20.i5.1165

31. Severe COVID- 19 Is Fueled by Disrupted Gut Barrier Integrity

Leila B. Giron, Harsh Dweep, Xiangfan Yin, Han Wang, Mohammad Damra, Aaron R Goldman, Nicole Gorman, Clovis S. Palmer, Hsin-Yao Tang, Maliha W. Shaikh, Christopher B. Forsyth, Robert A. Balk, Netanel F Zilberstein, Qin Liu, Andrew Kossenkov, Ah Keshavarzian, Alan Landay, Mohamed Abdel-Mohsen medRxiv 2020.11.13.20231209; doi: https://doi.org/l 0.1101/2020.11.13.20231209

32. Scott, David W et al. “Identification of a high-mannose ICAM- 1 glycoform: effects of ICAM-1 hypoglycosylation on monocyte adhesion and outside in signaling.” American journal of physiology. Cell physiology vol. 305,2 (2013): C228-37. doi: 10.1152/ajpcell.00116.2013

33. McCance, K. L., & Huether, S. E. (2010). Pathophysiology: The biologic basis for disease in adults and children (6th ed.) p. 194.

34. Black, Jacquelyn G, and Laura J. Black. Microbiology: Principles and Explorations. Hoboken, NJ: John Wiley & Sons, Inc, 2008. Print. P. 342.

35. Centers for Disease Control. Antibiotic Resistance Threats Report 2019, https://www.cdc.gov/ drugresistance/biggest-threats.htm l

36. G.F. Kroker, “Chronic Candidiasis and Allergy”, in Brostoff and S.J. Challacombe, eds., Food Allergy and Intolerance (Philadelphia: W.B. Saunders, 1987, 850-72.

37. Delaloye, Julie, and Thierry Calandra. “Invasive candidiasis as a cause of sepsis in the critically ill patient” Virulence vol. 5,1 (2014): 161-9. doi:10.4161/viru.26187

38. Amorim Dos Santos, Juliana et al. “Oral mucosal lesions in a COVID-19 patient: New signs or secondary manifestations?.” International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases vol. 97 (2020): 326-328. doi: 10.1016/j.ijid.2020.06.012

39. TODD, R M, and N V O'DONOHOE. “Acute acquired haemolytic anaemia associated with herpes simplex infection.” Archives of disease in childhood vol. 33,172 (1958): 524-6. doi: 10.1136/adc.33.172.524

40. National Institutes of Health. “Hemolytic Anemia” https://www.nhlbi.nih.gov/health-topics/hemolytic-anemia

41. Joseph Adrian L Buensalido et al. "Haemophilus Influenzae Infections”, Medscape, 2019. https://emedicine.medscape.com/article/218271-overview

42. Array o-Mendoza, Melissa et al. “Effect of testosterone and estrogen supplementation on the resistance to systemic Candida albicans infection in mice.” Heliyon vol. 6,7 e04437. 12 Jul. 2020, doi: 10.1016/j.heliyon.2020.e04437

43. US Department of Health and Human Services/Centers for Disease Control and Prevention. “Disparities in Incidence of COVID-19 Among Underrepresented Racial/Ethnic Groups in Counties Identified as Hotspots During June 5-18, 2020 — 22 States, Februaiy-June 2020.” Morbidity and Mortality Weekly Report, CDC, 21 August 2020, https://www.cdc.gov/mmwr/volumes/69/wr/mm6933e 1.htm. Accessed 5 December 2020.

44. Le, Chi Huu Hong. “The Prevalence of Anemia and Moderate-Severe Anemia in the US Population (NHANES 2003-2012).” PloS one vol. 11,11 e0166635. 15 Nov. 2016, doi: 10.1371/joumal.pone.0166635

45. Trattler Ross, Jones Adrian. “Better Health through Natural Healing”. Hinkler Books Pty Ltd; 2nd edition (October 1, 2004). P. 67-68

46. Musharraf HM, Arman MSI. Prophetic medicine is the cheapest, safest and the best remedy in the prevention and treatment of hypertension (high blood pressure) - a mini review. Int J Mol Biol Open Access. 2018;3(6):245-250. DOI: 10.15406/ijmboa.2018.03.00084 47. Wani, Bilal & Wani, Mohammad & Khan, Amina & Bodha, R & Mohidin, Fayaz & Hamid, Aadil. (2011). Some Herbs Mentioned in the Holy Quran and Ahadith and their Medicinal Importance in Contemporary Times. 44. 3888-3891.

48. Ahmad, Aftab et al. “A review on therapeutic potential of Nigella sativa: A miracle herb.” Asian Pacific journal of tropical biomedicine vol. 3,5 (2013): 337-52. doi: 10.1016/S2221-1691(13)60075-1

49. Zahara K, Tabassum S, Sabir S, Arshad M, Qureshi R, Amjad MS, Chaudhari SK. A review of therapeutic potential of Saussurea lappa-An endangered plant from Himalaya. Asian Pac J Trap Med. 2014 Sep;7S1:S60-9. doi: 10.1016/S1995-7645(14)60204-2. PMID: 25312191.

50. Imam Ibn Majah ^ “Sunan Ibn Majah”. www.Sunnah.com Book 31, Hadith 12.

51. Imam Abu Daud

“Sunan Abu Daud”. www.Sunnah com Sunan Abi Dawud 3877

52. Sunnan Ibn Majah. Book 36, Hadith 94, https://sunnah.com/ibnmajah/36/94. Accessed 2020.

53. Finer, Lawrence B. “Trends in premarital sex in the United States, 1954-2003.” Public health reports (Washington, D.C. : 1974) vol. 122,1 (2007): 73-8. doi: 10.1177/003335490712200110

54.

55. “Global Morality”. Pew Research Center. 2013. https://www.pewresearch.org/global/interactives/global-morality/

56. Watanabe, Kenji et al. “Traditional Japanese Kampo Medicine: Clinical Research between Modernity and Traditional Medicine-The State of Research and Methodological Suggestions for the Future.” Evidence-based complementary and alternative medicine : eCAM vol. 2011 (2011): 513842. doi: 10.1093/ecam/heq067

57. Reid D. (1996). The Shambhala Guide to Traditional Chinese Medicine. Boston, MA: Shambhala Publications. [Google Scholar]

58. Nishimura G. Evaluation of clinical efficacy of hochuekkito in improving nutritional/immune status in patients with surgery for large intestine carcinoma. Progress in Medicine 29: 84-5 (2009).

59. Tatsumi, K., et al. Hochuekkito improves systemic inflammation and nutritional status in elderly patients with chronic obstructive pulmonary disease. Journal of the American Geriatrics Society 57, 169-170 (2009).

60. Liu, X.Q., Wu, L. & Guo, X.J. Effect of Bu-Zhong-Yi-Qi-Tang on deficiency of N-glycan/nitric oxide and islet damage induced by streptozotocin in diabetic rats. World J Gastroenterol 15, 1730-1737 (2009).

61. Kiyohara, H., et al. Polysaccharide-containing Macromolecules in a Kampo (Traditional Japanese Herbal) Medicine, Hochuekkito: Dual Active Ingredients for Modulation of Immune Functions on Intestinal Peyer’s Patches and Epithelial cells. Evid Based Complement Altemat Med (2009).

62. Motoo Y, Nakatani N, Shimasaki T, et al. Usefulness of hochuekkito for fatigue associated with cancer chemotherapy*. Gan Chiryo no Ayumi (Advances in Cancer Treatment) 28: 39-43 (2009).

63. Yang, S.H. & Yu, C.L. Antiinflammatory effects of Bu-zhong-yi-qi-tang in patients with perennial allergic rhinitis. Journal of ethnopharmacology 115, 104-109 (2008).

64. Kobayashi H, Ishii M, Takeuchi S, et al. Efficacy and safety of a traditional herbal medicine, hochu-ekki-to in the long-term management ofkikyo (delicate constitution) patients with atopic dennatitis: A 6-month, multicenter, double-blind, randomized, placebo-controlled study. Evidence-based Complementary and Alternative Medicine: eCAM 1-7 (2008).

65. Matsumoto, T., Moriya, M., Kiyohara, H., Tabuchi, Y. & Yamada, H. Hochuekkito, a Kampo (Traditional Japanese Herbal) Medicine, and its Polysaccharide Portion Stimulate G-CSF Secretion from Intestinal Epithelial Cells. Evid Based Complement Altemat Med (2008).

66. Shinozuka, N., Tatsumi, K., Nakamura, A., Terada, J. & Kuriyama, T. The traditional herbal medicine Hochuekldto improves systemic inflammation in patients with chronic obstructive pulmonary disease. Journal of the American Geriatrics Society 55, 313-314 (2007).

67. Lee, David YWet al. “Traditional Chinese herbal medicine at the forefront battle against COVID-19: Clinical experience and scientific basis.” Phytomedicine : international journal of phytotherapy and phytopharmacology vol. 80 (2021): 153337. doi: 10.1016/j.phymed.2020.153337

68. Takanashi K, Dan K, Kanzaki S, Hasegawa H, Watanabe K, Ogawa K. Hochuekldto, a Japanese Herbal Medicine, Restores Metabolic Homeostasis between Mitochondrial and Glycolytic Pathways Impaired by Influenza A Virus Infection. Pharmacology. 2017;99(5-6):240-249. doi: 10.1159/000455918. Epub 2017 Feb 2. PMID: 28147362.

69. Matsumoto, Tsukasa et al. “Hochuekldto, a Kampo (traditional Japanese herbal) Medicine, Enhances Mucosal IgA Antibody Response in Mice Immunized with Antigen-entrapped Biodegradable Microparticles.” Evidence-based complementary and alternative medicine : eCAM vol. 7,1 (2010): 69-77. doi: 10.1093/ecam/heml66

70. Burns JJ, Zhao L, Taylor EW, Spelman K. The influence of traditional herbal formulas on cytokine activity. Toxicology. 2010 Nov 28;278(1): 140-59. doi: 10.1016/j.tox.2009.09.020. Epub 2009 Oct 7. PMID: 19818374.

71. Mills, S., Bone, K., 2000. Principles and Practice of Phytotherapy. Churchill Livingston,

New York.

72. Yimer EM, Tuem KB, Karim A, Ur-Rehman N, Anwar F. Nigella sativa L. (Black Cumin): A Promising Natural Remedy for Wide Range of Illnesses. Evid Based Complement Altemat Med. 2019 May 12;2019: 1528635. doi: 10.1155/2019/1528635. PMID: 31214267; PMCID: PMC6535880.

73. Honey and Nigella sativa against COVID-19 in Pakistan (HNS-COVID-PK): A multi-center placebo-controlled randomized clinical trial. Sohaib Ashraf, Shoaib Ashraf, Moneeb Ashraf, Muhammad Ahmad Imran, Larab Kalsoom, Uzma Nasim Siddiqui, Iqra Farooq, Zaighum Habib, Sidra Ashraf, Muhammad Ghufran, Muhammad Kiwan Akram, Nighat Majeed, Zain-ul-Abdin, Rutaba Akmal, Sundas Rafique, Khawar Nawaz, Muhammad Ismail K Yousaf, Sohail Ahmad, Muhammad Sarmad Shahab, Muhammad Faisal Nadeem, Muhammad Azam, Hui Zheng, Amber Malik, Mahmood Ayyaz, Talha Mahmud, Qazi Abdul Saboor, Ali Ahmad, Muhammad Ashraf, Mateen Izhar, for the COALITION COVID-19 Shaikh Zayed, Abubakar Hilal, Arz Muhammad, Zeeshan Shaukat, Ayesha Khaqan, Kanwal Hayat, Shahroze Arshad, Muhammad Hass an, Abeer-bin-Awais, Ammara Ahmad, Tayyab Mughal, Abdur Rehman Virk, Muhammad Umer, Muhammad Suhail, Sibgha Zulfiqar, Saulat Sarfraz, Muhammad Imran Anwar, Ayesha Humayun, RAKhokhar, S Siddique. medRxiv 2020.10.30.20217364; doi: https://doi.org/10.1101/2020.10.30.20217364 74. Susan L. Swain, corresponding author K. Kai McKinstry, and Tara M. Strutt. Expanding roles for CD4+ T cells in immunity to viruses. Nat Rev Immunol 2012; 12(2): 136-148. Published online 2012 Jan 20. doi: 10.1038/nri3152

75. Forouzanfar F, Bazzaz BS, Hosseinzadeh H. Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on antimicrobial effects. Iran J Basic Med Sci. 2014 Dec;17(12):929-38. PMID: 25859296; PMCID: PMC4387228.

76. Kang, Soowon et al. “Direct Antiviral Mechanisms of Interferon-Gamma.” Immune network vol. 18,5 c33. 17 Oct 2018, doi:10.4110/in.2018.18.e33

77. Bensiameur-Touati, Karima et al. “In Vivo Subacute Toxicity and Antidiabetic Effect of Aqueous Extract of Nigella sativa.” Evidence-based complementary and alternative medicine : eCAM vol. 2017 (2017): 8427034. doi: 10.1155/2017/8427034

78. Qidwai, Wans & Hamza, Hasan & Qureshi, Riaz & Gilani, Anwar-ul. (2009). Effectiveness, Safety, and Tolerabihty of Powdered Nigella sativa ( Kalonji ) Seed in Capsules on Serum Lipid Levels, Blood Sugar, Blood Pressure, and Body Weight in Adults: Results of a Randomized, Double-Blind Controlled Trial. Journal of alternative and complementary medicine (New York, N.Y.). 15. 639-44. 10.1089/acm.2008.0367.

79. Hamimatus Zainiyah, Ni Wayan Noviani, Rubiati Hipni. The positive effect of black cumin ethanol extract (Nigella sativa) on decreasing serum TNF-a levels and interleukin-8 levels in mice model of preeclampsia. Biomedical Research 2018; 29 (21): 3801-3806

80. Nicolas Dupin, Cyril Fisher, Paul Kellam, Sam Ariad, Micheline Tulliez, Nathalie Franck, Eric van Marck, Dominique Salmon, Isabelle Gorin, Jean-Paul Escande, Robin A. Weiss, Kari Alitalo, Chris Boshoff. Distribution of human herpesvirus-8 latently infected cells in Kaposi’s sarcoma, multicentric Castleman’s disease, and primary effiision lymphoma. Proceedings of the National Academy of Sciences Apr 1999, 96 (8) 4546-4551; DOI: 10.1073/pnas.96.8.4546.

81. Mackow ER, Gavrilovskaya IN. Hantavirus regulation of endothehal cell fimctions. Thromb Haemost. 2009 Dec;102(6): 1030-41. doi: 10.1160/TH09-09-0640. PMID: 19967132.

82. P. Galea, C. Vermot-Desroches, C. Le Contel, J. Wj denes, J.-C. Chermann. Circulating cell adhesion molecules in HIV 1 -infected patients as indicator markers for AIDS progression, Research in Immunology, Volume 148, Issue 2, 1997, Pages 109-117, ISSN 0923-2494, httns://doi.org/10.1016/S0923-2494(97)82482-0. (http://www.sciencedirect.com/science/article/pii/S0923249497824820)

83. Collins LF, Havers FP, Tunali A, Thomas S, Clennon JA, Wiley Z, Tobin-D'Angelo M, Parrott T, Read TD, Satola SW, Petit RA 3rd, Farley MM. Invasive Nontypeable Haemophilus influenzae Infection Among Adults With HIV in Metropolitan Atlanta, Georgia, 2008-2018. JAMA. 2019 Dec 24;322(24):2399-2410. doi: 10.100 l/jama.2019.18800. PMID: 31860046; PMCID: PMC6990662.

84. Raja, Aarti et al. “CD4 binding site antibodies inhibit human immunodeficiency virus gpl20 envelope glycoprotein interaction with CCR5.” Journal of virology vol. 77,1 (2003): 713-8. doi: 10.1128/jvi.77.1.713-718.2003

85. Puigdomenech I, Massanella M, Izquierdo-Useros N, Ruiz-Hemandez R, Curriu M, Bofill M, Martinez-Picado J, Juan M, Clotet B, Blanco J. HIV transfer between CD4 T cells does not require LFA-1 binding to ICAM- 1 and is governed by the interaction of HIV envelope glycoprotein with CD4. Retrovirology. 2008 Mar 31;5:32. doi: 10.1186/1742-4690-5-32. PMID: 18377648; PMCID: PMC2359761. 86. Mehlotra, Rajeev K. “Chemokine receptor gene polymorphisms and COVID-19: Could knowledge gained from HIV/AIDS be important?.” Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases vol. 85 (2020): 104512. doi: 10.1016/j.meegid.2020.104512

87. Sanders, Rogier & Jong, Esther & Baldwin, Chris & Schuitemaker, Joost & Kapsenberg, Martien & Berkhout, Ben. (2002). Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells. Journal of virology. 76. 7812-21.

10.1128/JVI.76.15.7812-7821.2002.

88. Allen, A.G., Chung, C.H., Atkins, A., et al., 2018. Gene editing of HIV-1 co-receptors to prevent and/or cure virus infection. Front Microbiol. 9, 2940.

89. Xu, M.M., 2020.

biology, gene editing, and warnings for the fixture of CRISPR-Cas9 as a human and humane gene editing tool. Cell Biosci. 10,48.

90. Onifade, Abdulfatah Adekunle et al. “Nigella sativa concoction induced sustained seroreversion in HIV patients.” African journal of traditional, complementary, and alternative medicines : AJTCAM vol. 10,5 332-5. 12 Aug. 2013

91. Islam, Mohammad Nazrul et al. “Revisiting pharmacological potentials of Nigella sativa seed: A promising option for COVID-19 prevention and cure.” Phytotherapy research : PTR, 10.1002/ptr.6895. 12 Oct 2020, doi: 10.1002/ptr.6895

92. Klein, Joshua S et al. “A dimeric form of the HIV- 1 antibody 2G12 elicits potent antibody-dependent cellular cytotoxicity.” AIDS (London, England) vol. 24,11 (2010): 1633-40. doi: 10.1097/qad.0b013e32833ad8c8

93. Zitzmann N, Block T, Methta A, Rudd P, Burton D, Wilson I, Platt F, Butters T, Dwek RA. Glycosylation: disease targets and therapy. Adv Exp Med Biol. 2005;564: 1-2. doi:

10.1007/0-387-25515-X_1. PMID: 16400797.

94. Platt EJ, Gomes MM, Kabat D. Kinetic mechanism for HIV-1 neutralization by antibody 2G12 entails reversible glycan binding that slows cell entry. Proc Natl Acad Sci U SA. 2012 May 15;109(20):7829-34. doi: 10.1073/pnas.1109728109. Epub 2012Apr 30. PMID: 22547820; PMCID: PMC3356642.

95. Nielsen F, Mikkelsen BB, Nielsen JB, Andersen HR, Grandjean P. Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clin Chem.

1997 Jul;43(7): 1209-14. PMID: 9216458.

96. Mostafa, Randa M et al. “Antioxidant effect of garhc (Album sativum) and black seeds (Nigella sativa) in healthy postmenopausal women.” SAGE open medicine vol. 1 2050312113517501. 24 Dec. 2013, doi:10.1177/2050312113517501

97. Sultan, Muhammad Tauseef et al. “Nigella sativa fixed and essential oil modulates glutathione redox enzymes in potassium bromate induced oxidative stress.” BMC complementary and alternative medicine vol. 15 330. 18 Sep. 2015, doi:10.1186/sl2906-015-0853-7

98. Salem ML, Hossain MS. Protective effect of black seed oil from Nigella sativa against murine cytomegalovirus infection. Int J Immunopharmacol. 2000 Sep;22(9):729-40. doi:

10.1016/s0192-0561(00)00036-9. PMID: 10884593.

99. Tardif, Melanie R, and Michel J Tremblay. “Presence of host ICAM-1 in human immunodeficiency virus type 1 virions increases productive infection of CD4+ T lymphocytes by favoring cytosolic delivery of viral material.” Journal of virology vol. 77,22 (2003): 12299-309. doi: 10.1128/jvi.77.22.12299-12309.2003 100. Onifade, A. A., Jewell, A. P, and Okesina, A. B. SERONEGATIVE CONVERSION OF AN HIV POSITIVE SUBJECT TREATED WITH NIGELLA SATIVAAND HONEY. Afr. J. Infect. Dis. (2015) 9(2): 47 - 50 http://dx.doi.org/10.4314/ajid.v9i2.6

101. Pandey MM, Rastogi S, RawatAK. Saussurea costus: botanical, chemical and pharmacological review of an ayurvedic medicinal plant J Ethnopharmacol. 2007 Apr 4;110(3):379-90. doi: 10.1016/j.jep.2006.12.033. Epub 2007 Jan 20. PMID: 17306480.

102. Jeong S J, Itokawa T, Shibuya M, Kuwano M, Ono M, Higuchi R, Miyamoto T. Costunolide, a sesquiterpene lactone from Saussurea lappa, inhibits the VEGFR KDR/Flk-1 signaling pathway. Cancer Lett. 2002 Dec 10; 187(1-2): 129-33. doi: 10.1016/s0304-3835(02)00361-0. PMID: 12359360.

103. Min JK, Lee YM, Kim JH, Kim YM, Kim SW, Lee SY, Gho YS, Oh GT, Kwon YG. Hepatocyte growth factor suppresses vascular endothelial growth factor-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-kappaB pathway. Circ Res. 2005 Feb 18;96(3):300-7. doi: 10.1161/01.RES.0000155330.07887.EE. Epub 2005 Jan 6. PMID: 15637298.

104. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J Biol Chem. 2001 Mar 9;276(10):7614-20. doi: 10.1074/jbc.M009705200. Epub 2000 Dec 6. PMID: 11108718.

105. Morbidelli L, Orlando C, Maggi CA, Ledda F, Ziche M. Proliferation and migration of endothelial cells is promoted by endothelins via activation of ETB receptors. Am J Physiol. 1995 Aug;269(2 Pt 2):H686-95. doi: 10.1152/ajpheart.1995.269.2.H686. PMID: 7653633.

106. Gokhale AB, Damre AS, Kulkami KR, SarafMN. Preliminary evaluation of anti-inflammatory and anti-arthritic activity of S. lappa, A. speciosa and A. aspera. Phytomedicine. 2002 Jul;9(5):433-7. doi: 10.1078/09447110260571689. PMID: 12222664.

107. Hao Wang, Zixuan Yuan, Mahmud Arif Pavel, Robert Hobson, Scott B. Hansen. The role of high cholesterol in age-related COVID19 lethality. Version 4. bioRxiv. Preprint NaN NaN [revised 2020 Jul 29], doi: 10.1101/2020.05.09.086249]

108. Saleem, T S Mohamed et al. “Aqueous extract of Saussurea lappa root ameliorate oxidative myocardial injury induced by isoproterenol in rats.” Journal of advanced pharmaceutical technology & research vol. 4,2 (2013): 94-100. doi: 10.4103/2231-4040.111525

109. Jeong S J, Itokawa T, Shibuya M, Kuwano M, Ono M, Higuchi R, et al. Costunolide, a sesquiterpene lactone from Sassuera lappa, inhibits the VEGFR KDR/Flk-1 signaling pathway. Cancer Lett 2002; 187: 129-133.

110. Saif-Al-Islam, Mahmoud. Saussurea costus may help in the treatment of COVID-19. Sohag Medical Journal. Vol. 24 No. 3 July 2020.

111. Silveira, Damans et al. “COVID-19: Is There Evidence for the Use of Herbal Medicines as Adjuvant Symptomatic Therapy?.” Frontiers in pharmacology vol. 11 581840. 23 Sep. 2020, doi: 10.3389/fphar.2020.581840

112. Chu DT, Wong WL, Mavligit GM. Immunotherapy with Chinese medicinal herbs I. Immune restoration of local xenogeneic graft-versus-host reactions in cancer patients by fractionated Astragalus membranaceus in vitro. Journal of clinical laboratory immunology, 1988, 25: 119-123. 113. Yang YZ et al. Effect of Astragalus membranaceus on natural killer cell activity and induction of alpha- and gamma-interferon in patients with coxsackie B viral myocarditis. Chung-hua i hseuh tsa chih (English Edition), 1990, 103:304-307.

114. Bombardelli E, Pozzi R. Polysaccharides with immunomodulating properties from Astragalus membranaceus. Europe patent, 1991, 441:278.

115. Chu DT et al. Fractionated extract of Astragalus membranaceus, a Chinese medicinal herb, potentiates LAK cell cytotoxicity generated by a low dose of recombinant inteiieukin-2. Journal of clinical laboratory immunology, 1988, 26: 183-187.

116. Chu DT, Wong WL, Mavligit GM. Immunotherapy with Chinese medicinal herbs II.

Reversal of cyclophosphamide-induced immune suppression by administration of fractionated Astragalus membranaceus in vivo. Journal of clinical laboratory immunology, 1988, 25: 125-129.

117. Chang HM, But PPH, eds. Pharmacology and applications of Chinese materia medica, Vol. 2. Singapore, World Scientific Publishing, 1987.

118. Morazzoni P, Bombardelli E. Astragalus membranaceus (Fish.) Bge. Milan, Indena, 1994.

119. Adesso, Simona et al. “Astragalus membranaceus Extract Attenuates Inflammation and Oxidative Stress in Intestinal Epithelial Cells via NF-KB Activation and Nrf2 Response.” International journal of molecular sciences vol. 19,3 800. 10 Mar. 2018, doi: 10.3390/ijms 19030800

120. Zhou KS, Mancini C, Doria G. Enhancement of the immune response in mice by Astragalus membranaceus extracts. Immunopharmacology, 1990, 20:225-233.

121. Institute of Basic Medical Sciences, The Chinese Academy of Medical Sciences. Immunity parameters and blood cAMP changes in normal persons after ingestion of Radix Astragali.

Chung hua i hsueh t’sa chih, 1979, 59:31-34.

122. World Health Organization, WHO Consultation on Selected Medicinal Plants, Vol.1, pg. 56

123. National Institutes of Health. Astragalus. Last updated August 2020. https://www.nce ih.nih.gov/health/astraealus

124. Abdul-Majeed Bin Aziz Alzandani. The Use of A Herbal Composition for the Treatment of A Person Infected with HIV. World Intellectual Property Organization. International Publication Number: WO 2012/039574 Al. https' //patents gnogla cnm/patent/WQ2011039574A 1/en

125. Leung A, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics, 2 ed. New York, John Wiley, 1996.

126. Tomoda M et al. A reticuloendothelial system-activating glycan from the roots of Astragalus membranaceus. Phytochemistry, 1992, 31:63-66.

127. Bruneton J. Pharmocognosy, phytochemistry, medicinal plants. Paris, Lavoisier, 1995:400-404.

128. Hikino H. Orienal medicinal plants. In: Wagner H, Hildno H, Farnsworth NR, eds. Economic and medicinal plant research Vol. 1. London, Academic Press, 1985.

129. Jin L, Zhang LM, Xie KQ, Ye Y, Feng L. Paeoniflorin suppresses the expression of intercellular adhesion molecule- 1 (ICAM-1) in endotoxin-treated human monocytic cells. Br J Pharmacol. 2011 Sep;164(2b):694-703. doi: 10.1111/j.l476-5381.2011.01464.x. PMID: 21542832; PMCID: PMC3188904.

130. Mao QQ, Ip SP, Xian YF, Hu Z, Che CT. Antidepressant-like effect of peony: a mini-review. Pharm Biol. 2012 Jan;50(l):72-7. doi: 10.3109/13880209.2011.602696. PMID: 22196583. 131. Carabotti, Manila et al. “The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.” Annals of gastroenterology vol. 28,2 (2015): 203-209.

132. Kumasaka T, Quinlan WM, Doyle NA, Condon TP, Sligh J, Takei F, Beaudet Al, Bennett CF, Doerschuk CM. Role of the intercellular adhesion molecule- 1(ICAM- 1) in endotoxin-induced pneumonia evaluated using ICAM- 1 antisense oligonucleotides, anti-ICAM- 1 monoclonal antibodies, and ICAM-1 mutant mice. J Clin Invest 1996 May 15;97(10):2362-9. doi:

10.1172/JCI 118679. PMID: 8636417; PMCID: PMC507317.

133. Qiuyan Guo, Koji Mizuno, Katsuki Okuyama, Na Lin, Yanqiong Zhang, Hideki Hayashi, Norio Takagi, Takashi Sato, Antineuropathic pain actions of Wu-tou decoction resulted from the increase of neurotrophic factor and decrease of CCR5 expression in primary rat glial cells, Biomedicine & Pharmacotherapy, Volume 123, 2020, 109812, ISSN 0753-3322, https://doi.org/10.1016/j.biopha.2020.109812.

134. Chen, YF., Lee, MM., Fang, HL. et al. Paeoniflorin inhibits excitatory amino acid agonist-and high-dose morphine-induced nociceptive behavior in mice via modulation of

N-methyl-D- aspartate receptors. BMC Complement Altem Med 16, 240 (2016). https://doi.org/10.1186/s12906 -016-1230 -x

135. Fusco Davide, Dinallo Vincenzo, Marafini Irene, Fighuzzi Michele M., Romano Barbara, Monteleone Giovanni. Antisense Ohgonucleotide: Basic Concepts and Therapeutic Application in Inflammatory Bowel Disease. Frontiers in Pharmacology. Vol. 10. 2019 https://www.frontiersin.org/article/10.3389/fphar.2019.00305 doi: 10.3389/fphar.2019.00305

136. Mao Q, Huang Z, Ip S, Che C. Antidepressant-like effect of ethanol extract from Paeonia lactiflora in mice. Phytother Res. 2008 Nov;22(11): 1496-9. doi: 10.1002/ptr.2519. PMID: 18570231.

137. Woo WS et al. A review of research on plants for fertility regulation in Korea. Korean journal of pharmacognosy, 1981, 12:153-170.0

138. Keys JD. Chinese herbs, their botany, chemistry, and pharmacodynamics. Rutland, VT, CE Tuttle, 1976.

139. Pharmacopoeia of the People’s Republic of China (English ed.). Guangzhou, Guangdong Science and Technology Press, 1992.

140. He, Dong-Yi, and Sheng-Ming Dai. “Anti-inflammatory and immunomodulatory effects of paeonia lactiflora pall., a traditional Chinese herbal medicine.” Frontiers in pharmacology vol. 2 10. 25 Feb. 2011, doi: 10.3389/fphar.2011.00010

141. Mukherjee, P.K., Mukherjee, D., Maji, A.K., Rai, S. and Heinrich, M. (2009), The sacred lotus (Nelumbo nucifera)- phytochemical and therapeutic profile. Journal of Pharmacy and Pharmacology, 61: 407-422. https://doi.org/10.1211/ipp.61.04.0001

142. Marafini, Irene, and Giovanni Monteleone. “Therapeutic Oligonucleotides for Patients with Inflammatory Bowel Diseases.” Biologies : targets & therapy vol. 1447-51. 15 Jim. 2020, doi: 10.2147/BTT.S257638

143. Walter Reinisch, Kenneth Hung, Mina Hassan-Zahraee, Fabio Cataldi, Targeting Endothelial Ligands: ICAM- 1/alicaforsen, MAdCAM-1, Journal of Crohn's and Colitis, Volume 12, Issue suppl_2, August 2018, Pages S669-S677, https://doi.org/10.1093/ecco-jcc/jjy059

144. Vainer B, Nielsen OH. Changed colonic profile of P-selectin, platelet-endothelial cell adhesion molecule- 1 (PECAM-1), intercellular adhesion molecule- 1 (ICAM-1), ICAM-2, and ICAM-3 in inflammatory bowel disease. Clin Exp Immunol. 2000 Aug;121(2):242-7. doi:

10.1046/j.1365-2249.2000.01296.x PMID: 10931137; PMCID: PMC1905699.

145. Tiruppur Venkatachallam, Suresh Kumar et al. “Chemical composition of Nigella sativa L. seed extracts obtained by supercritical carbon dioxide.” Journal of food science and technology vol. 47,6 (2010): 598-605. doi:10.1007/sl3197-010-0109-y

146. Zhang T, Yang Y, Du G, Chen R. [Study on chemical constituents from the roots of Saussurea lappa], Zhongguo Zhong Yao Za Zhi. 2011 Jun;36(12): 1620-2. Chinese. PMID: 22007546.

147. Li, W. -Z., Li, W. -P., Zhang, W, Yin, Y. - Y, Sun, X. -X., Zhou, S. - S., Xu, X. -Q. and Tao,

C. - R (2011), Protective Effect of Extract of Astragalus on Learning and Memory Impairments and Neurons Apoptosis Induced by Glucocorticoids in 12 -Month Male Mice. Anat Rec, 294:

1003-1014. https://doi.org/10.1002/ar.21386

148. Rai S, Wahile A, Mukheijee K, Saha BP, Mukheijee PK. Antioxidant activity of Nelumbo nucifera (sacred lotus) seeds. J Ethnopharmacol. 2006 Apr 6;104(3):322-7. doi: 10.1016/j.jep.2005.09.025. Epub 2005 Oct 18. PMID: 16239089.

149. Lin, Jin-Yuam & Wu, Ann-Ru & Liu, Chien-Jung & Lai, Ymg-Shu. (2006). Suppressive effects of lotus plumule (Nelumbo nucifera Geartn.) supplementation on LPS-induced systemic inflammation in a BALB/c mouse model. Journal of Food and Drug Analysis. 14. 10.38212/2224-6614.2472.

150. Mazumder UK et al. Antifertility activity of seed of Nelumbo nucifera in mice. Ind J Exp Biol 1992; 30: 533-534.

151. World Health Organization, WHO Consultation on Selected Medicinal Plants, Vol.1, pg. 168-182.

152. Scaghone F, Ferrara F, Dugnani S, Falchi M, Santoro G, Fraschini F. Immunomodulatory effects of two extracts of Panax ginseng C.A. Meyer. Drugs Exp Clin Res. 1990;16(10):537-42. PMID: 2100737.

153. Lee, Nam-Hun et al. “Safety and tolerability of Panax ginseng root extract: a randomized, placebo-controlled, clinical trial in healthy Korean volunteers.” Journal of alternative and complementary medicine (New York, N.Y.) vol. 18,11 (2012): 1061-9. doi:10.1089/acm.2011.0591

154. Jones BD, Runikis AM. Interaction of ginseng with phenelzine. Journal of clinical psychopharmacology, 1987, 7:201-202.

155. Shader RI, Greenblatt DJ. Phenelzine and the dream machine-ramblings and reflections. Journal of clinical psychopharmacology, 1985, 5:67.

156. Chang HM, But PPH, eds. Pharmacology and applications of Chinese materia medica, Vol. 2. Singapore, World Scientific Publishing, 1987.

157. Tang W, Eisenbrand G, eds. Chinese drugs of plant origins, chemistry, pharmacology, and use in traditional and modem medicine. Berlin, Springer-Verlag, 1992.

158. Yamada H. Purification of anti-ulcer polysaccharides from the roots of Bupleurum falcatum. Planta medica, 1991, 57:555-559.

159. Yamada H, Hirano M, Kiyohara H. Partial structure of anti-ulcer pectic polysaccharide from the roots of Bupleurum falcatum L. Carbohydrate research, 1991, 219: 173-192.

160. World Health Organization, WHO Consultation on Selected Medicinal Plants, Vol.1, pg.

67-77. 161. Law, Betty Yuen-Kwan et al. “Autophagic effects of Chaihu (dried roots of Bupleurum Chinense DC or Bupleurum scorzoneraefolium WILD).” Chinese medicine vol. 921. 11 Sep. 2014, doi: 10.1186/1749-8546-9-21

162. Ren, Xia et al. "Identifying potential treatments of COVID-19 from Traditional Chinese Medicine (TCM) by using a data-driven approach.” Journal of ethnopharmacology vol. 258 (2020): 112932. doi: 10.1016/j.jep.2020.112932

163. Kim, S. O., Park, J. Y, Jeon, S. Y, Yang, C. H., Kim, M. R"Saikosaponin a, an active compound of Radix Bupleuri, attenuates inflammation in hypertrophied 3T3-L1 adipocytes via ERK/NF-KB signaling pathways". International Journal of Molecular Medicine 35.4 (2015): 1126-1132.

164. Ekiert, Halina et al. “Significance of Artemisia Vulgaris L. (Common Mugwort) in the History of Medicine and Its Possible Contemporary Applications Substantiated by Phytochemical and Pharmacological Studies.” Molecules (Basel, Switzerland) vol. 25,194415. 25 Sep. 2020, doi: 10.3390/molecules25194415

165. Lian G, Li F, Yin Y, Chen L, Yang J. Herbal extract of Artemisia vulgaris (mugwort) induces antitumor effects in HCT-15 human colon cancer cells via autophagy induction, cell migration suppression and loss of mitochondrial membrane potential. J BUON. 2018 Jan-Feb;23(l):73-78. PMID: 29552763.

166. D'Ovidio, Valeria et al. “Impact of COVID-19 Pandemic on Colorectal Cancer Screening Program.” Clinical colorectal cancer, S1533-0028(20)30101-8. 30 Jul. 2020, doi: 10.1016/j.clcc.2020.07.006

167. Di Renzo, Laura et al. “Psychological Aspects and Eating Habits during COVID-19 Home Confinement: Results of EHLC-COVID-19 Italian Online Survey.” Nutrients vol. 12,72152. 19 Jul. 2020, doi: 10.3390/hul2072152

168. Guo, Yu-Bin et al. “Association between Diet and Lifestyle Habits and Irritable Bowel Syndrome: A Case-Control Study.” Gut and liver vol. 9,5 (2015): 649-56. doi: 10.5009/gnll3437

169. Chang, H-C et al. “Irritable bowel syndrome and the incidence of colorectal neoplasia: a prospective cohort study with community-based screened population in Taiwan.” British journal of cancer vol. 112,1 (2015): 171-6. doi: 10.1038/bjc.2014.575

170. Blagojevic, P; Radulovic, N.; Palic, R; Stojanovic, G. Chemical composition of the essential oils of Serbian wild-growing Artemisia absinthium and Artemisia vulgaris. J. Agric. Food Chem. 2006, 54, 4780-4789.

171. Erel, B.; Aydin, F.; Ballar, P. In vitro cytotoxic properties of six Artemisia L. species.

Turkish J. Pharm. Sci. 2011, 8, 247-251.

172. Temraz A, El-Tantawy WH. Characterization of antioxidant activity of extract from Artemisia vulgaris. Pak J Pharm Sci. 2008 Oct;21(4):321-6. PMID: 18930849.

173. El-Tantawy, Walid Hamdy. “Biochemical effects, hypohpidemic and anti-inflammatory activities of Artemisia vulgaris extract in hypercholesterolemic rats.” Journal of clinical biochemistry and nutrition vol. 57,1 (2015): 33-8. doi: 10.3164/jcbn.14-141

174. Duffy, et al. Why are RNA virus mutation rates so damn high? PloS Biol. 2018. httPs://doi.org/ 10.1371/journal. pbio 3000003.

175. Salikhova, R A. et al. “Antimutagenic properties of medicinal angehca (Angelica archangelica L.) studied with the micronucleus test” Bulletin of Experimental Biology and Medicine 115 (2004): 390-392. 176. Maurya, Anupam & Verma, Dr Subash & Gupta, Vijay & Shankar, M.. (2017). Angehca archangelica L.-A Phytochemical and Pharmacological Review. Asian Journal of Research in Chemistry. 10. 852. 10.5958/0974-4150.2017.00142.0.

177. Janiak MK, Wincenciak M, Cheda A, Nowosielska EM, Calabrese EJ. Cancer immunotherapy: how low-level ionizing radiation can play a key role. Cancer Immunol Immunother. 2017 Jul;66(7): 819-832. doi: 10.1007/s00262-017-1993-z. Epub 2017 Mar 30. PMID: 28361232; PMCID: PMC5489643.

178. Kumar D, Bhat ZA, Shah MY. Anti-anxiety activity of successive extracts of Angehca archangelica Linn, on the elevated T-maze and forced swimming tests in rats. J Tradit Chin Med. 2012 Sep;32(3):423-9. doi: 10.1016/s0254-6272(13)60049-7. PMID: 23297567.

179. Fratemale D, Flamini G, Ricci D. Essential oil composition and antimicrobial activity of Angehca archangehca L. (Apiaceae) roots. J Med Food. 2014 Sep; 17(9): 1043-7. doi:

10.1089/jmf.2013.0012. Epub 2014 May 2. PMID: 24788027.

180. Fratemale, Daniele & Flamini, Guido & Ricci, D.. (2014). Essential oil composition of Angehca archangehca L. (Apiaceae) roots and its antifungal activity against plant pathogenic fungi. Plant Biosystems - An International Journal Dealing with all Aspects of Plant Biology. 150. 1-6. 10.1080/11263504.2014.988190.

181. Bhat, Zulfiqar & Kumar, Dinesh & Shah, M.Y.. (2011). Angehca archangehca Linn. isAngal on earth for the treatment of diseases: A review.. IJNPND. 1. 36-50. 10.4103/2231-0738.77531.

182. Amraei, Razie, and Nader Rahimi. “COVID- 19, Renin-Angiotensin System and Endothelial Dysfunction.” Cells vol. 9,7 1652. 9 Jul. 2020, doi: 10.3390/cells9071652

183. Amraie, Razie et al. “CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2 and are differentially expressed in lung and kidney epithelial and endothelial cells.” bioRxiv : the preprint server for biology 2020.06.22.165803. 23 Jim. 2020, doi: 10.1101/2020.06.22.165803. Preprint

184. Davies, Julie et al. “Neuropilin-1 as a new potential SARS-CoV-2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID-19.” Molecular medicine reports vol. 22,5 (2020): 4221-4226. doi: 10.3892/mmr.2020.11510

185. Daly JL, Simonetti B, Klein K, Chen KE, Williamson MK, Anton-Plagaro C, Shoemark DK, Simon-Gracia L, Bauer M, Hollandi R, Greber UF, Horvath P, Sessions RB, Helenius A, Hiscox JA, Teesalu T, Matthews DA, Davidson AD, Collins BM, Cullen PJ, Yamauchi Y. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science. 2020 Nov 13;370(6518):861-865. doi:

10.1126/science.abd3072. Epub 2020 Oct 20. PMID: 33082294.

186. Ulrich, Henning, and Micheli M Pillat. “CD 147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement” Stem cell reviews and reports vol. 16,3 (2020): 434-440. doi: 10.1007/sl2015-020-09976-7

187. Kerr JR Cell adhesion molecules in the pathogenesis of and host defence against microbial infection. Mol Pathol. 1999 Aug;52(4):220-30. doi: 10.1136/mp.52.4.220. PMID: 10694943; PMCID: PMC395703.

188. Tong, Ming et al. “Elevated Expression of Serum Endothelial Cell Adhesion Molecules in COVID-19 Patients.” The Journal of infectious diseases vol. 222,6 (2020): 894-898. doi: 10.1093/infdis/jiaa349

189. Tardif, Melanie R, and Michel J Tremblay. “Presence of host ICAM-1 in human immunodeficiency virus type 1 virions increases productive infection of CD4+ T lymphocytes by favoring cytosolic delivery of viral material.” Journal of virology vol. 77,22 (2003): 12299-309. doi: 10.1128/jvi.77.22.12299-12309.2003

190. Rege A.A., Ambaye RY, Deshmukh R.A. Evaluation of in vitro inhibitory effect of selected plants and Shilajit on HIV-reverse transcriptase. Indian J. Nat Prod. Res. 2012;3:145-151.

191. Prakash P, Gupta N. Therapeutic uses of Ocimum sanctum Linn (Tulsi) with a note on eugenol and its pharmacological actions: a short review. Indian J Physiol Pharmacol. 2005 Apr;49(2): 125-31. PMID: 16170979.

192. Rege, Anuya & Ambaye, Ramkrishna & Deshmukh, Ranjana. (2010). In-vitro testing of anti-HIV activity of some medicinal plants. Indian Journal of Natural Products and Resources. 1. 193-199.

193. Silprasit K., Seetaha S., Pongsanarakul P, Hannongbua S., Choowongkomon K. Anti-HIV- 1 reverse transcriptase activities of hexane extracts from some Asian medicinal plants. J. Med. Plants Res. 2011;5:4194-4201.

194. Baliga MS, Rao S, Rai MP, D'souza P. Radio protective effects of the Ayurvedic medicinal plant Ocimum sanctum Linn. (Holy Basil): A memoir. J Cancer Res Ther. 2016 Jan-Mar;12(l):20-7. doi: 10.4103/0973-1482.151422. PMID: 27072205.

195. Devi PU, Ganasoundari A. Radioprotective effect of leaf extract of Indian medicinal plant Ocimum sanctum. Indian J Exp Biol. 1995 Mar;33(3):205-8. PMID: 7601491.

196. Minasyan, Hayk. “Sepsis: mechanisms of bacterial injury to the patient” Scandinavian journal of trauma, resuscitation and emergency medicine vol. 27,1 19. 14 Feb. 2019, doi: 10.1186/sl3049-019-05964

197. UMAMAGESWARI, A.; KUDAGI, B. L.. Anti-inflammatory and analgesic properties of Ocimum sanctum: a comparative study using animal models. International Journal of Basic & Clinical Pharmacology, [S.1.], v. 4, n. 5, p. 981-986, dec. 2016. ISSN 2279-0780. Available at: <https://www.ijbcp.com/indexphp/ijbcp/article/view/225/208>. Date accessed: 23 dec. 2020. doi:http://dx.doi.org/10.18203/2319-2003 ijbcp20150878.

198. Vohora SB, Garg SK, Chaudhury RR Antifertility screening of plants. 3. Effect of six indigenous plants on early pregnancy in albino rats. Indian J Med Res. 1969 May ;57(5): 893-9. PMID: 5820437.

199. Mizutani T, Satoh K, Nomura H. Hepatotoxicity of eugenol and related compounds in mice depleted of glutathione: structural requirements for toxic potency. Res Comtnun Chem Pathol Pharmacol. 1991 Jul;73(1):87-95. PMID: 1882130.

200. Gautam, M K, and R K Goel. “Toxicological Study of Ocimum sanctum Linn Leaves: Hematological, Biochemical, and Histopathological Studies.” Journal of toxicology vol. 2014 (2014): 135654. doi: 10.1155/2014/135654

201. Sharma G. Antiasthmatic effect of Ocimum sanctum. Sacitra Ayurveda, 1983, 35:665-668.

202. Lei J, Kusov Y, Hilgenfeld R Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein. Antiviral Res. 2018 Jan; 149:58-74 [PubMed: 29128390]

203. Langereis, J D., Jonge M L. Invasive Disease Caused by Nontypeable Haemophilus Influenzae. Emerging Infectious Diseases Vol. 21, No. 10, October 2015. DOI: http://dx.doi.org/10.3201 /eid2110.150004

204. Wu, Z.; McGoogan, J.M. Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020, 323, 1239-1242. 205. Chen XM, Tait AR, Kitts DD. Flavonoid composition of orange peel and its association with antioxidant and anti-inflammatory activities. Food Chem. 2017 Mar 1;218: 15-21. doi:

10.1016/j.foodchem.2016.09.016. Epub 2016 Sep 6. PMID: 27719891.

206. F avela-Hemandez, Juan Manuel J et al. “Chemistry and Pharmacology of Citrus sinensis.” Molecules (Basel, Switzerland) vol. 21,2247. 22 Feb. 2016, doi: 10.3390/molecules21020247

207. Muhtadi, Haryoto, Azizah T, Suhendi A, Yen KH. Antidiabetic and antihypercholesterolemic activities of Citrus sinensis peel: in vivo study. Natl J Physiol Pharm Pharmacol 2015;5:382-385.

208. World Health Organization, WHO Consultation on Selected Medicinal Plants, Vol.2, pg. 277-287

209. Chen H, Tang X, Liu T, Jing L, Wu J. Zingiberene inhibits in vitro and in vivo human colon cancer cell growth via autophagy induction, suppression of PI3K/AKT/mTOR Pathway and caspase 2 deactivation. J BUON. 2019 Jul-Aug;24(4): 1470-1475. PMID: 31646793.

210. Mazza, G, and B D. Oomah. Herbs, Botanicals & Teas. Lancaster: Technomic Publishing Compary, 2000. Print

211. Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol. 1991 Jan 4;38(1): 19-24. doi:

10.1016/0028-2243(9 l)90202-v. PMID: 1988321.

212. Yamamoto H, Mizutani T, Nomura H. [Studies on the mutagenicity of crude drug extracts. I]. Yakugaku Zasshi. 1982 Jun;102(6):596-601. Japanese, doi: 10.1248/yakushil947.102.6_596. PMID: 6757409.

213. Chang, Ying-ling et al. “Glycyrrhetinic acid inhibits ICAM- 1 expression via blocking JNK and NF-kappaB pathways in TNF -alpha-activated endothehal cells.” Acta pharmacologica Sinica vol. 31,5 (2010): 546-53. doi:10.1038/aps.2010.34

214. Mitscher LA, Park YH, Clark D, Beal JL. Antimicrobial agents from higher plants. Antimicrobial isoflavanoids and related substances from Glycyrrhiza glabra L. var. typica. J Nat Prod. 1980 Mar-Apr;43(2):259-69. doi: 10.1021/np50008a004. PMID: 7381508.

215. Chakravarthi, Kosuri Kalyan, and Ramakrishna Avadhani. “Beneficial effect of aqueous root extract of Glycyrrhiza glabra on learning and memory using different behavioral models: An experimental study.” Journal of natural science, biology, and medicine vol. 4,2 (2013): 420-5. doi: 10.4103/0976-9668.117025

216. World Health Organization, WHO Consultation on Selected Medicinal Plants, Vol.1, pg. 183-193.

217. Kilicgun H, Dehen A. In vitro antioxidant effect of Rosa canina in different antioxidant test systems. Phcog Res. 2009;1:417-420.

218. Aresenescu A. Pharmacognostical research on the species Rosa canina L. (in Romanian): UMF Cluj-Napoca; 2008.

219. Orhan N, Aslan M, Hosbas S, Deliorman O. Antidiabetic effect and antioxidant potential of Rosa canina fruits. Phcog Mag. 2009;5:309^-315. doi: 10.4103/0973-1296.58151.

220. Gorton HC, Jarvis K. The effectiveness of vitamin C in preventing and relieving the symptoms of virus-induced respiratory infections. J Manipulative Physiol Ther. 1999 Oct;22(8):530-3. doi: 10.1016/s0161-4754(99)70005-9. PMID: 10543583.

221. Kerasioti, Efihalia et al. “Polyphenolic Composition of Rosa canina, Rosa sempervivens and Pyrocantha coccinea Extracts and Assessment of Their Antioxidant Activity in Human Endothelial Cells.” Antioxidants (Basel, Switzerland) vol. 8,492. 6 Apr. 2019, doi: 10.3390/antiox8040092

222. Deliorman Orhan D,

Kiipeli E, Yesilada E. In vivo anti-inflammatory and antinociceptive activity of the crude extract and fractions from Rosa canina L. fruits. J Ethnopharmacol. 2007 Jun 13;112(2):394-400. doi: 10.1016/j.jep.2007.03.029. Epub 2007 Mar 30. PMID: 17482395.

223. Medscape. Rose Hips. https://reference.medscape.com/dnig/rosa-canina-rose-hips-344509

224. RxList. Rose Hips Supplements. https://www.rxlist.com/rose hip-nage2/supplements.htm

225. Song, Ge et al. “Fungal Co-infections Associated with Global COVID-19 Pandemic: A Clinical and Diagnostic Perspective from China.” Mycopathologia vol. 185,4 (2020): 599-606. doi: 10.1007/sl 1046-020-00462-9

226. McCance, Kathryn L., et al. Pathophysiology The Biologic Basis for Disease in Adults and Children. Seventh ed., St. Louis, Elsevier Mosby, 2014. P. 306

227. Gassen, N. C., Jan, P., Thomas, B., Frederik, D., Jackson, E., Katja, W., Marcel, A. M. (2020). Analysis of SARS-CoV-2 controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics. bioRxiv, 04(15), 997254. https://doi.org/10.1101/2020. 04.15.997254

228. Dong, X., & Levine, B. (2013). Autophagy and viruses: Adversaries or allies? Journal of Innate Immunity, 5(5), 480-493. https://doi.org/ 10.1159/000346388

229. Hayflick L: Biological aging is no longer an unsolved problem, Arm N Y Acad Sci 1100:1-13, 2007. Review.

230. World Health Organization, WHO Consultation on Selected Medicinal Plants, Vol.2, pg.

12-24.

231. Martinez-Lopez, Nuria et al. “System-wide Benefits of Intermeal Fasting by Autophagy.”

Cell metabolism vol. 26,6 (2017): 856-871.e5. doi: 10.1016/j.cmet2017.09.020

232. Shamsuzzoha M et al. Antifertility effect in mice of medicinal plant family Acanthaceae. Lancet, 1978, ii:900.

233. Panossian A et al. Effect of Andropraphis paniculata extract on progesterone in blood plasma of pregnant rats. Phytomedicine, 1999, 6:157-161.

234. Esposito D, Chen A, Grace MH, Komamytsky S, Lila MA. Inhibitory effects of wild blueberry anthocyanins and other flavonoids on biomarkers of acute and chronic inflammation in vitro. JAgric Food Chem. 2014 Jul 23;62(29):7022-8. doi: 10.102 l/jf4051599. Epub 2014 Jan 17. PMID: 24397282.

235. Zahedi, Hoda Sadat et al. "Effects of polygonum cuspidatum containing rcsveratrol on inflammation in male professional basketball players.” International journal of preventive medicine vol. 4,Suppl 1 (2013): S1-4.

236. Lakhan, Ram et al. “Prevalence of Depression, Anxiety, and Stress during COVID-19 Pandemic.” Journal of neurosciences in rural practice vol. 11,4 (2020): 519-525. doi: 10.1055/S-0040-1716442

237. Walsh, Kathleen Marie et al. “Effects of a Mindfulness Meditation App on Subjective Well-Being: Active Randomized Controlled Trial and Experience Sampling Study.” JMIR mental health vol. 6,1 el0844. 8 Jan. 2019, doi: 10.2196/10844

Claims

Claim 1: A composition for preventing, treating, and curing COVID-19 compromising herbs: Nigella sativa and Sassurea lappa.

□ Nigella sativa

□ Common Name· Black Seed

□ Forumulation Function: Main Herb

□ Main Active Constituent : Thymoquinone

□ Other constituents: n-Nonanea, Tricyclene, Camphene, β-Pinene,

2,4,(10)-Thujadiene, Sabinene, β-Myrcene. 1,8-Cineole, a-Terpinene, Limonene, γ-Terpinene, cis-Sabinene hydrate, allo-Ocimenola, Linalool 1087, Terpinolene, trans-Sabinene hydrate, STerpinen-l-ol, 1,5,8-p-Menthatrienea, Bomeol, Pinocarvone, trans-Dihydrocarvone, Dihydrocarvonea, Ocimenone (E)a, Thymoquinone, Thymol, Carvacrol, 2-Undecanone, n-Octyl isobutyratea, α-Longipinene, Citronellyl acetatea, Thymohydroquinone methyl ethera, Cyclosativene, α-Longicyclene, α-Copaene, α-Longifolene, (Z)-Caryophyllenea, β-Caiyophyllene, Thymohydroquinone dimethylethera, Aromadendrenea, Thymohydroquinone, Davanonea, 8-Heptadecenea, Dihydrofamesyl acetatea, Pimaradienea, Palmitic acid, Pimara-8( 14), 15-diene, Octadecanoic acid, Quinones, Monoterpene hydrocarbons, Oxygenated monoterpenes, Sesquiterpene hydrocarbons, Oxygenated sesquiterpenes, Diterpenes, Alkane, Alkenes Fatty acids, Fatty acid esters (145).

□ Plant Part Used: Seed

□ Primary Target for COVID-19 & Clinical Outcomes- Suppress viral load of COVID-19. Increase the number and improve function of CD4 T-cells, and increase in the production of interferon (INF) gamma (74-76, 98), decreases in plasma MDA levels (95)

□ Herbal Actions: Antibacterial, Antifungal, Antiviral, Antiparasitic, Anticancer, Antioxidant, Antihypertensive, Anti-Inflammatory, Antimicrobial (72)

□ Daily Recommended Dosage: 80mg/kg/day

□ Dosage Rationale:

□ A recent multi-center placebo-controlled randomized clinical trial conducted in Pakistan tested Honey and Nigella sativa against COVID-19. The study included adults showing moderate or severe COVID-19 disease. The patients were randomly assigned to receive the following dosage: honey (1 gm/Kg/day) and encapsulated Nigella sativa seeds (80 mg/Kg/day) or a placebo up to 13 days along with receiving standard care. The formulation was administered in 2-3 divided doses each day. The results showed that the Honey & Nigella sativa (HNS) medication groups symptoms were alleviated 50% more than the placebo group. Additionally, HNS cleared COVID-194 days earlier than the placebo groups in both the moderate and severe groups. Participants reported feeling better and resuming normal activities by day 6 (63.6% verses 10.9% in moderate cases). The HNS group also saw higher hospital discharge rates in severe cases (50% versus 2.8% in the placebo group). Lastly, in severe cases, the mortality rate was 4 times lower than the placebo group. Notably, no HNS related adverse effects were noted

(73). https://www.medrxiv.org/content/10.1101/2020.1030.20217364v4 full p

(73).

□ A 2006-2007 double blind trial was conducted at Aga Khan University Hospital, Karachi to gauge the safety, tolerance, and effectiveness of powdered Nigella sativa seed capsules on serum lipid levels, blood sugar, blood pressure, and body weight in adults. 123 participants were recruited for this study-64 was placed in the intervention group and 59 were placed in the control group. Due to high dropout rate only 39 participants from the intervention group and 34 participants from the control group completed the study. The intervention group received 2capsules daily. Each capsule contained 500mg of crushed powdered Nigella sativa seed for 6 weeks. The control group received dietary recommendations and calcium lactate powder placebos. The results yielded positive trends across all variables studied with no adverse effects noted. The study proved the safety and tolerability of Nigella sativa (78).

□ In vivo study of the activity of Nigella sativa seed powder- human participants were given 3g/day for 8 weeks. Conclusions: reduction in oxidative stress as evidenced by a decrease in plasma MDA levels and increases in activity in erythrocyte GSH-Px, GST, and SOD (96, 97)

□ In vivo study of antifungal activity of Nigella sativa water extract Mice were treated with 6.6ml/kg equal to 5mg of estimated protein once daily for 3 days. A 5 fold decrease of Candida albicans bacteria was observed in the kidneys, an 8 fold decrease in the liver, and an 11 fold decrease in the spleen in mice treated with extract. Results proved that Nigella sativa aqueous extracts are effective in inhibiting Candida albicans infections.

□ Toxicology & Safety:

□ Daily dosing of thirty (30) six-to-eight week old non-pregnant female mice for 6 weeks with an aqueous extract of Nigella sativa via gavage using an esophageal probe. The water extraction was performed by macerating ISO g of black seed powder in 500ml of water for 12 hours at 203°F. The mixture was then filtered with a muslim cloth into a glass Petri dish where it was left for 8 hours at 194°F. The mice were kept under fasting conditions 12 hours prior to the gavage. The mice were split into 6 groups- a control group that received distilled water and 5 groups each receiving one of the following dosages: 2g/kg/day, 6.4g/kg/day, 21g/kg/day, 33g/kg/day, and 6g/kg/day. One mouse died after 2 weeks of treatment with 6.4g/kg/day. Two mice died after the 3rd week of treatment with 21g/kg/day. Three mice died after the 5th week of treatment with 60g/kg/day. No other deaths were reported (77). □ An in vivo study testing the effect of an alcohol based Nigella sativa extract on pregnant mice. Mice were injected with human serum to achieve the symptoms of preeclampsia. Results showed that a dose of 1500mg/kg/day was optimal for lowering IL-8 and TNF-a levels in models of preeclampsia. It should be noted that IL-6 levels increased at 2000mg/kg/day doses (79). It should be noted that the Milhu Shamsi formulation is non-alcoholic and thus substantially less potent than alcoholic extracts.

□ Powdered and Aqueous extracts of Nigella sativa are safe for pregnant and breastfeeding women (100).

□ Sassurea Lappa

□ Common Name: Indian Costus

□ Formulation Function: Specific □ Main Active Constituent: Sesquiterpene lactones

□ Other constituents: lbeta-hydroxycolartin, 5alpha-hydroxy-beta-costic acid,

11 alpha, 13-dihydroxydehidrocostuslactone , 11,13-dihydro-7, 11 -dehydro- 13-hydroxy-3-desoxyzaluzanin C,

8 alpha-hydroxyl- 1 IbetaH- 11, 13-dihydrodehydrocostuslactone, Soulangianolide A, Syringaresinol , Scopoletin among many other constituents (146). □ Plant Part T Used: Root

□ Primary Target for COVID-19 + Clinical Outcomes: Inhibition of I CAM 1 Upregulation, Inhibition of angiogenesis, Inhibition of Hepatocyte growth factor (which causes ICAM1 Upregulation) (101) Sassurea lappa has been found to inhibit the Vascular Endothelial Growth Factor expression ofICAMI, induced chemotaxis (movement of somatic cells), bacteria, and other single celled or multicellular organisms of human umbilical vein endothelial cells (HUVECs) in a dose dependent manner (101, 105).

□ Herbal Actions: Anti-Inflammatory, Anticancer, Hepatoprotective, Anti-ulcer, Cholagogic, Immunomodulator.

□ Daily Recommended Dosage: ,5-600mg/kg/day though lOOmg/kg/day has proven to be ideal for ICAM1 downregulation. □ Dosage Rationale:

□ An alcohol extract of Sassurea lappa at doses of 50, 100, and 200 mg/kg/, p.o., was used to evaluate its effectiveness against acute and chronic inflammation in symptomatic mice and rats. Sassurea lappa proved an effective treatment for acute and chronic inflammation at doses of 50-200 mg/kg (106)

□ An in vivo study designed to evaluate the cardioprotective effect of aqueous extract of root Sassurea lappa (AESL) against induced myocardial injury in rats. The rats were given the aqueous extract of Sassurea lappa in three different doses: (100, 200, and 300 mg/kg, p.o. orally). Consistent oral administration of AESL greatly improved the level of myocardial LDH, CK, AST, TEARS, and GSH. The extract was compared with standard treatment a-tocopherol. 200mg/kg proved the most beneficial dosage to protect against isoproterenol induced myocardial injury. Additionally, AESL up to a dose of 2000 mg/kg did not produce any signs of toxicity and mortality (108).

□ “By in vivo method the neovascularization of mouse comeal stimulated by vascular endothelial growth factor is reported to be inhibited at a dosage of 100 mg/kg/day. Inhibition of of vascular endothelial growth factor on VEGFR KDRZFlk-l was also proved through signaling pathways (109)

□ Herbal Composition of Saussurea lappa for the Treatment of a Subject infected with HIV. Clinical research revealed HIV “undetectable” and CD4 T-cells increased after participants were administered either an aqueous extract or capsulated extract of 0.4g/kg - 0.6g/kg, three times per day for 6 months. Only one patient had adverse effects during the study which included diarrhea. 36 participants were involved in this study. WIPO Patent # WO 201 1/039574 AI (124).

□ Contraindications: Not a lot of research on pregnant/breastfeeding women.

□ Toxicology & Safety: Sassureal lappa has proved to be safe in in vivo studies of humans, rabbits, and pigs at dosage of up to 16g/day for the treatment and eradication of HIV (124).

□ Rabbits and guinea pigs were used in a toxicity study of Sassurea lappa which was conducted at the School of Medical Sciences, Pharmacology Department, University of Science and Technology, Sana’a Republic, Yemen. Each was given an oral, aqueous dosage of 16g (the maximum recommended dose) then observed for a period of 2 weeks. All of the animals were alive two weeks after receiving the maximum dosage and no abnormalities were observed. At the end of the observation the animals were sacrificed and dissected. Upon examination of the eyes, liver, lung, and spleen it was determined that there were no extraordinary syndromes and no acute toxicity (124).

Claim 2: A composition of claim 1, wherein the composition further comprises Astragalus membranaceus.

□ Common Name- Astragalus

□ Formulation Function Synergistic Herb

□ Main Active Constituents: Triterpene saponins (astragalosides I-X and isoastragalosides I-IV), and polysaccharides (e.g. astragalan, astraglucan AMem-P) (125-126)

□ Plant Part Used: Root

□ Primary Target for COVID-19 + Clinical Outcomes: Tmmunopotentiating (112-116), Induction of Phagocytosis - the removal of pathogens and cellular debris i.e. bacteria and viruses from the middle ear in non-infected and asymptomatic persons. Performs the same function after COVID-19 has spread through the body through promotion of Phagocytosis via the reticular endocrine system or RES thus clearing pathogens on a cellular level (117-118) by facilitating the antibody response to a T-dependent antigen. Enhancement of this response is correlated with an increase in T-helper cells in normal and immunosuppressed mice (120). Astragalus also acts as an effective anti-inflammatory and antioxidant agent for intestinal diseases such as Candida albicans infection (119)

□ Herbal Actions: Immunomodulator (112-116)

□ Daily Recommended Dosage: 16,000 mg per day. 9-30g dried root Immunostimulant effect seen at a dose of 16g/day for adults for 20 days as evidenced by increased serum IgM, IgE, and cyclic AMP concentrations (121). ¼ of this dosage for children.

□ Dosage Rationale. Toxicity, and Safety: According to the National Institutes of Health there are no high-quality studies in people of astragalus for any health condition. However, they do report that Astragalus may be safe when used by mouth at appropriate dosages. Further, it is reported that doses up to 60 grams daily for up to 4 months have been reported without any adverse effects (123).

□ 12 month old male mice were used in a study to assess the effects of Astragalus on learning and memory impairments and neuron apoptosis induced by glucocorticoids. In this study the mice were chronically treated with stress-level dexamethasone (DEX 5mg/kg) and an aqueous extract of Astragalus in doses of either 10, 20, and 40 mg/kg or Ginsenoside Rgl (6.5 mg/kg) for 21 days. Findings showed that Astragalus has a positive effect on learning and memory and most importantly no adverse effects were observed (147).

□ Contraindications: No data for pregnant or breastfeeding population and consequently not suggested for use in these populations. No herb/drug interaction or pediatric use studied-no generally recommended. No adverse reactions (122).

□ Inclusion Rationale: Theoretically, Sassurea lappa and Astragalus membranaceus seem to complement one another well. This is due to Sassurea lappa’s possible inhibition of ICAM-1 upregulation rendering the COVID-19 virus unable to attach making way for Astragalus membranaceus to “sweep” away pathogens from the body specific to where they are most concentrated (endothelial cells).

Claim 3: A composition of claim 1, wherein the composition further comprises Paeonia lactiflora.

□ Common Name: Peony Root □ Formulation Function· Synergistic Herb

□ Main Active Constituent: Paeoniflorin. a monoterpene glycoside (127-128). □ Primary Target for COVID-19 + Clinical Outcomes- Decrease pain depression, and anxiety in COVID-19 patients via increasing hippocampal glucocorticoid receptor messenger RNA (mRNA) expression. Down Regulation of ICAM- 1 and CCR5 expression. Paeonia lactiflora is a potent herb that has been scientifically proven to suppress the expression of ICAM-1 and CCR5 due to endotoxins. In patients with disrupted gut barriers this Paeonia lactiflora aids in tapping into the gut-brain axis guiding interactions between enteric microbiota and the central and enteric nervous systems. The gut brain axis (GBA) is a bidirectional communication signaling from gut-microbiota to the brain and from the brain to gut-microbiota through neural, endocrine, immune, and humoral links (131). Enhancement of the hippocampal glucocorticoid receptor messenger RNA (mRNA) expression may allow the messenger RNA to pick up cues from antisense oligonucleotides. Antisense oligonucleotides are short, single stranded DNA molecules that interact with messenger RNA to prevent translation of a targeted gene. They have proven effective treatments in bowel diseases (135). Their DNA sequence is complementary to the specific mRNA target Binding leads to the degradation of the DNA sequences with failure of production essentially acting as an enzyme inhibitor for ICAM- 1 and CCR5 (induced by endotoxin-induced pneumonia) in conjunction with Peony Root (130-134).

□ Herbal Actions: Targets the hypothalamic-pituitary-adrenal axis (HPA), wide applications for stagnated blood conditions, Analgesic, Antiallergic, Anti-Inflammatory, Anticancer, Antioxidant, Immunomodulatory, Neuroprotective, Anti-depressant, Adaptogen (130,140).

□ Daily Recommended Dosage: 80 mg/kg/day (130) maximum daily oral dose of crude herb 15,000 mg (139)

□ Dosage Rationale/Toxicity:

□ In vivo study testing the antidepressant-like effect of ethanol extract from

Paeonia lactiflora in mice via intragastric administration revealed that beneficial effects were seen at 80-160mg/kg/day for 6 weeks-indications: inhibition of the serum corticosterone level and increasing hippocampal glucocorticoid receptor messenger (RNA) mRNA expression. Administration at this dosage did not reveal toxicity (136). □ Treatment Duration: 6 weeks max.

□ Inclusion Rationale: Down regulates ICAM-1 expression elevated in LPS-induced U937 cells and TNFa stimulated HUVECs. Paeonia lactiflora suppresses the activation of the NF-KB pathway, which regulates the expression of ICAM-1 (129). Due to its effect on HUVECs it is a reinforcing synergistic herb that will further support Sassurea lappa in inhibiting abnormal vascular endothelial growth. Further, Paeoniflorin has been shown (in conjunction with other natural herbs) to increase NFG and BDNF production which effectively suppresses CCR5 gene expression (133).

□ Contraindications and Precautions: Paeonia lactiflora may have abortifacient activity, therefore it is not recommended for use during pregnancy (137). There is no information on the use of this herb with children or breastfeeding mothers. Further, peony root might slow blood clotting and should not be used at least 2 weeks before surgery.

□ Drug Interactions: Paeonia lactiflora should not be combined with Fritillaria verticillata, Cuscuta j aponica, and Rheum officinale (138). May also interact with medications that slow blood clotting. Phenytoin (Dilantin) interacts with Paeonia lactiflora.

Claim 4: A composition of claim 1, wherein the composition further comprises Nelumbo nucifera.

□ Common Name: Lotus Seed □ Formulation Function· Synergistic Herb

□ Main Active Constituents: Dauricine, Pronuciferine, Dauricine, Lotusine, Liensinine, Isoliesinine, Neferine, Nuciferine, N-Nomuciferine, O-Nomuciferine, Roemerine, Armepavine, D(-)-3 ’bromo-O-methyl-armepavine, Procyanidin,

D- 1,2,3, 4-tetrahydro-6-methoxy- l-(p-methoxybenzly)-2-methyl-7-isoquinolinol, and Gallic acid. Rich in protein, amino acids, unsaturated fatty acids, and minerals. Chromium (0.0042%), sodium (1.00%), potassium (28.5%), calcium (22.10%), magnesium (9.20%), copper (0.0463%), zinc (0.0840%), manganese (0.356%)), and iron (0.1990%) (141). Plant Part Used: Seeds

□ Primary Target for COVID-19 + Clinical Outcomes: Antioxidant- increase in levels of superoxide dismutase (SOD) and catalase / decreases in the levels of thiobarbituric acid reactive substances (TBARS). Anti-Inflammatory- inhibits the production of pro-inflammatory cytokine tumor necrosis factor-a (TNF-a), increases anti-inflammatory cytokine IL-10 (149).

□ Herbal Actions: Anti-ischaemic, Antioxidant, Hepatoprotective, Antiproliferative, Anti-inflammatory, Anti-Arrhythmic, Anti-Fibrosis, Anti- Viral (141) □ Daily Recommended Dosage· 100 mg/kg/day (148)

□ Dosage Rationale/Toxicity:

□ In vivo study to assess the antioxidant activity of a hydro alcoholic extract of Nelumbo nucifera (HANN) using Swiss Albino mice. Mice were given an oral dose of HANN at 100 and 200 mg/kg body weight for 4 days prior to carbon tetrachloride (CCI (4)) treatment Results showed that the HANN treatment produced a significant dose -dependent increase in the level of superoxide dismutase (SOD) and catalase and a significant decrease in the level of thiobarbituric acid reactive substances (TBARS) when compared to CCI (4) treated control in the kidney and liver. Changes observed at 100 mg/kg body weight HANN treatment comparable to those observed for a standard vitamin E treatment at 50 mg/kg. No observation of toxicity up to the oral dose of 1,000 mg/kg body weight noted (148).

□ Inclusion Rationale: Due to Nulembo nuciferas’ potent free radical scavenging effects at the recommended dosage, it will reinforce Astragalus in the process of Phagocytosis.

□ Safety: Not enough reliable information on the safety of using Nelumbo nucifera for pregnant or breastfeeding mothers. Nelumbo nucifera has a Anti-fertility activity at 3 mg/kg. Additionally, it may lower blood sugar (150).

Claim 5: A composition of claim 1, wherein the composition further comprises Panax ginseng.

□ Common Name: Ginseng □ Formulation Function Synergistic Herb □ Main Active Constituent: Ginsenosides (Rgl)

□ Plant Part Used: Root

□ Primary Target for COVID-19 + Clinical Outcomes: To assist the body in adapting to the physiological stresses of COVID-19 infection, increase the production of white blood cells via an increase in chemotaxis of polymorphonuclear leukocytes and improve oxygen utilization.

□ Herbal Actions: Adaptogen, Anti-fatigue, Immunomodulator, Antioxidant, Anti-Diabetic, Anti-inflammatory, Hepatoprotective (151) □ Daily Recommended Dodage: 100 mg daily □ Dosage Rationale:

□ A double blind in vivo study designed to assess the immunomodulating effects of Panax ginseng- Three groups of 20 healthy human volunteers were either given 1) an aqueous extract of 100 mg Panax ginseng, 2) a standard extract of 100 mg Panax ginseng, or 3) a capsule containing lactose (control groups). Patients took 1 capsule every 12 hours for 8 weeks. Blood tests revealed an increase in chemotaxis of polymorphonuclear leukocytes, the phagocytic index, and the total number of T3 and T4 lymphocytes after 4 and 8 weeks of Ginseng therapy as compared to the control group. No toxicity reported (152).

□ Drug interactions: Panax ginseng may interact with phenelzine, a monoamine oxidase inhibitor (154-155)

□ Toxicology & Safety:

□ In vivo: The safety and tolerance of Panax ginseng was assessed through a randomized, double blind, placebo controlled study. 170 healthy Korean volunteers were randomly assigned to take a 20% ethanol extract of Panax ginseng root by mouth at dosages of either 1) 500 mg twice a day or 2) 1000 mg twice per day. The 3rd group received a placebo. There were no adverse events, deaths, or otherwise toxic effects reported (153).

□ Inclusion Rationale: Lethargy and fatigue are common symptoms in COVID-19 patients. There are three sedative herbs in the Milhu Shamsi formulation; Peony Root, Tulsi and Bupleurum. Ginseng as a therapeutic agent will offset the sedative effects of this formulation by making the patient feel more productive, alert, yet calm in the face of tremendous difficulty. Ginseng also provides beneficial synergistic effects when paired with Sassurea lappa and Peony Root. The two latter herbs inhibit chemotaxis of HUVECs while Ginseng increases chemotaxis of immune cells.

Claim 6: A composition of claim 1, wherein the composition further comprises Radix Bupleuri. □ Common Name- Bupleurum Root

□ Formulation Function: Synergistic Herb

□ Main Active Constituents: Triterpene saponins, including saiknsapnnin A, B 1-4), D, E, F, and H and related compounds including saikogenins A-G and polysaccharides, bupleurans 2IIb and 2IIc (156-159).

□ Plant Part Used: Root □ Primary Target for COVID-19 + Clinical Outcomes: Reduction of fever, pain and inflammation (160, 163).

□ Herbal Actions: Immunomodulator, Anti-Inflammatory., Anti-Ulcer, Antipyretic, Analgesic, Sedative, Hepatoprotective (160) act in synergy with the “Autophagy Jump Start” Blend by assisting with the induction of autophagy (161).

□ Daily Recommended Dosage: 200-800 mg/kg per day up to 9g / day (160)

□ Dosage Rationale:

□ Oral administration of 200-800 mg/kg of Bupleurum extract given to mice produced sedative, analgesic, and antipyretic effects. No toxic effects documented (160).

□ Toxicity:

□ In vitro study to determine the effects of Bupleurum root on anti-inflammatory activity on adipocytes using 3T3-LI cells revealed that the saikosaponins in Radix Bupleurum inhibits the expression of inflammatory associated genes and it is a viable inhibitor ofNF-xB activation. 3T3-LI cells were treated with 200 ul of various concentrations of the Bupleurum extract for 24 hours. The MTT assay revealed that the extract of Bupleurum did not affect cytotoxicity of the 3T3-L1 cells (163).

□ Contraindications: Radix Bupleuri causes sedation, caution should be taken in large doses. Possible synergistic effects with other sedative herbs. No data on the safety of this herb for use by pregnant and breastfeeding mothers (160).

□ Inclusion Rationale: Radix Bupleuri has been identified as a potential natural treatment for COVID-19 (162) the potency of its anti-inflammatory activity due to its saikosaponins is similar to the steroid prednisolone (160).

Claim 7: A composition of claim 1, wherein the composition further comprises Artemisia vulgaris.

□ Common Name: Mugwort □ Formulation Function · Synergistic Herb

□ Main Active Constituents: Sesquiterpenoid lactones including artemisinin, psilostachyin, psilostachyin C, and vulgarin. Flavonoids include kaempferol and quercetin, coumarin compounds (esculin, umbelliferone, and scopoletin) and essential oil (164). □ Plant Part Used: Leaf

□ Primary Target for COVID-19 + Clinical Outcomes: Induce autophagy as evidenced by increasing intracellular ROS and reduction MMP reduction. Inhibition of migration of colon cancer cells (165).

□ Inclusion Rationale: Those with diagnosed cancers are at high risk of developing severe complications from COVID-19 infection. In some cases a cytokine storm which causes severe tissue damage occurs in COVID-19 patients. This storm is instigated by interleukin 6 (IL-6) which acts on a large number of cells and tissues. IL-6 increases during colonic cancer, inflammatory bowel disorders, and infections due to viruses and bacteria (8).

A retrospective controlled study conducted in Italy to compare data of the colorectal cancer screening (CRCS) during the COVID-19 lockdown period (March 9-May 4, 2020) with those of the same period of 2019 (control group). In the lockdown group 60 endoscopies were performed whereas in the control group 238 CRCS colonoscopies were done. The results of this study revealed that despite the lower number of exams performed in the lockdown group there were more colorectal cancers than in the control group. Furthermore, the high-risk adenomas detection rate was significantly higher in the lockdown group than in the control group (166). A recent study also conducted in Italy, sought to understand the psychological aspects of eating habits during COVID-19 home confinement from April 24-May 18, 2020. 602 people participated in an online survey. The results showed that 63.3% of respondents experienced a depressed mood, 70.4% had anxious feelings, 46.2% were hypochondrial, and 52.2% experienced insomnia. Almost half of the respondents reported feelings of anxiousness due to their increase of food intake, “comfort food” in particular. The results also indicated that women were more likely to be more anxious and inclined to comfort food than men (167). It is well documented that poor lifestyle and dietary habits including lack of exercise, sleep deprivation, and irregular eating increase the incidence of inflammatory bowel disorders (168). Further, it has been established that inflammatory bowel disorders lead to increased risk for colorectal neoplasia (169).

Artemisia vulgaris extracts have been proven have an antifungal effect against Candida albicans and similar pathogens (170). Additionally, a methanolic extract prepared from arial parts of Artemisia vulgaris showed inhibitory effects against MCF7 and HeLa cancer cell lines (171) and colon cancer cells by inducing autophagy and inhibiting cell migration (165).

The use of Artemisia vulgaris, as well as other herbs in this formulation, makes Milhu Shamsi an appropriate drug for prevention of COVID-19 and its complications as it relates to inflammatory bowel disorders and colon cancer and as an appropriate drug intervention COVID-19 patients. Further, Artemisia vulgaris has been included in this formulation to aid in inducing autophagy, a key component in The Fitra30 COVID-19 Protocol.

□ Herbal Actions: Antioxidant, Hypolipemic, Hepatoprotective, Antispasmolytic,

Bronchodilatory, Analgesic, MAO inhibition, Antihypertensive, Estrogenic, Cytotoxic, Antifungal, Antibacterial, Anti-inflammatory, Antialergenic, Antimalarial, Anthelmintic (164).

□ Daily Recommended Dosage: 25-100 mg/kg/day □ Dosage Rationale / Toxicity:

□ An in vivo study was conducted by scientists in Egypt to assess the antioxidant capacity of Artemisia vulgaris. 15 healthy male rats weighing 150-200g each were used in the study. The rats were divided into 3 groups of 5. The first group (control group) enjoyed an unrestricted diet and water. They were treated with distilled water (2 ml/kg/p.o. only). The second group was treated orally with an aqueous extract of Artemisia vulgaris at a dose of 100 mg/kg. The third group was treated with Silymarin at a dose of 100 mg/kg. All animals were administered their respective interventions by orogastric catheter once daily for 42 days. The results showed that Artemisia vulgaris has strong antioxidant activity. There were no reported adverse effects or toxicity (172).

□ In vivo study to assess the effects of Artemisia vulgaris extract in hycholestoromic rats. 24 male Wistar albino rats weighing 120-140g were used for this experiment The animals were divided into 4 groups of 6 each. Group 1 was kept on a standard pellet diet Group two-these rats were fed a high fat diet (HFD) consisting of 3% cholesterol, 9% cotton seed oil, 10% olein oil, and 0.5% cholic acid for 8 weeks. Group three- were fed a HFD given an aqueous dose of Artemisia vulgaris (100 mg/kg per day) via stomach tube once daily for 4 weeks. The fourth group were fed a HFD and orally administered Atorvastatin by stomach tube once daily for a period of 4 weeks. The study concluded Artemisia vulgaris has hypolipidemic, anti-inflammatory, and antioxidant properties due to the polyphenols and saponins present in the herb. Further, no reported adverse effects were observed or toxicity noted (173).

□ Safety: The use of Artemisia vulgaris aqueous extracts in therapeutic doses is likely safe. However, persons allergic to Artemisia vulgaris or any plant in the Asteraceae family should avoid as there have been reported adverse effects after swallowing the plants pollen including; anaphylactic shock, breathing difficulties, bronchospasm, airway hypersensitivity, asthma attack, seasonal rhinitis, and conjunctivitis. Allergic skin reactions may also occur. In large doses Artemisia vulgaris may cause miscarriage, nausea, vomiting, and nervous system damage. Hypertension has also been reported. Artemisia vulgaris must be used with caution in patients with diabetes as it may cause blood glucose levels to rise (164).

Claim 8: A composition of claim 1, wherein the composition further comprises Angelica archangelica.

□ Common Name: Angelica Root □ Formulation Function: Synergistic Herb

□ Main Active Constituent:

□ Plant Part Used: Root

□ Primary Target for COVID-19 + Clinical Outcomes: To act as a natural antimutagen against COVID-19 (175). Radioprotective: provide protection against the harming of normal tissues and impeding immune functions through exposure to moderate to high levels radiation stemming from hospital treatments (radiation therapy) (177).

□ Inclusion Rationale: Angelica root exhibits strong Antioxidant activity which will strengthen the free radical scavenging potential of the overall formulation. Additionally, as a Antimicrobial agent, the essential oil content of Angelica root has proved effective against bacteria and fungus to include; Fusarium genus, Botrytis cinerea, Altemaria solani, Clostridium difficile, Clostridium perfringens, Enterococcus faecalis, Eubacterium limosum, Peptostreptococcus anaerobius, and Candida albicans (179-180).

□ Herbal Actions: Antitumor, Anti-anxiety, Cytotoxic Effect, Hepatoprotective, Antimutagenic, Butyrylcholinesterase Inhibitory Activity, Inhibition of Acetylcholinesterase, Antimicrobial, Antiseizure (176).

□ Daily Recommended Dosage: 100 mg/kg/day

□ Dosage Rationale:

□ Antimutagenic activity of an aqueous solution of Angelica archangelica and alcohol extracts of thio-TEPA against mutagenicity was studied by micronucleus tests in murine bone marrow cells. It was found that the reduction of Thio-TEPA’s mutagenic activity was enhanced when the Angelica root extracts were injected two hours before thio-TEPA treatment The reduction of micronuclear frequencies were as high as 77%. Aqueous extract dosages were tested at 50, 100, 500, and 1000 mg/kg (175). □ An in vivo study designed to evaluate the anti-anxiety effects of Angelica archangelica linn, using Albino rats. An acute toxicity study was conducted. Overnight healthy rats received successive extracts of Angelica archangelica (petroleum ether, chloroform, ethyl acetate, methanol and water) at doses of 100, 200, 400, 800, 1600, and 3200 mg/kg body weight and observed for 4 hours and again after 24 hours for abnormalities and mortality. Extracts at 3200 mg/kg were found to be safe. Further, it was concluded that Angelica archangelica exhibited strong anti-anxiety effects (178).

□ The Food and Drug Administration includes angelica in its list of herbs and spices that are generally regarded as safe (GRAS).

□ Not recommended for pregnant and breastfeeding women (181).

Claim 9: A composition of claim 1, wherein the composition further comprises Ocimum sanctum (Krishna).

□ Common Name: Tulsi

□ Formulation Function: Synergistic Herb

□ Main Active Constituent: Eugenol ( 1 -hydroxy-2-methoxy-4-allylbenzene) (191), orientin and vicenin (194) □ Plant Part Used: Leaf

□ Primary Targets for COVID- 19 + Clinical Outcomes: Interference of SARS-CoV-2/CD4 interaction (192, 193). Decrease inflammation as evidenced by inflammation markers which may include; including C -reactive protein (CRP), erythrocyte sedimentation rate (ESR), and plasma viscosity (PV) (197). Increase lung vital capacity and relieve laboured breathing (201).

□ Inclusion Rationale: In a previous study, the combination of aqueous extracts of Ocimum sanctum (Tulsi) and Withania somnifera (Ashwagandha) have showed significant inhibition of RNA Dependant DNA Polymerase (RDDP) function of HIV-reverse transcriptase (190). Additionally, this herbal combination is thought to inhibit gpl20/CD4 interaction by binding to CD4 but not to gpl20 (192) which shows the potentiality of this combination interfering with SARS-CoV2/CD4 interaction.

□ Herbal Actions: Antibacterial, Antifungal, Antiviral, Anti-HIV, Radioprotective, Antifertility, Anticancer, Antidiabetic, Antimicrobial, Hepatoprotective, Cardioprotective, Antiemetic, Antispasmodic, Analgesic, Adaptogenic and Diaphoretic (191).

□ Daily Recommended Dosage: 100 mg/kg/day

□ Dosage Rationale / Toxicology:

□ An in-vitro testing of anti-HIV activity of an aqueous extract of Ocimum sanctum using two Anti-HIV assays: 1) Reverse Transcriptase (RT) Inhibition Assay and 2) Gpl20 Binding Inhibition Assay. Results showed that aqueous extracts of Ocimum sanctum interfered with gpl20/CD4 interaction and inhibited viral Reverse Transcriptase (RT). The aqueous extracts were made using the decoction method using 3-20g of plant material to 50-200 ml. Distilled water (192). □ In-vivo study designed to test the radioprotective effect of an alcoholic and aqueous extract of Ocimum sanctum using albino mice. Mice were given either single or multiple doses of the extracts before whole-body exposure to 11 Gy(LD100/30) of 60Co gamma radiation for 5 consecutive days. The study found that the water extract was more effective and less toxic than the alcohol extract The maximum dose of the aqueous extract was 50 mg/kg/day however, a dose of 10 mg/kg/day for 5 days gave the maximum survival. Routes of administration included im, iv, po, and intraperitoneal. The intraperitoneal route gave the best protection for survival (70%) while the other routes produced 37-47% survival rates (195).

□ An in-vivo study to test the anti-inflammatory and analgesic properties of an aqueous extract Ocimum sanctum was conducted using Wistar albino rats weighing (150-200g). The rats were split into 4 groups of 6 each.

To test the anti-inflammatory activity of the herb the first group was given 0.9% normal saline (control group). The second group was given the aqueous extract of Ocimum sanctum at a dosage of 100 mg/kg. The third group was given Aspirin at a dosage of 150 mg/kg. The fourth group was given Celecoxib at a dosage of 20 mg/kg. All dosages were administered orally for 7 days. Raw paw edema induced by carrageenan and cotton pellet induced granuloma were the models used to screen the anti-inflammatory activity of Ocimum sanctum. The results showed that in the Carrageenan induced enema model, the aqueous extract of Ocimum sanctum (100 mg/kg) showed significant anti-inflammatory activity (13.43% inhibition at 2 hours). In the cotton pellet granuloma model 100 mg/kg the aqueous extract of Ocimum sanctum showed extremely significant inhibition of granuloma formation with a PI of 23.85% (197).

□ “The present study was aimed to study the acute and subacute toxicity studies with orally administered 50% ethanolic leaves extract of Ocimum sanctum Linn (OSE). In acute toxicity tests, four groups of mice (n = 6/group/sex) were orally treated with doses of 200, 600, and 2000 mg/kg, and general behavior, adverse effects, and mortality were recorded for up to 14 days. In subacute toxicity study, rats received OSE by gavage at the doses of 200, 400, and 800 mg/kg/day (n = 6/group/sex) for 28 days, and biochemical, hematological, and histopathological changes in tissues (liver, kidney, spleen, heart, and testis/ovary) were determined. OSE did not produce any hazardous symptoms or death and CNS and ANS toxicides in the acute toxicity test. Subacute treatment with OSE did not show arty change in body weight, food and water consumption, and hematological and biochemical profiles. In addition, no change was observed both in macroscopic and microscopic aspects of vital organs in rats.” (200) □ Contraindications / Safety: Ocimiim sanctum is contraindicated during pregnancy and lactation (198). Ocimum sanctum should be used with caution in patients taking drugs such as paracetamol (acetaminophen) that deplete glutathione (199).

Claim 10: A composition of claim 1, wherein the composition further comprises Citrus sinensis.

□ Common Name: Orange Peels □ Formulation Function· Synergistic Herb

□ Main Active Constituent: Nobiletin is responsible for its anti-inflammatory effects (205). Also includes flavonoids, steroids, hydroxy amides, alkanes, fatty acids, coumarins, peptides, carbohydrates, carbamates, alkylamines, carotenoids, volatile compounds, and nutritional elements to include potassium, magnesium, calcium, and sodium (206).

□ Plant Part Used: Peels

□ Primary Target for COVID-19 + Clinical Outcomes: Citrus sinensis is rich with Vitamin C which makes it potent source antioxidant- will help to protect cells from damage caused by free radicals (206).

□ Inclusion Rationale: To provide Vitamin C and support other herbs in the formulation that have antioxidant properties.

□ Herbal Actions: Antioxidant, Antifungal, Antiparasitic, Antiproliferative, Hypocholesterolemic, Antidiabetic (206).

□ Daily Recommended Dosage: 250 mg/kg

□ Dosage Rationale / Toxicity:

□ In vivo study to test antidiabetic and antihypercholesteroleic activities of citrus sinensis in rats. 25 rats were divided into groups of 5. Group 1 was given a negative control (0.5% cMC-Na), Group 2 was given a positive control (glibenclamide and simvastatin). Groups 3-5 were given alcoholic doses of Citrus sinensis at 125, 250, and 500 mg/kg body weight respectively. The extract of Citrus sinensis peels at a dose of 500 mg/kg showed the highest antidiabetic activity in the rat models. No acute toxicity was reported (207).

Claim 11: A composition of claim 1, wherein the composition further comprises Zingiber officinale. □ Common Name· Ginger

□ Formulation Function: Synergistic Herb

□ Main Active Constituent fsV Gingerols, Shogaols, and Zingiberene (208).

□ Plant Part Used: Root □ Primary Target for COVID-19 + Clinical Outcomes: Reduce inflammation, nausea, and vomiting (209).

□ Inclusion Rationale: Zingiberene, one of the main constituents of Zingiber officinale has proven to inhibit in vitro and in vivo human colon cancer cell growth via autophagy induction, suppression of PI3K/AKT/mTOR Pathway and caspase 2 deactivation (209). Therefore, this herb will provide synergistic effects with other anticancer herbs in this formulation. Further, due to its ability to induce autophagy, it will also enhance the effectiveness of The Autophagy Jump Start Blend. Lastly, Zingiber officinale will enhance the anti-inflammatory effect of the formulation due to its anti-inflammatory activity (209).

□ Herbal Actions: Cholagogic, Antiemetic, Anti-inflammatory (209), Antihepatotoxic

(210). □ Daily Recommended Dosage: 1000 mg per day

□ Dosage Rationale / Toxicity: In vivo, double blind randomized cross over clinical trial found that ginger (25 mg by mouth, 4 times per day) effectively treated harmful vomiting in pregnancy. No adverse effects were reported (211). □ Contraindications / Safety:

□ The Food and Drug Administration includes ginger in its list of herbs and spices that are generally regarded as safe (GRAS).

□ Ginger should be used with caution in patients taking anticoagulant drugs or those with blood coagulation disorders.

□ A hot water extract was found to be mutagenic in B2911 cells and Salmonella typhimurium strain TA 100 but not strain TA 98 (212).

□ Not recommended for children under 6 years of age.

Claim 12: A composition of claim 1, wherein the composition further comprises Rosa canina.

□ Common Name· Rose Hips

□ Formulation Function: Synergistic Herb □ Main Active Constituent: Vitamin C

□ Plant Part Used: Fruit

□ Primary Target for COVID-19 + Clinical Outcomes: Reduction of cough, fever, and congestion by increasing Vitamin C intake (220). Prevent and treat oxidative stress by decreasing Reactive Oxygen Species (221).

□ Inclusion Rationale: Rosa canina has been added to this formulation to synergize with Citrus sinensis thereby increasing the Vitamin C content Vitamin C has proven effective in preventing and relieving the symptoms of virus-induced respiratory infections (220).

□ Herbal Actions: Anti-inflammatory, Antioxidant, Anti-mutagen (217), Vitaminisant, Astringent, Cholagogue, Choleretic, Diuretic, Anti-diarrhoea (218), and Anti-diabetic (219). □ Daily Recommended Dosage: 1000 mg per day

□ Dosage Rationale / Toxicity:

□ The aqueous and ethanol extracts of Rosa canina L. (Rosace ae) fruits and the fractions prepared from the latter were investigated for their anti-inflammatory and antinociceptive activities in several in vivo experimental models. Extracts displayed potent anti-inflammatory and antinociceptive activities at a dose of 919 mg/kg without inducing acute toxicity. (222). □ Contraindications / Safety:

□ Rosa canina may have serious drug interactions with; demeclocycline, doxycycline, eltrombopag, fleroxacin, gemifloxacin, levofloxacin, minocycline, moxifloxacin, mycophenolate, ofloxacin, oxytetracycline, and tetracycline (223). □ Patients taking Rosa canina should be monitored closely when taking;

□ aluminum hydroxide

□ Amoxicillin

□ Ampicillin

□ calcium carbonate

□ Cimetidine

□ Deferoxamine

□ Dexlansopr azole

□ Enalapril

□ Esomepr azole

□ Famotidine

□ Flucloxacillin

□ Ibandronate

□ ibuprofen/famotidine

□ Lansoprazole

□ Levothyroxine

□ Liothyronine

□ Methotrexate

□ Methyldopa

□ Mycophenolate

□ Nafcillin

□ Nizatidine

□ Omeprazole

□ Oxacillin

□ Pantoprazole

□ Penicillamine

□ penicillin G aqueous

□ penicillin VK

□ Pivmecillinam

□ Probenecid

□ Rabeprazole

□ sodium bicarbonate

□ sodium citrate/citric acid

□ Temocillin

□ thyroid desiccated

□ Ticarcillin

□ Trientine

□ wheat germ extract (223)

□ Contraindicated in patients with Sickle Cell Anemia (224)

□ Unknown if safe for pregnant or breastfeeding women (224)

Claim 13: A composition of claim 1, wherein the composition further comprises Glycyrrhiza glabra.

□ Common Name: Licorice Root

□ Formulation Function: Synergistic Herb □ Main Active Constituent: Glycyrrhizin (GL) (210) □ Plant Part Used: Root

□ Primary Target for COVID-19 + Clinical Outcomes: Interference with virus to cell binding via inhibition of ICAM-1 expression by blocking JNK and NF-xB pathways (213).

□ Inclusion Rationale: This herb will work to offset any mutagenic effects of Zingiber officinale as Glycyrrhiza glabra has an antimutagenic effect against Salmonella typhimurium strains TA100 and TA98 (210). Glycyrrhiza glabra also inhibits the overgrowth of intestinal bacteria including Candida albicans (214).

□ Herbal Actions: Antimutagenic, Anticarcinogenesis, Detoxification, Antiulcer, Anti-inflammatory, Antihepatitis, Antiviral, Anti-AIDS, Antiatherogenic, Antioxidant (210).

□ Daily Recommended Dosage: 1000 mg per day

□ Dosage Rationale / Toxicity:

□ In vivo study to test the effectiveness of Hochuekkito a Kampo (traditional Japanese herbal) Medicine on mucosal IgA immune response using mice. The mice were given the aqueous Hochuekkito formulation which consisted of l.Sg of Glycyrrhizae Radix for 27 days orally via the intragastric route. Results showed that Hochuekkito enhances mucosal IgA Antibody response in mice immunized with antigen-entrapped biodegradable microparticles. No adverse effects were observed (69).

□ In vivo study to test the effects of Glycyrrhiza glabra on learning and memory impairment in 1 month old Wistar albino rats. Four doses 75, 150, 225, and 300 mg/kg of an aqueous extract of Glycyrrhiza glabra root was administered to the rats orally for six weeks. Results showed that all doses enhanced memory however, doses of 150 and 225 mg/kg had the most significant effect Memory impairment is thought to be brought on by age, oxidative stress, harmful free radicals, and inflammation. No adverse effects were observed (215).

□

□ Contraindicated in patients with hypertension, cholestatic disorders, or cirrhosis of the liver, hypokalaemia, or chronic renal insufficiency during pregnancy (216).

□ Prolonged use of large doses (more than 50g per day) for extended periods (more than 6 weeks) may increase the risk of water accumulation. Sodium excretion is reduced and potassium excretion is increased. Blood pressure may rise (216).

□ Glycyrrhiza glabra should not be taken concurrently with corticosteroid treatment (216).

□ Because it increases potassium loss, Glycyrrhiza glabra should not be administered for prolonged periods with thiazide and loop diuretics or cardiac glycosides. Because it reduces sodium excretion the effectiveness of drugs used in the treatment of hypertension could be reduced. Glycyrrhiza glabra should not be given in conjunction with spironolactone or amiloride (216).

□ The safety of using Glycyrrhiza glabra in women who are pregnant and nursing as well as in children has not been established (216). Claim 14: A composition for inducing autophagy compromising: Andrographis paniculate

□ Common Name: Kalmegh Powder

□ Main Active Constituent (s): The major constituents are diterpene lactones (flee and in glycosidic forms) including andrographolide, deoxyandrographolide, 11,

12-didehydro- 14-deoxy-andrographolide, neoandrographolide, andrographiside, deoxyandrographiside, and andropanoside (230).

□ Plant Part Used: Aerial parts □ Primary Target for COVID-19 + Clinical Outcomes: To aid the body in increasing the secretion of antimicrobial peptides which will help destroy pathogens particularly affecting endothelial cells.

□ Herbal Actions: Anti-human immunodeficiency virus (HIV) activity, Immuostimulatory, Antipyretic, Antidiarrhoeal, Anti-inflammatory, Antimalarial, Antivenom, Antihepatotoxic (230).

□ Daily Recommended Dosage: 1000 mg per day (230). □ Dosage Rationale / Toxicity: A standardized extract of A. Paniculate did not produce reproductive toxicity in male rats after 60 days of intragastric administration of 20-1000 mg/kg body weight daily (232).

□ No interruption of pregnancy, fetal resorption, or decrease in the number of live offspring was observed in pregnant rats after intragastric administration of an extract of the aerial parts at 2g/kg body weight during the first 9 days of gestation (233). □ Contraindications / Safety:

□ Should not be used during pregnancy or lactation (230).

□ Due to potential anaphylactic reactions, crude extracts should not be injected (230).

□ A. Paniculate may have synergistic effects with isoniazid (230).

□ May cause gastric discomfort, vomiting, and loss of appetite (230).

Claim 15: A composition of claim 1, wherein the composition further comprises Vaccinium angustifolium.

□ Common Name: Wild Blueberry Powder

□ Main Active Constituent fsV Polyphenols (234)

□ Plant Part Used: Fruit □ Primary Target for COVID-19 + Clinical Outcomes: To aid the body in increasing the secretion of antimicrobial peptides which will help destroy pathogens particularly affecting endothelial cells.

□ Herbal Actions: Antioxidant, Anti-inflammatory □ Daily Recommended Dosage: 500 mg daily

Claim 16: A composition of claim 1, wherein the composition further comprises Polygonum cuspidatum root □ Common Name: Japanese Knotweed

□ Main Active Constituent (s'): Resveratrol

□ Plant Part Used: Root

□ Primary Target for COVID-19 + Clinical Outcomes: To aid the body in increasing the secretion of antimicrobial peptides which will help destroy pathogens particularly affecting endothelial cells.

□ Herbal Actions: Antitumor, Antioxidant, Anti-inflammatory (235)

□ Daily Recommended Dosage: 200 mg per day

□ Dosage Rationale / Toxicity: “In vivo study including twenty healthy male professional basketball players were randomized into two groups (10 each). For 6 weeks, they received daily either 200 mg of polygonum cuspidatum extract (PCE) standardized to contain 20% trans-resveratrol equivalent to 40 mg trans-resveratrol or placebo. Indices of inflammation were measured before and after 6 weeks of supplementation.” No toxicity reported (235).