Pharmacotherapeutic Methods for Preventing and Treating COVID-19
While many drugs have shown varying levels of efficacy in vitro regarding SARS-Cov-2, due to the novelty of this virus, few medication regimens (with single drugs or in combination) have shown significant efficacy in vivo, and fewer still effectiveness against COVID-19 in actual clinical settings. Furthermore, for genuine effectiveness that encompasses multiple diverse populations, any pharmaceuticals:
1) must currently be widely available,
2) should be affordable,
3) should have well-established therapeutic profiles,
4) should have profiles that include relatively few and minor side effects.
These suggested pharmacotherapies meet all the criteria set forth. Furthermore, they comprise interventions beginning with prophylaxis and continuing through each stage of disease progression (often spanning several stages) as described below.
Stage 1 - Risk Of Exposure & Infection
Coronaviruses (CoVs) are enveloped, plus-strand RNA viruses belonging to the family
coronavirus family in the order of Nidovirales. SARS-CoV-2 has many common features with the Coronavirus family thus there are common underlying mechanisms.
Coronavirus delivery of virus particles into the host cell requires binding of the virus to cellular receptors followed by a clathrin-mediated endocytosis to create a viral endosome. This process is mediated by a viral surface glycoprotein termed Spike, a homotrimer of S proteins, binding to the type I integral membrane receptor angiotensin-converting enzyme-2 (ACE2). These receptors are expressed at high levels in type I and II alveolar cells in the lungs but are also found in the heart, kidneys, intestines and the rest of the respiratory tract
Stage 1 - Pre-Infection Prophylaxis
With rapid spread of the pandemic, huge portions of the world's population are at risk of exposure, with higher segments such as frontline healthcare workers, the elderly, people and those with pre-existing conditions and vitamin deficiencies being most susceptible to infection.
To effectively shield this population from infection, several measures should be taken according to current level of health and respective susceptibility to infection.
Optimisation of vitamin intake to strengthen the immune system:
Vitamin C is well documented in its ability to improve immune response to infections. Vitamin C affects the function of phagocytes, transformation of T lymphocytes and production of interferon. In particular, vitamin C increases the resistance of chick embryo tracheal organ cultures to infection caused by the coronavirus.
There are several mechanisms by which vitamin D activity is critical for immune defense: vitamin D acts to maintain tight junctions, promote the effect of antimicrobial peptides (i.e., cathelicidin and defensins), and moderate the inflammatory response.
Vitamin D deficiency has been demonstrated to have an exponentially negative effect on the rate of Co-morbidity in those infected with the virus (10x for <20ng/ml). The risk of vitamin D deficiency has been exacerbated by extended ‘shelter in place’ orders around the world.
Inhibiting Viral Membrane Fusion & Endocytosis:
“To show an effect you really have to treat early, I don’t know any drug that works better late in infection.” Giving a drug before exposure is as early as it gets.” - Matthew Frieman, Virologist of the University of Maryland School of Medicine.
Many viruses, including SARS-CoV, acidify endosomes in order to breach the cell membrane, release their genetic material and begin replication. Raising the endosomal pH of cell walls using a weak base such as Hydroxychloroquine prophylactically has been shown to interfere with the glycosylation of SARS-CoV-2, which limits the ability for SARS-CoV-2 spike proteins plugging into angiotensin-converting enzyme 2, or ACE2 receptors.
Sialic acid linked to glycoproteins and gangliosides is also used by many viruses as a receptor for cell entry. HCQ inhibits quinone reductase-2 by binding to sialic acids which also helps to prevent its spike proteins from gaining entry via these receptors thereby offering additional protection against infection.
The safety of Hydroxychloroquine has been noted by the WHO, stating the hundreds of millions of doses have been administered worldwide of the past few decades. Prophylaxis requires low dosages that effectively negate the chance of adverse side effects in almost all cases.
Further confirmation of the efficacy of low dose HCQ prophylaxis has been evidenced in Italy. SIR interrogated 1,200 rheumatologists throughout Italy to collect statistics on infections. Out of an audience of 65,000 chronic patients (Lupus and Rheumatoid Arthritis), who systematically take Plaquenil / hydroxychloroquine, only 20 patients tested positive for the virus. Nobody died, nobody is in intensive care, according to the data collected so far.
Stage 2 - Incubation & Viral Replication
Once internalised the fusion of virus with lysosomes depends on a low endosomal and lysosomal pH. Cathepsin B and L activity are inhibited by an elevated endosomal pH. Viral entry into the cytoplasm is likewise dependent on an acidic endosomal pH.
Once released into the cytosol, the virus utilizes a viral RNA-dependent RNA-polymerase (i.e. Replicase) to drive the viral replication, create virions for exocytosis, and thus further the infection of neighboring cells and transmit to the newly repackaged viral cells to other people. An individual viral particle called a virion is able to produce about a million new virions once inside a cell. Studies have shown that this pre-symptomatic replication stage exhibits the highest levels of viral shedding whereby hosts are the most likely to infect other people.
Pulmonary Scarring visible in scans of asymptomatic individuals, this is an unknown characteristic for the future.
Stage 2 - Asymptomatic Antiviral Therapy
Given that viruses are intracellular parasites that hijack cellular processes to replicate a virus’s genetic material, it is essential antiviral agents have the ability to enter cells.
Hydroxychloroquine, even at prophylactic dosages, has far reaching abilities for distribution throughout the human body, including entering cells. In doing so, it has been proven to inhibit both viral RNA replication and repackaging functions inside cells by decreasing the acidity of the cytoplasmic environment within key structures such as the endoplasmic reticulum and the golgi apparatus.
In addition, Zinc is able to effectively block virus RDRP (RNA-dependent RNA polymerase) replication of RNA through limiting its engagement with ribosomes by binding with these enzymes.
It is critical for zinc to be able enter cells to destroy the virus, which makes the discovery of an ionophore as important as zinc’s primary role in infection control. Hydroxychloroquine has been previously identified as an effective zinc ionophore which creates passageways for Zinc to penetrate cell walls.
The combination of these two agents acting together delivers a very powerful antiviral effect, prohibiting viral loads from escalating to the point of patients needing hospitalisation and importantly, from being able to be repackaged for transmission to new hosts.
Stage 3 - Symptomatic Phase
Previous studies on Human Coronavirus (HCoV-HKU1) indicate that infection of alveolar cells is associated with the surface expression of viral spike protein, mediating membrane fusion with neighboring cells leading to syncytium formation. This allows direct cell to cell spread of virus which could play a role in the pathogenesis of lung disease and immune system evasion.
Early symptoms mainly affect the upper respiratory tract, although increasing evidence is showing the scarring, bilateral ground-glass opacity is already presenting in the lungs of the infected.
When patients start to present symptoms of COVID-19, they have varied greatly across regions which is an indication of possible mutations of the virus. Younger, healthier people have a reasonable chance of recovering in an outpatient setting however those with pre-existing conditions have a much higher susceptibility to progressing to more severe conditions which require hospitalisation.
Stage 3 - Symptomatic Treatment
The symptomatic stage of infection has been the major focus for suggested therapeutic protocols promoted globally thus far. There is growing consensus that immediate treatment with the combination of Hydroxychloroquine, Azithromycin and Zinc is the best option for treatment at this stage of infection.
Supplementation with Vitamin C helps the epithelial layer in the respiratory tract to combat the virus and prevent rapid inflammation due to immune response to the increasing stress from the infection.
The later this treatment is started the lower the beneficial effects of the Hydroxychloroquine and Zinc therapy will be, the Azithromycin is well documented for its ability to clear ENT infections as well as assisting in clearing the lungs from mucous build up from pneumonia like symptoms which develop with acute cases.
Stage 4 - Intensive Care (Hypoxia & Organ Failure)
As the infection reaches maximum viral load in the body, moving down into the lower respiratory tract and increasingly affecting the lungs, leading to extensive scarring and inflammation of the alveoli. COVID-19 causes prolonged and progressive hypoxia by binding to the heme groups in the red blood cells.
Based on observations in USA, Spain, Italy, France and UK, and from postmortem of lungs involvement in COVID 19, all revealed pulmonary thrombosis which is not typical ARDS , but more alarming that it is patient hypoxemia that is not responding to PEEP but high oxygen flow.
In COVID-19 patient lungs, It is a fact that it affects both lungs at the same time and Pneumonia rarely ever does that, but COVID-19 does every single time.
Like methemoglobin, the COVID 19 virus structural protein, sticks to heme – displaces oxygen – which release iron-free ion , that leads to toxicity and causes inflammation of alveolar macrophages- that results in bilateral CT scan changes as it is a systemic response.
Lung inflammation results from the inability of both oxygen and CO2 exchange, leading to the ground glass on x rays, it mimics CO2 poisoning as an invisible enemy. COVID 19, SARS-CoV-2 is not ‘pneumonia’ or ARDS. Invasive ventilation is not only the wrong solution, but emergency intubation can harm and result in more damage, not to mention complications from tracheal scarring and stiff lung during the duration of intubation.
The COVID 19 virus attacks beta chain, dissociates heme, removing iron and converting it to porphyrin. The virus can dissociate oxy-Hb, carboxy-Hb and glycosylated Hb. When too much iron is in circulation, it begins to overwhelm the lungs’ counter measures begins, the process of pulmonary oxidative stress. This leads to damage and inflammation, which leads to the so-called Cytokine storm.
This will lead to multi-organ failure and high mortality. The lung damage seen on CT scans is due to the oxidative iron released from the haemolysed red blood cells which in turn overwhelm the natural defences against pulmonary oxidative stress and causes what is known as Cytokine storm which causes high patient mortality.
Once lymphocyte counts drop below 500, mortality is expected within 48 hours.
Stage 4 - ICU Treatment
There is no benefit of invasive ventilation, but patients may require frequent blood transfusions or plasmapheresis.
Patients must be managed on maximum oxygen flow through a hyperbaric chamber on 98% oxygen at double or multiple atmospheres of pressure, for 90 minutes twice per day for five days. This is in order to give what has left of their functioning haemoglobin a chance to carry enough oxygen to the organs and keep them alive.
Starting therapy with Hydroxychloroquine at this stage is likely too late to assist through its antiviral effects, however if treatment has been started earlier, ideally Stage 1, the immunomodulatory effects of the medicine will help to subdue the onset of the cytokine storm which has been shown to lead to respiratory failure.
Another beneficial effect of Hydroxychloroquine is its ability to limit blood coagulation which is another acute symptom of late stage SARS-CoV-2 infection which is being found throughout patients major organs.
Vitamin C is proving highly beneficial at this final stage of infection with intravenous administration of very high dosages to ICU patients.
Zinc is a vital component that limits the build up of superoxide by assisting the ACE2 receptors in the conversion of AT-11 to AT1,7. This process needs support as it becomes increasingly difficult with the increase of ACE2 receptors being blocked by SARS-COV-2 S-proteins attaching themselves to the cells in the lungs.
Recommended Treatment Per Stage:
Stage 1 Pre Exposure Prophylaxis:
1- Hydroxychloroquine 200mg once a week
2- Zinc sulphate 20mg once a day
3- Supplement with Vitamin C & D at daily recommended nutritional dosages
Stage 2 Post Exposure Prophylaxis:
1- Hydroxychloroquine 400mg once a week
2- Zinc sulphate 40mg once a day
3- Supplement with Vitamin C & D at daily recommended nutritional dosages
Stage 3 Symptomatic Therapy:
1- Hydroxychloroquine 400mg twice on day 1, 200mg twice a day for 4 days following
2- Azithromycin 500mg on day 1, 250mg once a day for 4 days
3- Zinc sulphate 220mg once a day for five days
4- Supplement with Vitamin C & D at daily recommended nutritional dosages
Stage 4 ICU Treatment
1- Hydroxychloroquine at minimal dosage ie 100 mg per day
2- Intravenous Vitamin C at high dose volumes
3- Hyperbaric oxygenation therapy to raise spO2 when acute levels of desaturation are reached
4- Plasmapheresis and blood transfusions will give supportive symptomatic relief.
5- Zinc sulphate 200mg once a day
Sources
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(PDF) COVID-19 illness in native and immunosuppressedstates: A clinical−therapeutic staging proposal
HCQ Prophylaxis For COVID19 Guidelines
(PDF) Aminoquinolines Against Coronavirus Disease 2019 (COVID-19): Chloroquine or Hydroxychloroquine
(PDF) Chloroquine is a potent inhibitor of SARS coronavirus infection and spread
Hydroxychloroquine Post Exposure Prophylaxis for Coronavirus Disease (COVID-19) - Full Text View
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Landscape analysis of therapeutics as 21st March 2020
Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro
Vitamins C and D Finally Adopted as Coronavirus Treatment
Modern Medicine Knew of the Zinc Cure for Coronavirus Infections a Decade Ago, But Failed To Put It Into Practice
Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19
Analysis of COVID-19 by Prof. Sharif Sultan (President of the International Society of Vascular Surgery)
Current Clinical Trials Featuring HCQ
Brazil-officially-embraces-early-hydroxychloroquine-based-treatment
A Study of Quintuple Therapy to Treat COVID-19 Infection - Full Text View
Is a combo of chloroquine and Zinc a cure for coronavirus?
Immediate-Treatment-Early-Stage-SARS-CoV-2
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Coronagate: the scandal to end all scandals | Martin Geddes on Patreon
Italy Finally Starts Mass Treatment with Hydroxychloroquine
Dr. Vladimir Zelenko has now treated 699 coronavirus patients with 100% success using Hydroxychloroquine Sulfate, Zinc and Z-Pak [UPDATES]
Hydroxychloroquine is now being used worldwide, according to a map from French Dr. Didier Raoult
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Trials of HCQ to prevent coronavirus infection begin in health care workers
American Medical Doctors Recommend Early COVID-19 Treatment Combining Hydroxychloroquine, Azithromycin & Zinc
Hydroxychloroquine-Based Treatment Can Also Work for the Elderly
Full 1061 Patients Hydroxychloroquine / Azithromycin Marseille Study Published