Research and Hypothesis for Creating Three Isopathic Cell Signaling Formulas for Coronavirus Relief
( Prophylactic, Symptomatic, Severe )
Exposure – Infection – Inflammation – Pneumonia – Pulmonary Failure – Mortality
Paul E. Opheim, MIM, MA
CEO/Research Director, Leptica Research LLC
in collaboration with Ann B. McCombs DO, DABHM, DNM
There is currently no effective pharmaceutical or vaccine therapy yet available to deal with the CoVID-19 pandemic. Even the seasonal Influenza Type A (IAV) vaccine was only 29% overall effective in 2019, per the CDC. Numerous researchers have concluded that any and all potentially viable therapeutic modalities must be considered when dealing with highly pathogenic viral infections. It was to address this urgent need that Leptica Research did this analysis on coronavirus, especially to determine if cell signaling factors (CSFs) might play a role in creating potentially effective isoenergetic cell signaling™ Cell Function Activator™ medicine(s) to use with exposure to CoVID-19 . That question has been answered in this white paper, and Leptica Research has accomplished the task of creating three safe (no side effects) and cost-effective formulas (Prophylactic, Symptomatic and Severe, which cost 17¢, $1.75 and $3.00 per person per day, respectively) that have a high probability of being clinically effective. Collaborator Comments and Clinical Experiences with isoenergetic cell signaling™ Cell Function Activator™ medicines follow the author’s Epilogue at the end of this paper, as do brief biographical sketches of both the author and collaborator.
Introduction and Historical Context
Barbara A. Brewitt, PhD, MDiv (1948-2009) is the original researcher of the isoenergetic cell signaling™ approach to healing. Through her doctoral research in Biological Structure (1989) at the University of Washington School of Medicine, as well as her post-doctoral studies as an NIH Fellow, Barbara became recognized as an international expert on cell-to-cell communication and broadened the understanding that growth factors (a type of cell signal) are related to health and healing . Her research was translated into 8 languages. Like all pioneers, however, Barbara was maligned by some colleagues who did not fully comprehend her research and attempted to discredit both her and her work. Nevertheless, by combining the principles of molecular biology and biophysics with those gleaned from homeopathy over a 250-year period, Barbara and I (as her Research Associate and principal investor) created nine different cell signaling formulas that were safe, clinically-proven and orally-delivered to address symptoms associated with such ailments as HIV, Autism and PTSD, as well as hormone and age-related imbalances, that have stood the test of time. Nine national and international patents were held by our company (Biomed Comm, Inc. in Seattle, WA). Homeopathic provings (or “proving trials”, where a homeopathically prepared substance is tested on healthy volunteers – “provers” – in order to reveal, through recording the effects, the state of health-disturbance that the substance induces) were done on human Growth Hormone (hGH) and Insulin-like Growth Factor-1 (IGF-1 ). Our first double-blind, placebo-controlled clinical study, published in 1995, proved that a set of non-molecular isopathic growth factors could prevent HIV-positive adults from losing lean body mass and experiencing opportunistic infections over a 6-month period. Our second clinical study was a blinded, placebo-controlled one with orphaned children in South Africa. It “unblinded” itself, however, when half of the children became more energetic and engaged. Our third most notable research study was on anti-aging, using homeopathic Human Growth Hormone (hGH). These studies were peer-reviewed and published in The Townsend Newsletter (now known as The Townsend Letter for Doctors) and the Journal of Complementary and Alternative Medicine. Multiple proof-of-hypothesis case studies conducted since 1995 (on Parkinson’s, leptin – for cravings and weight issues – PMS, menopause, chronic alcohol addiction, psoriasis, chronic Lyme Disease, Chronic Fatigue Syndrome and, currently, on latent HIV reactivation), as well as hundreds of anecdotal reports from medical practitioners around the world have repeatedly validated the effectiveness of these formulas. Subsequent to Barbara’s untimely death in 2009, I inherited the patents and proprietary information. Since then, I have researched and developed many other medicinal formulas for both chronic and acute conditions which are safe, cost-effective and have proven efficacy with no adverse side effects (see the complete list on my website: www.LepticaMedical.com – access is user-name and password-restricted for physicians).
The Purpose of this White Paper
A white paper is an authoritative report or guide that addresses issues and how to solve them. Its purpose is to inform readers concisely about a complex issue and present the author’s philosophy on the matter, as well as his/her specific solution(s) to resolve it. In this white paper, the complex issue is how to treat a pandemic infection such as CoVID-19 safely, effectively and cost-effectively. To understand my philosophy and the solution that, I believe, could achieve these goals, the reader will be introduced to:
- the nature and complexity of cell signaling factors (CSFs) – the molecules that are responsible for transmitting information between the cells of the body – and how they play a role in the way the body responds to a highly pathogenic coronavirus infection;
- how the evolution of CoVID-19 symptoms reflecting the difference in one’s state of health is, in part, dependent upon the change in ratios of various CSFs – for example, the presence of fever reflects the levels of specific pro-inflammatory CSFs (IL-1ß, IL-6, TNF-a);
- the concept that the variety and degree of CoVID-19 symptoms directly affects the choice and strength of the energetic frequencies of the CSFs used in the different formulas;
- the nature of isoenergetic cell signaling™ medicines and how they differ from homeopathic and pharmaceutical preparations; and how multiple CSFs can be uniquely combined in a Cell Function Activator™ medicine to effectively and safely complement diverse treatment protocols to accelerate the healing process of highly pathogenic coronavirus infections, e.g. CoVID-19.
Pandemics Past and Present – A Brief Overview
Pandemic viral infections are an on-going scourge sometimes faced by humankind as well as animals (e.g. swine flu). Highly pathogenic viruses create fever, viral pneumonia, encephalitis and acute respiratory distress syndrome (ARDS) as a result of excessive pro-inflammatory cytokine (a type of cell signaling molecule) and chemokine (small cytokines that attract white blood cells – WBC’s – to sites of infection) reactions that the body initiates in response to being exposed to virulent viral infections (Klein, 2012). Every year over 10,000 people in the United States alone die from influenza – primarily from Influenza Type A (IAV) viruses – including those who were immunized. Those who are severely afflicted with a sepsis-like response to the “cytokine storm” of these highly pathogenic viruses can be left with a compromised immune system that increases their susceptibility to future infections.
To reduce the risk of mortality from these pandemic viral infections, it is crucial to address virus-induced pulmonary failure, especially due to those infections affecting the lower respiratory tract.
Current vaccines are not completely protective against infections with seasonal influenza strains and are ineffective at protecting against emerging new or pandemic strains (Osterholm, 2012), including CoVID-19. To date, there are no vaccines – nor any safe and effective pharmacological means – that adequately address and effectively treat the CoVID-19 pandemic. Therefore, to minimize morbidity, mortality and reduce the economic burden on society, especially in the case of pandemic infections like CoVID-19, all plausible approaches having the potential to be effective against such viral exposures must be considered. In the past, in the United States alone, the cost of these highly pathogenic influenza virus outbreaks was more than $85 billion (Molinari, 2007). The potentially devastating health and economic effects of this CoVID-19 pandemic is no different and will likely have an even greater economic impact, possibly into the trillions of dollars.
Our Focus is only on the Coronavirus Family in this Analysis
It is beyond the scope or intention of this paper to do an analysis of all the various viral afflictions most common to humans. Even though the research for these three formulas was restricted to the Coronavirus family, it would not be surprising if there were overlap with other highly pathogenic viral infections (such as Influenza Type A Virus) with respect to the body’s antiviral responses to them, especially in the way they reproduce, proliferate and migrate in various organs and tissues.
A very brief overview follows of the order, genus and species of some of the more well-known viruses – divided by phylogenetic clustering (Fehr, 2015) – to show where CoVID-19 fits into the coronavirus viral hierarchy:
- Nidovirales order – all viruses in this order are RNA viruses and share an enveloped, non-segmented, positive-sense (polarity), single-stranded genetic structure.
- Coronaviridae (CoV) family – first identified in the mid-1960s and named for the crown-like spikes on their surface, seven of which can infect humans.
- Alpha group of coronaviruses
- HCoV-229E – associated with the common cold
- HCoV-NL63 – associated with acute laryngotracheitis (croup)
Beta group of coronaviruses
- HCoV-HKU1 – associated with the common cold
- HCoV-OC43 – associated with the common cold
- MERS-CoV – causes Middle East Respiratory Syndrome (or MERS
- SARS-CoV – causes Severe Acute Respiratory syndrome (or SARS
- SARS-CoV-2 – causes coronavirus disease 2019 (or CoVID-19)
- Delta group of coronaviruses – not a human contagion
- Gamma group of coronaviruses – not a human contagion
- Alpha group of coronaviruses
- Orthomyxoviridae family – includes the Influenza A (IAV) viruses
- Arteriviridae family
- Equine arteritis virus (EAV)
- Lactate dehydrogenase-elevating virus (LDV)
- Porcine respiratory and reproductive syndrome virus (PRRSV
- Simian hemorrhagic fever virus (SHFV)
- Roniviridae family – includes the yellow head virus (YHV) in shrimp
- Coronaviridae (CoV) family – first identified in the mid-1960s and named for the crown-like spikes on their surface, seven of which can infect humans.
Other virus families in this order which also have well-known members:
- Flaviviridae family – includes the dengue viruses
- Bunyaviridae family – includes the oropouche virus
- Togaviridae family – includes the following more-well-known examples
- Chikungunya virus (CHIKV)
- O’nyong-nyong virus (ONNV)
- Flaviviridae family – includes the dengue viruses
Frequency and Prevalence
CoVs are endemic in the human population, causing 15-30% of respiratory tract infections each year. Severity comes with those that cause a greater incidence of lower respiratory tract infections, e.g. SARS-CoV and MERS-CoV. CoVID-19 now joins these two highly pathogenic CoVs exhibiting this same characteristic.
Though not exclusively, the most susceptible people manifesting severe reactions are neonates, the elderly and individuals with underlying illnesses (Fehr, 2015). It is not surprising that those with undeveloped immune systems, those over age 65 and the significantly immunocompromised (“survivors” of sepsis or those who have other immune-compromising afflictions, e.g. organ transplant, HIV and COPD) are the most susceptible to these CoVs, as well as the secondary infections, complications and morbidity that come from these highly pathogenic viral influenza infections. Unknown genetic factors that compromise the immune response can also cause healthy adults and youth to be at risk. In addition, Immunosenescence (the gradual decline in immune functioning due to natural aging) enhances one’s susceptibility to viral infection and also renders vaccination less effective (Hernandez-Vargas, 2014).
It is also possible that one’s previous antibiotic usage (which compromises the gut biome) can adversely impact macrophage responsiveness to Types I and II interferons. This antibiotic use causes a reduced capacity early-on of these INFs to recognize viral pathogens, control viral replication and limit the inflammatory response. This reduction in macrophage responsiveness also includes less efficient production of multiple effector molecules (those which directly affect cell pathway responses): IFN-?, TNF-a, IL-2, MIP-1a and CD107a (Abt, 2012), which could subsequently create a degree of T-cell exhaustion. Because antibiotic usage also affects the aerobic and anaerobic commensal bacteria in the upper respiratory tract, an impaired beneficial bacterial presence due to their use could likewise result in impaired anti-viral actions, which could further result in the following (Abt, 2012):
- Greater epithelial cell necrosis and, in severe cases, loss of the bronchiole epithelial layer
- Increased exudate and dead cells in the bronchiolar lumen
- Reduced blood oxygenation saturation
- Impaired viral clearance
- Reduced virus-specific antibodies
- Peribronchiolar inflammation
- Weight loss
Abt and associates then conclude (bold is author’s emphasis): these data indicate that commensal-derived signals are critical in promoting optimal immunity against multiple viral infections at sites distinct from the gastrointestinal tract, and signals derived from commensal bacteria calibrate the activation threshold of antiviral immune response pathways in macrophages. This indicates an inherent inability to respond to viral infection. They further state that : for rapidly replicating viruses, such a delay in initiating antiviral pathways (expression of anti-viral defense genes and interferon-responsive pathways) and activating downstream events [such as humoral and cell-mediated adaptive immune responses] can have dramatic consequences, leading to failure to control infection, increased host morbidity and mortality. The consequences to which Abt and associates refer are cytokine storm and sepsis. De Vrese and associate further note (bold, caps and parenthesis are author’s emphasis): prophylactic probiotic [NOT antibiotic] administration can limit the duration and severity of respiratory viral infections in human subjects, especially when enhanced by corrective cell signaling and when antibiotics are used only to preserve life.
CoVID-19 Symptoms (those in amber are the most common)
- Chills / Hypothermia
- Difficulty moving
- Joint pain / arthritis
- Labored breathing / difficulty breathing
- Decrease or loss of smell (anosmia)
- Decrease or loss of taste (hypogeusia / ageusia)
- Persistent dry cough
- Persistent muscular weakness
- Persistent myalgia (muscle pain)
- Pyrexia (fever) – macrophages produce IL-1ß, IL-6 and TNF-a, which induce fever (Tamura, 2004).
- Shortness of breath
IL-17 is important in inducing the neutrophil response. Excessive neutrophil production, which rapidly infiltrates the lung and is an important source of pro-inflammatory cytokines (IL-1ß, TNF-a), correlates with worsening lung injury (Crowe, 2013). This is shown in:
- increased perivascular inflammatory infiltrates
- inflammation extending from the perivascular bed into the parenchyma
- capillary leaks
- lung epithelial apoptosis
MERS-CoV and SARS-CoV, both severe infections of the lower respiratory tract, have overall mortality rates of 35% and 10% respectively. In populations which have weak immune systems (infants, elderly) or are immunosuppressed (HIV+), the mortality rates can be greater than 50%(Gralinski, 2015). From early clinical reporting, CoVID-19 may have a similar severity.
A Complex Challenge Requires a Comprehensive Solution
Late-term symptom progression is less related to viremia and more likely to be associated with immunopathological damages resulting from excessive and inadequate cell signaling responses, such as:
- excessive pro-inflammatory interleukins, which can damage paracrine (nearby) healthy cells;
- inadequate interferon lambda signaling, which is only exhibited by epithelial cells, due to viral suppression of its expression; or
- overexpression of interferon alpha and beta signaling, which is also expressed on endothelial cells, and can result in systemic inflammation.
In the alveolar airspace we need to:
- reverse the loss of barrier function – there is functional and structural impairment of the tight AEC layer; thus, the alveolar-capillary barrier results in fluid leakage from the vascular compartment into the alveolar space, and persistent edema results (Peteranderl, 2016; Wolk, 2008)
- decrease inflammation
- repair the damaged epithelium
- improve edema fluid clearance
Introduction to My Research on Coronavirus
In 2016, with news of the zika, dengue and chikungunya viruses following warming trends northward to Florida, I became concerned about the potential dangers of these viruses to children and adults. I started looking at the scientific data then and, at the request of a doctor in Phoenix, I completed a formula to address the issue of cytokine storm and sepsis. (The current Coronavirus Severe Relief Signaling Formula is related to that formula and should help speed recovery from life-threatening CoVID-19 symptoms, leaving the body with enhanced and balanced immunity, as well as improved GI functioning.)
In December 2019, upon hearing of the outbreak of CoVID-19 in Wuhan, China, my thoughts turned to my graduate school classmates in Taiwan and Japan, so I returned to my 2016 research with a focus on highly pathogenic coronaviruses. My analysis came to fruition and concluded on March 15, 2020 with the realization that 3 distinctly individual formulas would work best to address the 3 phases of symptom development of highly pathogenic coronavirus infections:
Symptomatic (or infected and asymptomatic)
My reason for this conclusion is this: during the course of symptom development, the body activates a variety of antiviral responses that are related to specific CSFs (primarily interleukins and interferons), which form the basis of our innate immune response to pathogens. Due to the fact that the ratios of these CSFs change, maintaining a cell signaling balance of these factors to avoid a “cytokine storm” is both critical to the success of using these formulas to counter this CoVID-19 outbreak effectively and crucial for people start using them ASAP. More specifically, to avoid this event (also known as hypercytokinemia), maintaining the ratios of Th1/Th2/Th17 – innate immune T-cell responses governed by pro- and anti-inflammatory cell signaling factors (such as Type I, II and III interferons and interleukins 2,4,10,13 and 17) – is critical . To accomplish this goal, I saw that I not only had to modify these formulas to reflect the specific cell signaling changes that occur with exposure to highly pathogenic coronavirus infections, I also had to modify them to reflect the specific cell signaling changes that occur during the course of the body’s antiviral responses to and recovery from them .
Our Medicines: Unique + Anecdotally and Clinically Proven since 1995
Based on my research, the same approach I have seen work so well for the past 25 years (isoenergetic cell signaling™ formulas that have been isopathically-derived and homeopathically-prepared) can be employed to address the current coronavirus pandemic, specifically to stimulate and balance the body’s immune response to CoVID-19. I call these formulas Cell Function Activator™ medicines. They are not pharmaceutical drugs, nor are they traditional homeopathic remedies. They incorporate the best of scientific research, as well as safe and accurate homeopathic sequential kinetic preparation; and, through the addition of neuro-energetic signaling, they truly represent a different class of medicine. They are derived from recombinant DNA human proteins (polypeptides), acquired from established FDA-approved laboratories, which also produce bio-identical hormones. Through this derivative process, pure molecules are produced that are identical to what the body itself produces. This is accomplished by taking the human gene that produces each specific CSF and splicing it into laboratory yeast, which are then fed the foods (usually sugars) that make them multiply, after which they are separated. What results are pure CSF molecules exactly like those that the human body makes. The bio-electrical energy of these pure CSF molecules is identical to what the body produces, so it can recognize it as “self.”
Unlike homeopathic remedies, whose components come from the Homeopathic Pharmacopoeia of the United States and the concept of “like treats like”, our medicinal formulas are technically isopathic and should be thought of, distinguished from, and most accurately described as “identical treats identical”. The method of development of both kinds of medicines, however, is the same: sequential kinetic succussing (diluting) to specific frequencies (Vithoulkas, 1980). Because these frequencies can be detected past Avogadro’s number (the number of atoms or molecules in one mole of a substance equal to 6.0221 x 10 23 ) (Beauvais, 2018), they are technically defined as non-molecular and are thought to exist only in energetic form, which is why I have called them isoenergetic cell signaling™ medicines. Like homeopathic remedies, the different signaling frequencies (energies) each elicit different signaling responses. For example, IGF-1 (Insulin-like Growth Factor-1) at a homeopathic frequency of 12C can often relieve cramps associated with PMS within 10 minutes, whereas a 1M frequency of IGF-1 is a very powerful anti-depressant. For additional insights into the research on this topic, my collaborator and I highly recommend Richard Gerber, MD’s book Vibrational Medicine: the #1 Handbook of Subtle Energy Therapies (3rd edition, 2009).
Unlike pharmacological drugs (which are derivatives of molecules or synthetic creations and not identical to what the body produces), our medicinal formulas do not come with the potential for adverse side effects, nor must they undergo Phase I, II and III clinical trials to establish sufficient safety and efficacy. Another very important difference between our medicines and pharmacological drugs is that the latter rely primarily on a monotherapy approach, whereas our formulas are composed of multiple CSFs at specific signaling frequencies, allowing them to respond promptly and simultaneously to multiple cell-signaling pathways.
It is sometimes difficult to conceptualize this type of non-molecular medicine, so perhaps an example would better illustrate the ability of our Cell Function Activator™ formulas to elicit such a powerful effect. Let us say you get a whiff of something that instantly reminds you of an experience in the past, e.g. a summer family barbecue at the lake. Since large aromatic molecules cannot get past your olfactory lobe, how did that memory happen? Based on the premise in physics that all identical molecules uniquely possess a specific “electrical” energy or resonance, your olfactory nerve endings were able to sense that energy, producing an instantaneous recall of time, space and events, as well as an awakening of the senses. (For additional insights into the research on this topic, I highly recommend Chandler Burr’s book The Emperor of Scent, 2004.) Another example: how do specific smells or sounds immediately elicit responses to past trauma, even if the trauma was consciously forgotten? Both examples graphically illustrate the power of our neuro-energetic system. Merging the concepts of energy medicine, neurology and endocrinology with structural biochemistry and cellular/systems biology provides the basis to understand our medicines and how they can work so effectively.
Our goals in addressing the current coronavirus pandemic with this isoenergetic cell signaling™ approach are, first and foremost, to safely and effectively strengthen the body’s own innate antiviral immune response to resist initial exposure to the virus. An equally important goal is to reduce migration of this virus to the lower respiratory tract, primarily to significantly decrease the risk of mortality due to increased susceptibility and potential adverse responses of a compromised immune system to viral and bacterial pneumonia.
Challenges – Balancing Virus Elimination and Immune Pathology for a Safe Recovery
Our primary challenge is how to minimize the severity of the body’s antiviral responses to promote recovery and thereby reduce hospitalizations and mortality. To accomplish this task, we must figure out how to control the cytokine storm and neutrophil-driven inflammation during catastrophic viral pneumonia (Ito, 2015). For effective host protection from excessive, life-threatening immunopathology, research shows a need to inhibit systemic cytokine and chemokine over-production and still stimulate sufficient innate immune cell recruitment.
Our next challenge is to figure out how to optimize the bone marrow response to signals from infected lungs to generate the correct number of leukocytes to attack respiratory viral infections.
Our final challenge: how can we solve both of these challenges in a highly effective manner, free of adverse side effects, and still be extremely cost effective? As we had already experienced with the success of our formulas for Parkinson’s, COPD, PTSD and CTE (just to name a few), it seems to me that the right combination of cell-signaling factors at the right frequencies should be able to meet all of these challenges.
From my research, I determined that we must focus on stimulating and balancing Type I, II and III interferons (IFN-a/ß/?, gamma and lambda, respectively) and the interactions of specific interleukins. When the expression of these cytokines and chemokines is inhibited and imbalanced, these CSF’s can promote morbidity and mortality. Through the induction of aberrant inflammatory responses during viral infection, these factors can support immune suppression and balance lymphoid tissue disorganization and CD4 T-cell dysfunction (Teijaro, 2016).
Advantages of a Cell Function Activator™ Medicine
Repeated administration is possible.
- Due to the transient effectiveness of some medications (TLR-4 antagonists, for example), repeated treatments can be difficult.
These medicines are highly cost-effective – each 2-oz formula costs only US$120.
The Prophylactic formula lasts 102 weeks (almost 2 years)
- …youth & adults need 2 sprays (sub-lingual) twice/week spaced evenly during the week
The Symptomatic formula lasts just over 68 days (2.3 months)
- …youth & adults need 2 sprays (sub-lingual) 3 times a day (upon arising, mid-afternoon and before bedtime or approximately every 8 hrs)
The Severe formula lasts 40 days (1.3 months)
- …youth & adults need 2 sprays 5 times a day (approximately every 5 hrs
- The Prophylactic formula lasts 102 weeks (almost 2 years)
- Since 1995, there have been no adverse side effects reported from taking this type of medicine, and it has been proven to be safe and clinically effective over time.
It is not a pharmaceutical drug or drug derivative.
- It is derived from isopathic recombinant DNA human proteins and homeopathically prepared to a non-molecular strength beyond Avogadro’s number (6.0221 x 10-23).
- It is non-prescription.
- Because it is prepared by sequential kinetic succussing (diluting) to specific frequencies, it falls under a homeopathic classification, though it is technically an isopathic Cell Function Activator™ medicine and not a homeopathic remedy.
How to Select Which Formula to Use
The correct application of these 3 formulas depends first on the body’s current state of being: symptomatic or asymptomatic. When asymptomatic, the Prophylactic formula should be taken to stimulate certain CSFs in the body (specific interferons and interleukins) to respond appropriately if exposed to a potential coronavirus. If you become symptomatic, use the following Self-Assessment of Symptoms form to help determine which formula to use next: Symptomatic or Severe.
Self-Assessment of Symptoms (SAS) Form – for Medical Practitioners and/or Patients
The SAS form is meant to be used to evaluate one’s current state of health to assist in determining which formula to use if exposure to a highly pathogenic coronavirus (e.g. CoVID-19) has happened or is suspected. This form does not replace the need to consult with a licensed medical practitioner once awareness of such an exposure has occurred. NOTE : not one (or even several) symptoms on this form can determine the presence or absence of a coronavirus infection or antibodies – only a reliable test from a reputable medical professional, clinic or hospital can do that or determine if it needs to be done.
Before starting any of the 3 formulas, complete the SAS form first, so that a baseline state of current health can be established. Chronic or frequent presence of symptoms when not feeling symptomatic will help to identify when becoming symptomatic has begun, especially with concurrent symptoms listed in amber on this form. Specific instructions follow on how to use the SAS form. Note that it is color-coded to help the user determine which formula to use.
- If exposure to a highly pathogenic coronavirus has occurred OR is even a possibility, fill out the SAS form and start the Prophylactic (pre-symptomatic) formula immediately.
- If any symptoms listed on the SAS form begin to occur, fill out the SAS form again, start the Symptomatic formula immediately AND consult with a licensed medical professional as soon as possible. Note that the “incubation” (or asymptomatic) period for these viruses can be up to 14 days, so there could be some overlap between a possible exposure and onset of symptoms.
- If symptoms become progressively worse, immediately seek emergency medical help AND start the Severe formula.
Oral – Gastrointestinal
|Score 0 = not an issue1 = very mild or hardly noticeable10 = very severe|
|Decrease in sense of smell||0||1||2||3||4||5||6||7||8||9||10|
|Decrease in sense of taste||0||1||2||3||4||5||6||7||8||9||10|
|Loss of appetite||0||1||2||3||4||5||6||7||8||9||10|
|Dehydration (yellow urine)||0||1||2||3||4||5||6||7||8||9||10|
|Score 0 = not an issue1 = very mild or hardly noticeable10 = very severe|
|Persistent dry cough||0||1||2||3||4||5||6||7||8||9||10|
|Shortness of breath||0||1||2||3||4||5||6||7||8||9||10|
|Feeling chest is compressed||0||1||2||3||4||5||6||7||8||9||10|
|Score 0 = not an issue1 = very mild or hardly noticeable10 = very severe|
|New joint pain / arthritis||0||1||2||3||4||5||6||7||8||9||10|
|Chills / feel cold||0||1||2||3||4||5||6||7||8||9||10|
|Fever, esp >100.8° F||0||1||2||3||4||5||6||7||8||9||10|
|Profuse sweating (w/o exertion)||0||1||2||3||4||5||6||7||8||9||10|
|Persistent muscular pain||0||1||2||3||4||5||6||7||8||9||10|
|Persistent muscular weakness||0||1||2||3||4||5||6||7||8||9||10|
|Strange or odd body Sensations||0||1||2||3||4||5||6||7||8||9||10|
As has been frequently stated in many of the references that were researched in preparing this white paper, there is currently no effective pharmaceutical or vaccine therapy yet available to deal with the CoVID-19 pandemic. Even if a vaccine were available, it should be noted that the seasonal Influenza Type A (IAV) vaccine has never been shown to prevent transmission of the flu; the best it can do is to limit the symptoms in an infected person (https://www.drbrownstein.com/should-you-get-the-flu-shot/, 2019) and https://www.drbrownstein.com/wsj-article-on-flu-shots:-perfect-example-of-fake-news!/, 2019). It is to the credit of numerous researchers cited in the References section who have concluded that any and all potentially viable therapeutic modalities must be considered when dealing with highly pathogenic viral infections. It was to address this urgent need that I did this research on coronavirus, especially to determine if CSFs might play a role in creating potentially effective isoenergetic cell signaling™ Cell Function Activator™ medicines to use with exposure to CoVID-19. As previously outlined in this white paper in detail, I believe I have answered that question and accomplished that task. All that remains now is to apply the three formulas that emerged from my research to see if they will prove to be as effective as it seems they have the potential to be, knowing that no harm will likely come from using this approach, based upon the results obtained from using it successfully for many other medical conditions over the past 25 years.
Overview of the Remainder of this White Paper
What follows next reflects my thought process and the research I did to determine which CSFs needed to be specifically considered to correct the imbalance in the human cell signaling system that can occur when exposed to a highly pathogenic coronavirus like CoVID-19.
To enable the reader to understand this complex research effort, I have included many terms (and their abbreviations and relevant definitions) to provide a context for the discussion of the specific CSFs that were taken into consideration to accomplish this task. A list of the CSF’s (including their abbreviations and definitions) involved in understanding their interaction with and impact upon highly pathogenic viruses in general, and CoVID-19 in particular, follows these terms and abbreviations. All the research that I did has been included in the References section.
Terms and Abbreviations
|AEC||Airway epithelial cells|
|ALI||Acute lung injury: non-cardiogenic pulmonary edema, capillary leak, hypoxemia (Crowe, 2009)|
|Apoptosis||Programmed cell death through pathways governed by cell signaling factors|
|ARDS||Acute respiratory distress syndrome – most severe form of ALI|
|AT2||Alveolar type II (epithelial) cells|
|Autophagy||The breakdown and recycling or elimination of cells|
|BAL||Bronchoalveolar lavage (fluid) – also known as BALF|
|CARD||Caspase activation and recruitment domain – a caspase is a protease enzyme that plays an essential role in programmed cell death and inflammation.|
|CD4+ T-cells||CD4+ T-cells – one of the 4 types of T-cells (lymphocyte WBCs that protect the body from pathogens and cancer cells). CD4+ cells are essential in the formation of protective memory CD8+ T-cells, which are activated following infection or immunization to support memory CD8+ T-cell development (Laidlaw, 2016).|
|CD8+ T-cells||CD8+ T-cells – one of the 4 types of T-cells, also known as tissue-resident memory cells. These memory CD8+ T-cells adapt to the local tissue microenvironment and interact with other immune cells during their development to maintain, as well as confer, immune protection (Rosato, 2017).|
|CD14||CD14 – a lipopolysaccharide-binding protein which functions as an endotoxin receptor. This CSF is anchored to and expressed at the cell surface (mainly in monocytes, macrophages and neutrophils). It is also a co-receptor and amplifies TLR-mediated pro-inflammatory and immunomodulatory responses (Raby, 2016).|
|CD69||CD69 – a membrane-bound, C-Type II lectin protein receptor encoded by the CD69 gene. This CSF regulates the differentiation of regulatory T-cells (Treg), formerly known as suppressor T-cells, as well as the secretion of IFN-γ, IL-17 and IL-22 (Cibrian, 2017).|
|cDCs||Conventional dendritic cells – innate immune cells that reside in tissues which, following tissue infection or injury become activated and migrate to draining lymph nodes to promote adaptive immune responses (https://rdcu.be/b3j8N, 2020).|
|CSFs||Cell signaling factors – the molecules that are responsible for transmitting information between the cells of the body, which include hormones, cytokines, chemokines, adipokines, growth factors and neurotrophic factors.|
|DAD||Diffuse alveolar damage|
|DLN||Draining lymph node|
|ENaC||Epithelial sodium channel|
|H_N_||Hemagglutinin ___ Neuraminidase ___ : there are 16 different hemagglutinins (HA) and 9 different neuraminidases (NA), and re-assortment of these two antigens determines the influenza A virus subtype (Hale, 2010).|
|H1N1||Highly pathogenic avian (swine flu) influenza strain: 1918 and 2009 (pandemic strains)|
|H5N1||Highly pathogenic avian (bird flu) influenza strain|
|H7N9||Highly pathogenic avian (bird) influenza strain|
|HPAI||Highly pathogenic avian (bird) influenza|
|IAV||Influenza A Virus: e.g. H1N1, H5N1, 1918 Spanish flu|
|ILD||Interstitial lung disease – an umbrella term for a large group of disorders that cause scarring (fibrosis) of the lungs, which then causes stiffness, making it difficult to breathe. Characterized by a dry, hacking cough. Examples are: scleroderma, pulmonary fibrosis, hypersensitivity pneumonitis and sarcoidosis (www.WebMD.com>lung>interstitial-lung-disease, 2019).|
|IPF||Idiopathic pulmonary fibrosis – the most common type of ILD. It is most often caused by the Mycoplasma pneumoniae, characterized by inflammation of the air sacs or the web of tissue surrounding the air sacs (interstitium), causing alveolar epithelial cell injury/cell activation, expansion of the fibroblast/myofibroblast population and exaggerated accumulation of extracellular matrix (ECM) components, which ultimately results in the destruction of the lung parenchyma (Pardo, 2012).|
|ISGs||Interferon-stimulated genes – genes which direct antiviral and immunomodulatory actions that can limit infection (Takaoka, 2006).|
|MAIT||Mucosal-associated invariant T-cells|
|MAVS||Mitochondrial antiviral signaling protein|
|MDA5||Melanoma differentiation-associated gene 5|
|MERS||Middle East respiratory syndrome – caused by one of the viruses in the CoV family|
|MMP||Matrix metalloprotease – in humans, a diverse group of 23 signaling proteins|
|MODS||Multiple organ dysfunction syndrome – occurs when there is excessive inflammatory cytokine response (cytokine storm) that can result in tissue damage and apoptosis.|
|NF-KB||Nuclear factor kappa B – a protein complex that controls the transcription of DNA, cytokine production and cell survival/apoptosis|
|pDCs||Plasmacytoid dendritic cells – cells which play a critical role in regulating pulmonary function by suppressing inflammation (Kang, 2017).|
|RAS||Renin-angiotensin system – a hormone system that regulates blood pressure, as well as fluid and electrolyte balance and systemic vascular resistance.|
|RIG-I||Retinoic acid-inducible gene I|
|RSV||Respiratory syncytial virus – a member of the family Paramyxoviridae, which preferentially infects lung epithelial cells (Monick, 2005)|
|SARS||Severe acute respiratory syndrome – caused by one of the viruses in the CoV family|
|SIRS||Systemic inflammatory response syndrome – caused by an overexpression of inflammatory CSFs which are expressed on numerous cells in tissues and organs throughout the body.|
|TRAIL||TNF-related apoptosis-inducing ligand – may play a distinct role in pathogenesis and pathogen elimination (Gyukovska, 2016)|
|Zoonotic||Of wild or domestic animal origin|
Cell Signaling Factors
CSFs play a significant role in determining molecular pathways which influence cell functioning, and they have differing functions. Some initiate signaling pathways, some are involved in pathway progression and others are expressed as a result of the pathway’s actions. Some CSFs are pro-inflammatory, and others are anti-inflammatory. Some CSFs can also be both, depending on whether they are over- or under-expressed. With symptom progression during a CoV infection, the expression and ratios of these signaling factors vary. Thus, it is necessary for the formulas to vary, depending upon which CSFs from the following list are used. The specific CSFs used in each formula I make, as well as the specific potencies used in each formula, are proprietary.
Research has demonstrated that the following CSFs are involved in acute viral respiratory issues. They may be either (or both) over- and under-expressed, and even exert pro- and anti-inflammatory actions. It is beyond the scope of this paper to present a comprehensive explanation detailing each of their interactions; instead, I will present some of their most relevant functions. Please refer to the References section for a more detailed presentation of the research to explain each of these CSFs many functions.
|ACE2||ACE2 is a homolog of ACE and cleaves a single amino acid from Angiotensin II. ACE2 appears to play a protective role in ARDS, as ACE2 is a receptor for the SARS-CoV (Kaparianos, 2011).|
|ACTH||Adrenocorticotrophic hormone – an important component of the hypothalamic-pituitary-adrenal axis is secreted by the anterior pituitary gland. It is often produced by biological stress, though can be inhibited by excessive infection and the presence of a high concentration of persistent organic pollutants and mycotoxins (Gray, 2015 unpub).This inhibition results in extreme sensitivity to bacterial infection and endotoxic shock due to its suppression of pro-inflammatory mediators (Bucala, 1996).|
|ATG5||Autophagy-related 5 gene – Autophagy and apoptosis are two major and interconnected host cell responses to viral infection, including Influenza A Virus (IAV). Inhibition of autophagy induction blocks both virus replication and apoptosis pathways. IAV can inhibit autophagic formation via interaction with the autophagy-related genes (ATGs), such as ATG5 and other cell signaling pathways (Zhang, 2014).|
|CCL2||Chemokine ligand 2 (also known as MCP-1) – elevated levels are associated with a hyper-inflammatory response.|
|CTGF||Connective tissue growth factor – located on the TGFβ1-CTGF axis, overexpression of this CSF contributes to fibrogenesis (Gralinski, 2013).|
|E2||Estrogen 2 – one of the three estrogen reproductive hormones, predominantly found in females. In higher doses, E2 suppresses inflammatory cytokines and chemokines (including TNF-α and CCL2) and is also mediated, in part, by the inhibition of NF-KB transcriptional activity (Klein, 2012).|
|EGF||Epidermal growth factor – the elevated host response of this CSF’s receptor signaling can lead to pulmonary fibrosis. After the SARS-CoV outbreak in 2003, many older survivors developed residual pulmonary fibrosis (Venkataraman, 2017).|
|FGF-2||Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) – a growth factor and signaling protein encoded by the FGF2 gene that is required for lung epithelial recovery. FGF-2 promotes myofibroblast differentiation and proliferation, in cooperation with the profibrotic growth factor TGF-β1 (Guzy, 2015). Care must be taken, however, not to create a signaling imbalance, which could lead to pulmonary fibrosis.|
|GAL-1||Galectin-1 – a ubiquitously expressed lectin (carbohydrate-binding proteins) which can reduce influenza viral loads and decrease inflammation and apoptosis through binding to the influenza envelope of glycoproteins (Yang, 2011).|
|G-CSF||Granulocyte-colony stimulating factor – a glycoprotein that stimulates the bone marrow to produce granulocytes (WBCs that contain secretory granules in their cytoplasm, i.e. a neutrophil, basophil, or eosinophil) and stem cells and release them into the bloodstream. In the H1N1 pandemic, excess production of G-CSF contributed to severe immunopathology, including excessive recruitment of neutrophils and mononuclear cells in the lungs (To, 2016).|
|GM-CSF||Granulocyte-macrophage colony-stimulating factor – a glycoprotein that confers viral resistance by enhancing innate immune mechanisms that depend on alveolar macrophages (Huang, 2011).|
|HGF||Hepatocyte growth factor – a CSF that has multiple biological effects on stem cells, epithelial proliferation and wound healing, including the ability to ameliorate the enlargement of airspaces and alveolar wall destruction (Hegab, 2008). HGF also inhibits the production of MCP-1/CCL2 in response to TNF-α.|
|HIF-1α||Hypoxia inducible factor 1-alpha – a CSF that plays an important role in the evolution and propagation of the inflammatory process. Humans infected with H1N1 influenza develop large areas virtually devoid of alveolar epithelial cells, requiring both expansion and migration of surviving AEC2s and more undifferentiated progenitors to restore alveolar epithelial barriers. HIF-1α inhibition can improve lung function by re-directing airway progenitor responses toward rapid AEC2 expansion and migration (Xi, 2018).|
|HSP-70||Heat shock protein-70 – one of the HSPs, a family of proteins that are produced by cells in response to stressful conditions. HSP-70 may contribute to the avoidance of excessive inflammation (Takashima, 2018).|
|INF-α||Interferon alpha – a member of the Type I Interferons. IFN-α treatment restricts IAV replication but exacerbates disease, thus increasing pulmonary proinflammatory cytokine secretion by pDCs and cDCs, innate cell recruitment and epithelial cell death, unlike IFN-λ treatment (Davidson, 2016). IFN-α is essential for curbing viral propagation and restricting viral pathogenesis (Teijaro, 2016; Sheehan, 2015).|
|INF-β||Interferon beta – also a member of the Type I Interferons. This CSF can be expressed within the first 2-4 hours of post-infection pathogen recognition. Alphavirus-infected cells induce a viral-protective response and become unable to response to IFN-β treatment. Very low sub-protective doses of IFN-β, which do not induce the antiviral response in uninfected cells, have a very strong stimulatory effect on the cell’s ability to express Type I IFNs and activate interferon-stimulated genes during subsequent infection (Frolov, 2012).|
|IFN-γ||Interferon gamma – the only one in the Type II Interferon family. IFN-γ is mainly produced by immune cells (activated T-cells, natural killer cells and macrophages) and shows a response against viruses, bacteria and pathogens (Stanifer, 2019). The natural killer (NK) cells that appear in pulmonary lymphocytes after influenza virus infection produce IFN-γ and limit viral spread by virus-infected cell lysis (Tamura, 2004).|
|IFN-λ1||Interferon lambda 1 (also known as IL-29) – this CSF effectively limits the spread of respiratory viruses in a contact transmission setting, in part due to its inhibition of viral replication in the upper airways (Klinkhammer, 2018). IFN-λ1 signaling is necessary for the negative regulation of IL-10 and its immunoregulatory network, which links with aberrant CD8+ T cell responses during IAV infections (Hemann, 2019). IFN-λ1 also lowers the frequency of AEC apoptosis, as compared to IFN-α (Davidson, 2016).|
|IFN-λ2||Interferon lambda-2 (also known as IL-28A) – like the other IFN-lambdas, this CSF is produced by AECs and shares its mucosal antiviral immune response with IFNλ1 and IFNλ3 (Ueki, 2013). When AECs are virally infected, IL-8 is produced and IFN-λ production is inhibited.|
|IFN-λ3||Interferon lambda-3 (also known as IL-28B) – this CSF shares similar antiviral functions with IFN-λ1 and IFN-λ2.|
|IFN-ω||Interferon omega – a member of the Type I Interferon group (which includes IFNα and INFβ) that possesses similar Type I Interferon antiviral properties.|
|IL-1β||Interleukin 1-beta – elevates inflammation level.|
|IL-2||Interleukin-2 – enhances the production of regulatory T (Treg) cells.|
|IL-4||Interleukin-4 – an anti-inflammatory signaling protein that drives Th2 polarization, resulting in the inhibition of IL-12 and IFNγ-driven Th1 differentiation (Tanaka, 2008). IL-4 is crucial to help balance pro-inflammatory over-expression.|
|IL-6||Interleukin-6 – elevates inflammation level and is significantly over-produced in individuals with SARS (Chien, 2006). In the H1N1 pandemic, excess production of IL-6 contributed in the same way that G-CSF did – see details in G-CSF description, above (To, 2016).|
|IL-7||Interleukin-7 – down-regulates SOCS-3 and promotes production of cytoprotective IL-22, which attenuates (reduces the effects of) liver pathology (Pellegrini, 2011).|
|IL-8||Interleukin-8 – was over-expressed in the H1N1 pandemic. Excess production of IL-8 contributed in the same way that G-CSF and IL-6 did – see details in G-CSF description, above (To, 2016).|
|IL-10||Interleukin-10 – a Th2 T-cell promoting protein, which is under-produced in patients with SARS (Chien, 2006), and can result in excessive inflammation. In the H1N1 pandemic, excess production of IL-10 contributed in the same way that G-CSF, IL-6 and 8 did – see details in G-CSF description, above (To, 2016).|
|IL-12||Interleukin-12 – an inflammatory protein and an anti-viral cytokine that is under- expressed with SARS. It is important for the development of Th-1 cells, which have potent antiviral activities (Trinchieri, 2003).|
|IL-13||Interleukin-13 – a Th2 anti-inflammatory cytokine that induces macrophage activation (Mantovani, 2013).|
|IL-15||Interleukin-15 – controls release of the proinflammatory IL-18 from human monocytes, which induces the antiviral protein IFN-γ (Sattler, 2015).|
|IL-17||Interleukin 17 – this CSF’s receptor is activated by IL-17A and IL-17F. Signaling may be detrimental in the response to an influenza virus challenge (Crowe, 2013).|
|IL-18||Interleukin-18 – a potent pro-inflammatory cytokine that is induced by IL-15 which, in turn, induces MAIT (Loh, 2016).|
|IL-22||Interleukin-22 – has been shown to act in a synergistic manner with Type III IFNs, leading to an increase in STAT1 (the primary transcription factor activated by interferons) activation, which then leads to an increase in the Type III IFN-dependent expression of interferon-stimulated genes (ISGs) (Stanifer, 2019).|
|IL-25||nterleukin-25 – this CSF’s receptor is highly expressed by CD14+ cells in human blood and, in response to IL-25, can down-regulate the expression of inflammatory cytokines induced by TLR ligands, including TNF-α and IFN-γ (Caruso, 2009).|
|IL-27||Interleukin-27 – exhibits broad anti-inflammatory activity via suppression of Th1/Th2/Th17 effector CD4+ T cells and the stimulation of IL-10. It also antagonizes IL-2, and its upregulation during inflammation may limit Treg cells at sites of infection, which shows that it may be necessary for optimal/balanced regulatory functions under inflammatory conditions (de Aquino, 2014).|
|IP-10||Interferon-gamma-inducible protein 10 (also known as CXCL10) – a chemokine produced by T-cells, monocytes, endothelial cells and keratinocytes after stimulation with IFN-γ, whose levels are significantly elevated during SARS infection (Chien, 2006). In the H1N1 pandemic, excess production of IP-10 contributed in the same way that G-CSF, IL-6, IL-8 and IL-10 did – see details in G-CSF description, above (To, 2010).|
|LEP||Leptin – a hormone made predominantly by fat cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger which, in turn, diminishes fat storage in adipocytes. LEP has been found to delay the cleavage of Bid and the migration of Bax in the mitochondrial release of Cytochrome c in the pro-apoptotic cascade. In addition, LEP also delays the mitochondria-derived activator of caspase, as well as the activator of both caspase-8 and caspase-3, thus delaying cell death activation. Leptin also activates both the PI3K and MAPK signaling pathways, resulting in the inhibition of the mitochondrial death pathway. These functions make leptin a critical cytokine in the survival of neutrophils by blocking apoptosis, similar to G-CSF (Bruno, 2005). It is the infection itself, as well as its replication within cells, the progression to cell death and the subsequent release of the cell’s contents that must happen before the virus can be released from the body. Thus, delaying cell death is one way in which the body is able to reduce viral replication and viral load.|
|MCP-1||Monocyte chemo-attractant protein-1 (also known as CCL2) – contributes to protection against influenza. However, if this CSF is in excess, it can be inflammatory, as seen in the H1N1 pandemic, when excess production of MCP-1 contributed in the same way that G-CSF, IL- 6,8,10 and IP-10 did – see details in G-CSF description, above (To, 2016). This dichotomous effect is similar to TNF-α.|
|MDA5||Melanoma differentiation-associated gene-5 – a pattern recognition receptor protein that recognizes cytoplasmic viral double-stranded RNA and initiates rapid innate antiviral responses (Takashima, 2018). MDA5 also recognizes measles virus and picornavirus which includes poliovirus and encephalomyocarditis virus) (Gitlin, 2006).|
|MIF||Macrophage migration inhibitory factor – a pro-inflammatory cytokine that acts within the cytokine cascade in concert with glucocorticoids to control the “set point” of the immune and inflammatory response. As an important regulator of innate immunity, MIF can promote the following pro-inflammatory protein expressions: TNF-α, IL-1β, IL-2, IL-6, IL-8 and IFN-γ (Baugh, 2003). In the case of ARDS, the pro-inflammatory nature of MIF may counter-regulate the anti-inflammatory effects of glucocorticoids on cytokines expression from alveolar macrophages. This increased MIF expression correlates with the development of ARDS in septic patients (Beishuizen, 2001). The role MIF plays in ARDS may be due to its ability to upregulate the neutrophil chemo-attractant MIP-2 (Makita, 1998).|
|Perforin||Perforin – one of the primary T-cell-mediated antiviral effectors, along with IFN-γ (de Aquino, 2014).|
|S1P||Sphingosine 1 phosphate – a protein that modulates IFN-α signaling through CD69 (Teijaro, 2016; Shiow, 2006).|
|SOCS-3||Suppressor of cytokine signaling-3 – a feedback inhibitor of the JAK/STAT3 pathway (a chain of interactions between proteins in a cell). The STAT3 pathway triggers a variety of gene responses, depending on stimulation by proteins such as IL-6, IL-10 and other growth factors, resulting in pro- and anti-inflammatory responses (Gao, 2018). The STAT3/SOCS3 expression level and responses can activate or inhibit (respectively) IL-27, LEP, IL-10, G-CSF, IL-6 and others in the IL-6 family of signaling proteins (Gao, 2018).|
|TEST||Testosterone – a predominantly male reproductive hormone. TEST declines with age as well as with increased toxic load (Gray, 2015 unpub), and may contribute to increased morbidity in males. In an experiment, a murine animal model inoculated with Influenza A Virus showed greater morbidity, clinical disease and pulmonary inflammation, as well as reduced antibody responses, in older males than in younger males (vom Steeg, 2016).|
|TGF-β1||Transforming Growth Factor-beta 1 – an anti-inflammatory CSF that promotes CTGF and inhibits the expression of IFN-γ.|
|TLR3, 7/8, 9||Toll-like receptors 3, 7/8, and 9 – CSF’s that recognize viral nucleic acids. Their sensors scan the extracellular and endosomal (cytoplasmic) spaces looking for RNA and DNA viral genomes that have been lysed from virus particles outside the cell. When they detect them, they then initiate a signaling sequence leading to the secretion of interferons and other pro-inflammatory molecules (Garcia-Sastre, 2017). These TLR ligands induce Type III interferons (Odendall, 2015), which viruses are able to suppress.|
|TLR-4||Toll-like receptor 4 – a TLR ligand which has sensors that recognize molecular patterns of viruses, bacteria and fungi that initiate innate immune responses to invading pathogens. TLR-4 is involved in promoting viral recognition (Totura, 2015).|
|TSLP||Thymic stromal lymphopoietin – a cytokine that activates immune cells after being activated by IFN-λ (Ye, 2019).|
|TNF-α||Tumor necrosis factor alpha – a cell signaling protein (cytokine) involved in systemic inflammation that makes up part of the acute phase reaction. TNF-α elevates inflammation and has stronger anti-viral activity against the influenza virus than IFN-α/β or IFN-γ do (Hernandez-Vargas, 2014).|
|VEGF||Vascular endothelial growth factor – induced by HIF-1α and promotes AT2 cell proliferation after lung injury (McClendon, 2017).|
After a thorough analysis of the information gleaned from my references, the three formulas previously outlined and discussed were conceptualized and then derived in the manner previously described. Only time will tell if I accomplished my task well enough or not. However, based upon my research efforts and experiences of the past 25 years in determining which CSF’s seem to play specific roles in specific “disease” states (or imbalanced cell signaling states), and at which potencies they must be used to reverse that imbalance, I feel quite confident that these three formulas will be at least as effective as my previous ones have been. Most importantly, however, I deeply believe that the people who choose to include these formulas, along with whatever other treatment protocols they may elect to use during the current CoVID-19 pandemic, have nothing to lose (especially their mortality) and – potentially – everything to gain, including the possibility of having an even healthier immune system than when they were first exposed to this highly pathogenic coronavirus.
References – articles in amber are highly recommended
I wish to profoundly thank the hundreds of researchers who have dedicated their lives to researching the myriad complexities of how cell signaling factors and pathways influence each other over the course of viral infection. Without their targeted focus and the insights they presented in the following papers, my analysis would not have been possible.
* Abt MC, Osborne LC, Monticelli LA, et.al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012 Jul;37(1):158-170.
* Assuncao-Miranda I, Cruz-Oliveira C, Da Poian AT. Molecular mechanisms involved in the pathogenesis of alphavirus-induced arthritis. Hindawi BioMed Res Intl. 2013;Article 973516.1-11.
* Baugh JA, Connelly SC. Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation. J of Endocrinology. 2003;179:15-23.
* Beauvais F. Benveniste’s experiments explained by a non-conventional experimenter effect. Medicines. 2018;5(28):1-18.
* Beishuizen A, Thijs LG, Haanen C, Vermes I. Macrophage migration inhibitory factor and hypothalamo-pituitary-adrenal function during critical illness. The J of Clinical Endo and Metabol. 2001;86(6):2811-2816
* Betakova T, Kostrabova A, Lachova V, Turianova L. Cytokines induced during influenza virus infection. Curr Pharm Des. 2017;23(18):2616-2622.
* Bhattacharya J, Westphalen K. Macrophage-epithelial interactions in pulmonary alveoli. Semin Immunopathol. 2016 Jul;38(4):461-469.
* Bozza FA, Salluh JI, Japiassu AM, et.al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Critical Care. 2007 Apr;11(2):1-8.
* Brown AJ, Won JJ, Graham RL, et.al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic delta coronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Research. 2019;169:1-10.
* Brown DM, Lee S, de la Luz Garcia-Hernandez M, Swain SL. Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J of Virology. 2012 Jun;86(12):6792-6803.
* Bruno A, Conus S, Schimd I, Simon HU. Apoptotic pathways are inhibited by leptin receptor activation in neutrophils. The J of Immunology. 2005;174:8090-8096.
* Bucala R. MIF rediscovered: cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response. The FASEB Journal. 1996 Dec;10:1607-1613.
* Bugge TH, Antalis TM, Wu QY. Type II transmembrane serine proteases. The J of Biol Chem. 2009 Aug;284(35):23177-23181.
* Carow B, Rottenberg ME. SOCS3, a major regulator of infection and inflammation. Frontiers in Immunology. 2014 Feb;5: Article 58.1-13.
* Caruso R, Stolfi C, Sarra M, et.al. Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase-dependent induction of Socs-3. Blood. 2009 Apr;113(15):3512-3519.
* Cervantes-Barragan L, Zust R, Weber F, et.al. Control of coronavirus infection through plasmacytoid dendritic-cell-derived type I interferon. Blood. 2007 Feb;109(3):1131-1137.
* Chaaitanya IL, Muruganandam N, Sundaram SG, et.al. Role of proinflammatory cytokines and chemokines in chronic arthropathy in CHIKV infections. Viral Immunol. 2011 Aug;24(4):265-271.
* Channappanayar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017 Jul;39(5):529-539.
* Chien JY, Hsueh PR, Cheng WC, et.al. Temporal changes in the cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology. 2006 Nov;11(6):715-722.
* Chirathaworn C, Poovorawan Y, Lertmahaarit S, Wuttirattanakowit N. Cytokine levels in patients with chikungunya virus infection. Asian Pac J Trop Med. 2013 Aug;6(8):631-634.
* Chow A, Her ZS, Ong EKS, et.al. Persistent arthralgia induced by chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. The J of Infectious Diseases. 2011 Jan;203:149-157.
* Ciancanelli MJ, Abel L, Zhang SY, Casanova JL. Host genetics of severe influenza: from mouse Mx1 to human IRF-7. Curr Opin Immunol. 2016 Feb;38:109-120.
* Cibrian D, Sanchez-Madrid F. CD69: from activation market to metabolic gatekeeper. Eur J Immunol. 2017 Jun;47(6):946-953.
* Cortjens B, de Boer OJ, de Jong R, et.al. Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease. J Pathol. 2016 Feb;238(3):401-411.
* Crane MJ, Lee KM, Fitzgerald ES, Jamiesson AM. Surviving deadly lung infections: innate host tolerance mechanisms in the pulmonary system. Frontiers in Immunology. 2018 Jun;9(1421):1-18.
* Croker BA, Kiu H, Pellegrini M, et.al. IL-6 promotes acute and chronic inflammatory disease in the absence of SOCS3. Immunol Cell Biol. 2012 Jan; 90(1):124-129.
* Crowe CR, Chen K, Pociask DA, et.al. Critical role of IL-17RA in immunopathology of influenza infection. J Immunol. 2009 Oct;183(8):5301-5310.
* Davidson S, Maini MK, Wack A. Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J of Interferon & Cytokine Research. 2015;35(4):252-264.
* Davidson S, McCabe TM, Crotta S, et.al. IFN-? is a potent anti-influenza therapeutic without the inflammatory side effects of IFN-a treatment. EMBO Molecular Medicine. 2016;8(9):1099-1112.
* de Aquino MTP, Kapil P, Hinton DR, et.al. IL-27 limits central nervous system viral clearance by promoting IL-10 and enhances demyelination. The J of Immunology. 2014;193:285-294.
* de Paus RA, van Wengen A, Schimdt I, et.al. Inhibition of the type I immune responses of human monocytes by IFN-a and IFN-ß. Cytokine. 2013 Feb;61(2):645-655.
* de Vrese M, Schrezenmeir J. Probiotics, Prebiotics, and Synbiotics Adv Biochem Eng Biotechnol, 2008;111:1-66.
* Donn RP, Ray DW. Macrophage migration inhibitory factor: molecular, cellular and genetic aspect of a key neuroendocrine molecule. J of Endocrinology. 2004;182:1-9.
* Dumoutier L, Tounsi A, Michiels T, et.al. Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-?1. The J of Biological Chemistry. 2004 Jul;279(31):32269-32274.
* Dupuis-Maguiraga L, Noret M, Brun S, et.al. Chikungunya disease: infection-associated markers from the acute to the chronic phase of arbovirus-induced arthralgia. PLOS Neglected Tropical Diseases. 2012 Mar;6(3):Article e1446.1-10.
* Fehr AR, Perlman S. Coronaviruses: an overview of the replication and pathogenesis. Methods Mol Biol 2015;1282:1-23.
* Frolov I, Akrymuk M, Akhrymuk I, et.al. Early events in alphavirus replication determine the outcome of infection. J Virology. 2012 Feb;86(9):5055-5066.
* Gack MU, Albrecht RA, Urano T, et.al. Influence A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by RIG-I. Cell Host Microb. 2009 May;5(5):439-449.
* Galani IE, Triantafyllia V, Eleminiadou EE, et.al. Interferon-? mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness. Cell Press. Immunity. 2017;46:875-890.
* Gao Y, Zhao HL, Wang P, et.al. The roles of SOCS3 and STATE3 in bacterial infection and inflammatory diseases. 2018;88:312727.1-13.
* Garcia-Sastre A. Antiviral response in pandemic influenza viruses. Emerging Infectious Diseases. 2006 Jan;12(1):44-47.
* Garcia-Sastre A. Ten strategies of interferon evasion by viruses. Cell Host Microbe. 2017 Aug;22(2):176-184.
* Gassen NC, Niemeyer D, Muth D, et.al. SKP2 attenuates autophagy through Beclin1-ubiquination and its inhibition reduces MERS-coronavirus infection. Nature Communications. https://doi.org/10.1038/s41467-019-13659-4. 1-16.
* Giannopoulou M, Dai CS, Tan XY, et.al. Hepatocyte growth factor exerts its anti-inflammatory action by disrupting nuclear factor- K B signaling. The Amer J of Pathology. 2008 Jul;173(1):30-41.
* Gitlin L, Barchet W, Gilfilian S, et.al. Essential role of mda-5 in type I IRN responses to polyriboinosinic: polyribocytidylic acid and encephalomyocarditis picornavirus. PNAS. 2006 May;103(22):8459-8464.
* Goff PH, Hayashi T, He WQ, et.al. Synthetic toll-like receptor 4 (TLR4) and TLR7 ligands work additively via MyD88 to induce protective antiviral immunity in mice. J of Virology. 2017 Oct;91(19):e01050-17.1-12.
* Gralinski LE, Bankhead III A, Jeng S, et.al. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. Mbio.asm.org. 2013 Jul-Aug;4(4):e00271-13.1-12.
* Gralinski LE, Baric RS. Molecular pathology of emerging coronavirus infections. J Pathol. 2015;235: 185-195.
* Guzy RD, Stoilov, Elton TJ, et.al. Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to Bleomycin. Am J of Resp Cell and Mol Biol. 2015 Jan;52(1):116-128.
* Gyurkovska V, Ivanovska N. Distinct roles of TNF-related apoptosis-inducing ligand (TRAIL) in viral and bacterial infections: from pathogenesis to pathogen clearance. Inflamm Res. 2016 Jun;65(8):427-437.
* Hale BG. Innate immune evasion strategies of influenza viruses. Future Microbiol. 2010 Jan;5(23):1-29.
* Hegab AE, Kubo H, Yamaya M, et.al. Intranasal HGF administration ameliorates the physiologic and morphologic changes in lung emphysema. Mol Therapy. 2008;16(8):1417-1426.
* Hemann EA, Green R, Turnbull JB, et.al. Interferon-? modulates dendritic cells to facilitate T cell immunity during infection with influenza A virus. Nat Immunol. 2019 Aug;20(8):1035-1045.
* Hermant P, Michiels T. Interferon- ? in the context of viral infections; production, response and therapeutic implications. J of Innate Immunity. 2014;6:563-574.
* Hermseh T, Moltedo B, Moran TM, Lopez CB. Anti-viral instruction of bone marrow leukocytes during respiratory viral infections. Cell Host Microbe. 2010 May;7(5):343-353.
* Hernandez-Vargas EA, Wilk E, Canini L, et.al. The effects of aging on influenza virus infection dynamics. J Virology. 2014 Apr;88(8):4123-4131.
* Herold S, Steinmueller M, von Wulffen W, et.al. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. JEM. J Exp Medicine. 2008;205(13):3065-3077.
* Hiscott J. Triggering the innate antiviral response through IRF-3 activation. The J of Biol Chem. 2007 May;282(21):15325-15329.
* Hogg AE, Bowick GC, Herzog NK, et.al. Induction of granulysin in CD8 + T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1. JLB. 2009 Jul;Article 2429222.1-13.
* Hogner K, Wolff T, Pleschhka S, et.al. Macrophage-expressed IFN-B contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. PLOS Pathogens. 2013 Feb;9(2):e42246488.1-16.
* Hong TH, Chang CH, Lin CF, et.al. Biomarkers of early sepsis may be correlated with outcome. J of Translational Medicine. 2014;12(146):1-8.
* Honke N, Shaabani N, Cadeddu G, et.al. Enforced viral replication activates adaptive immunity and is essential for the control of a cyptopathic virus. Nat Immunol. 2011 Nov;13(1):51-57.
* Honke N, Shaabani N, Merches K, et.al. Immunoactivation induced by chronic viral infection inhibits viral replication and drives immunosuppression through sustained IFN-1 responses. Eur J of Immunology. 2016;46:372-380.
* Huang FF, Barnes PF, Feng Y, et.al. CM-CSF in the lung protects against lethal influenza infection. Am J Respir Crit Care Med. 2011;184:259-268.
* Imai Y, Kuba K, Neely GG, et.al. Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008 Apr;133:235-249.
* Ito Y, Correll K, Zemans R, et.al. Influenza induced IL-8and GM-CSF secretion by human alveolar epithelial cells through HGF/c-Met and TGF-a/EGFR signaling. Am J Physiol Lung Cell Mol Physiol. 2015 Jun;308(11):L1178-1188.
* Iwata-Yoshikawa N, Okamura T, Shimizu Y, et.al. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. Pathogenesis and Immunity. J of Virology. 2019 Mar;93(6):e01815-18.1-15.
* Jackson WT. Viruses and the autophagy pathway. Virology. 2015 May;479-480:450-456.
* Jewell NA, Cline T, Mertz SE, et.al. Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J of Virology. 2010 Nov;84(21):11515-11522.
* Jordan WJ, Eskdale J, Srinivas S, et.al. Human interferon lambda-1 (IFN-lambda1/IL-29) modulates the Th1/Th2 response. Genes Immun. 2007 Apr;8(3):254-261. PMID 17361203.
* Kalinowski A, Uei I, Gundula MO, et.al. EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production. Am J Physiol Lung Cell Mol Physiol. 2014 Jul;307(2):L186-L196.
* Kam YW, Simarmata D, Chow A, et.al. Early appearance of neutralizing immunoglobulin G3 antibodies is associated with chikungunya virus clearance and long-term clinical protection. JID. 2012 Apr;205:1147-1154.
* Kang M, Choi DH, Choi YW, et.al. Intranasal introduction of Fc-fused interleukin-7 provides long-lasting prophylaxis against lethal influenza virus infection. J of Virology. 2016 Mar;90(5):2273-2284.
* Kang MC, Park HW, Choi DH, et.al. Plasmacytoid dendritic cells contribute to the protective immunity induced by intranasal treatment with Fc-fused interleukin-7 against lethal influenza virus infection. Immune Network. 2017 Oct;17(5):343-351.
* Kaparianos A, Argyropoulou E. Local renin-angiotensin II systems, angiotensin-converting enzyme and its homologue ACE2: their potential role in the pathogenesis of chronic obstructive pulmonary disease, pulmonary hypertension and acute respiratory distress syndrome. Curr Med Chem. 2011;18(23):3506-3515.
* Kelvin AA, Banner D, Silvi G, et.al. Inflammatory cytokine expression is associated with chikungunya virus resolution and symptom severity. PLOS One. 2011 Aug;5(8):e1279.1-12.
* Kido H. Influenza virus pathogenicity regulated by host cellular proteases, cytokines and metabolites, and its therapeutic options. Proc Jpn Acad Scr. 2015.91(8):351-368.
* Kim S, Kim MJ, Kim CH, et.al. The superiority of IFN-? as a therapeutic candidate to control acute influenza viral lung infection. Am J Respir Cell Mol Biol. 2017 Feb;56(2):202-212.
* Klein SL, Hodgson A, Robinson DP. Mechanisms of sex disparities in influenza pathogenesis. J Leukoc Biol. 2012 Jul;92(1):67-73.
* Klinkhammer J, Schnepf D, Ye L, et.al. IFN-? prevents influenza virus spread from the upper airways to the lungs and limits virus transmission. eLIFESciences.org. 2018 Apr; Article#33354.1-18.
* Kuba K, Imai Y, Renninger JM. Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol. 2006 Jun;6(3):271-276.
* Laidlaw BJ, Craft J, Kaech SM. The multifaceted role of CD4+ T cells in the regulation of CD8+ T cell memory maturation. Nat Rev Immunol. 2016 Feb;16(2):102-111.
* Lam QLK, Lu LW. Role of leptin in immunity. Cellular & Molecular Immunology. 2007 Feb;4(1):1-13.
* LaPorte M, Naesens L. Airway proteases: an emerging drug target for influenza and other respiratory virus infections. Curr Opin in Virology. 2017;24:16-24.
* Lappi-Blanco E, Soini Y, Kinnula V, Paakko P. VEGF and bFGF are highly expressed in intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia. J Pathol. 2002 Feb;196(2):220-227.
* Larson DF, Horak K. Macrophage migration inhibitory factor: controller of systemic inflammation. Biomed Central Critical Care. 2006 Apr;10(138):1-3.
* Lau SK, Lau CC, Chan KH, et.al. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. J Gen Virol. 2013 Dec;94(Pt12):2679-2690.
* Lau YL, Peiris JSM, Law HKW. Role of dendritic cells in SARS coronavirus infection. Hong Kong Med J. 2012;18(Suppl3):S28-S30.
* Li M, Liu X, Zhou Y, Su SB. Interferon-lambdas: the modulators of antivirus, antitumor, and immune responses. J Leukoc Biol. 2009 Jul;86(1):23-32.
* Liu Q, Ma J, Strayer DR, et.al. Emergence of a novel drug resistant H7N9 influenza virus: evidence based clinical potential of a natural IFN-a for infection control and treatment. Expert Rev Anti Infect Ther. 2014 Feb;12(2):165-169.
* Loh LY, Wang ZF, Sant S, et.al. Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation. PNAS. 2016 Sep;113(36):10133-10138.
* Lohanchanakul J, Phuklia W, Thannagith M, et.al. High concentrations of circulating interleukin-6 and monocyte chemotactic protein-1 with low concentrations of interleukinb-8 were associated with severe chikungunya fever during the 2009-2010 outbreak in Thailand. Microbiol Immunol. 2012 Feb;56(2():134-138.
* Loo YM, Fornek J, Crochet N, et.al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J of Virology. 2008 Jan;82(1):335-345.
* Luan YY, Dong N, Xie M, et.al. The significance and regulatory mechanisms of innate immune cells in the development of sepsis. J of Interferon and Cytokine Research. 2014;34(1):2-15.
* Lum FM, Teo TH, Lee WWL, et.al. An essential role of antibodies in the control of chikungunya virus infection. The J of Immunology. 2013;190:6295-6302.
* Lundstrom W, Fewkes N, Mackall CL. IL-7 in human health and disease. Scemin Immunol. Jun 2012;24(3):218-224.
* Makita H, Nishimura M, Miyamoto K, et.al. Effect of anti-macrophage migration inhibitory factor antibody on lipopolysaccharide-induced pulmonary neutrophil accumulation. Am J Respir Crit Care Med. 1998 Aug;158(2):573-579.
* Mantovani A, Biswas SK, Galdiero MR, et.al. Macrophage plasticity and polarization in tissue repair and remodeling. J Pathol. 2013;229:176-185.
* Matthaei M, Budt M, Wolff T. Highly pathogenic H5N1 influenza A virus strains provoke heterogeneous IFN-a/ß responses that distinctively affect viral propagation in human cells. PLOS One. 2013 Feb;1-12.
* McClendon J, Jansing NL, Redente EF, et.al. Hypoxia-inducible factor 1a signaling promotes repair of the alveolar epithelium after acute lung injury. The Am J of Pathology. 2017 Aug;187(8):1772-1786.
* Melville MW, Hansen WJ, Freeman BC, et.al. The molecular chaperone hsp40 regulates the activity of P58IPK, the cellular inhibitor of PKR. Proc Natl Acad Sci USA 1997 Jan;94:97-102.
* Melville MW, Tan SL, Wambach M, et.al. The cellular inhibitor of the PKR protein kinase, p58 IPK , is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity. The J of Biol Chem. 1999 Feb;274(6):3797-3803.
* Menachery VD, Yount Jr BL, Josset L, et.al. Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2′-O-methyltransferase activity. J of Virology. 2014 Apr;88(8):4251-4264.
* Menachery VD, Eisfeld AJ, Schafer A, et.al. Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses. Mbio.asm.org. 2014 May;5(3):e01174-14.1-11.
* Message SD, Laza-Stanca V, Mallia P, et.al. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. PNAS. 2008 Sep;105(36):13562-13567.
* Moltedo B, Lopez CB, Pazos M, et.al. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity. The J of Immunology. 2009 Aug;183:3569-3573.
* Monick MM, Cameron K, Staber J, et.al. Activation of the epidermal growth factor receptor by respiratory syncytial virus results in increased inflammation and delayed apoptosis. The J of Biological Chem. 2005 Jan;280(3):2147-2158.
* Monteiro JM, Harvey C, Trinchieri G. Role of interleukin-12 in primary influenza virus infection. J of Virology. 1998 Jun;72(6):4825-4831.
* Mordstein M, Kochs G, Dumoutier L, et.al. Interferon-? contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLOS Pathogens. 2008 Sep;4(9):e10000151.1-7.
* Moro K, Kabata H, Tanabe M, et.al. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat Immunol. 2016 Jan;17(1):76-86.
* Nakanaga T, Nadel JA, Ueki IF, et.al. Regulation of interleukin-8 via an airway epithelial signaling cascade. Am J Physiol Lung Cell Mol Physiol. 2007;292:L1289-L1296.
* Narasaraju T, Yang E, Samy RP, et.al. Combination therapy with hepatocyte growth factor and oseltamivir confers enhanced protection against influenza viral pneumonia. Curr Mol Med. 2014;14(5):690-702.
* Narasaraju T, Ng HH, Phoon MC, Chow VTK. MCP-1 antibody treatment enhances damage and impedes repair of the alveolar epithelium in influenza pneumonitis. Am J Respir Cell Mol Biol. 2010;42:732-743.
* Odendall C, Kagan JC. The unique regulation and functions of type III interferons in antiviral immunity. Curr Opin Virol. 2015 Jun;12:47-52.
* Otero M, Lago R, Gomez R, et.al. Towards a pro-inflammatory and immunomodulatory emerging role of leptin. Rheumatology. 2006;45:944-950.
* Padovan E, Spagnoli GC, Ferrantini M, Heberer M. IFN-a2a induces IP-10/CXCL10 and MIG/CXCL9 production in monocyte-derived dendritic cells and enhances their capacity to attract and stimulate CD8 + effector T Cells. J of Leukocyte Biol. 2002 Apr;71:669-676.
* Pan HY, Yano M, Kido H. Effects of inhibitors of toll-like receptors, protease-activated receptor-2 signalings and trypsin on influenza A virus replication and upregulation of cellular factors in cardiomyocytes. The J of Med Investigation. 2011;58:19-28.
* Pardo A, Selman Moises. Role of matrix metalloproteases in idiopathic pulmonary fibrosis. Fibrogenesis & Tissue Repair. 2012;5(suppl1):59.1-5.
* Patil DR, Hundekar SL, Arankalle VA. Expression profile of immune response genes during acute myopathy induced by chikungunya virus in a mouse model. Microbes Infect. 2012 May;14(5):457-469.
* Pauli EK, Schmoke M, Worlff T. Influenza A virus inhibits type I IFN signaling via NF- K B-dependent induction of SOCS-3 expression. PLOS Pathogens. 2008 Nov;4(11):e1000196.1-15.
* Paz S, Sun Q, Nakhaei P, et.al. Induction of IRF-3 and IRF-7 phosphorylation following activation of the RIG-I pathway. Cell Mol Biol (Noisy-le-Grand). 2006 May;52(1):17-28.
* Pellegrini M, Calzascia T, Toe JG, et.al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell. 2011 Feb;144:601-613.
* Perot BP, Boussier J, Yatim N, et.al. Autophagy diminishes the early interferon-ß response to influenza A virus resulting in differential expression of interferon-stimulated genes. Cell Death and Disease. 2018 May;9:539-554.
* Peteranderl C, Herold S. The impact of the interferon/TNF related apoptosis-inducing ligand signaling axis on disease progression in respiratory viral infection and beyond. Frontiers in Immunology. 2017 Mar;8:Artile 313.1-18.
* Peteranderl C, Morales-Nebreda L, Selvakumar B, et.al. Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. The J of Clin Investigation. 2016 Apr;125(4):1566-1580.
* Petitdemange C, Wauquier N, Rey J, et.al. Control of acute dengue virus infection by natural killer cells. Frontier in Immunology. 2014 May;5(209):1-5.
* Phanthanawiboon S, Limikittikul K, Sakai Y, et.al. Acute systemic infection with dengue virus leads to vascular leakage and death through tumor necrosis factor-a and Tie2/angiopoietin signaling in mice lacking type I and II interferon receptors. PLOS One. 2016 Feb;e0148564.1-17.
* Pitha PM. Unexpected similarities in cellular responses to bacterial and viral invasion. PNAS. 2004 Jan;101(3):695-696.
* Plumb AW, Patton DT, Seo JH, et.al. Interleukin-7 but not thymic stromal lymphopoietin, plays a key role in the T cell response to influenza A virus. PLOS One. 2012 Nov;7(11):Article e50199.1-8.
* Prestwood TR, Morar MM, Zellweger RM, et.al. Gamma interferon (IFN-?) receptor restricts systemic dengue virus replication and prevents paralysis in IFN-a/ß receptor-deficient mice. J of Virology. 2012 Dec;86(23):12561-12570.
* Price GE, Gaszewski-Mastarlarz A, Moskophidis D. The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice. J of Virology. 2000 May;74:3996-4003.
* Raby AC, Labeta MO. Therapeutic boosting of the immune response: turning to CD14 for help. Curr Pharmaceut Biotech. 2016;17:414-418.
* Randall RE, Goodbourn S. Interferons and viruses: an interplay between induction, signaling, anti-viral responses and virus countermeasures. J of General Virology. 2008;89:1-47.
* Reardon C, McKay DM. TGF-ß suppresses IFN-?-STAT1-dependent gene transcription by enhancing STAT1-PAIS1 interactions in epithelia but no monocytes/macrophages. The J of Immunology. 2007;178:4284-4295.
* Ritter C, Tomasi CD, Dal-Pizzol F, et.al. Inflammation biomarkers and delirium in critically ill patients. Critical Care. 2014;18:1-6.
* Rogo LD, Rezaei F, Marashi SM, et.al. Seasonal influenza A/H3N2 virus infection and IL-1B, IL-10, IL-17, and IL-28 polymorphisms in Iranian population. J Med Virol. 2016 Dec;88(12):2078-2084.
* Rosato PC, Beura LK, Masopust D. Tissue resident memory T cells and viral immunity. Curr Opin Virol. 2017 Feb;22:44-50.
* Savarin C, Bergmann CC. Fine tuning the cytokine storm by IFN and IL-10 following neurotropic coronavirus encephalomyelitis. Frontiers in Immunology. 2018 Dec;9:Article 3022.1-8.
* Sharma K, Tripathi S, Ranjan P. Influenza A virus nucleoprotein exploits Hsp40 to inhibit PKR activation. PLOS One. 2011 Jun;6(6):e20215.1-12.
* Sattler A, Dang-Heine C, Reinke P, Babel N. IL-15 dependent induction of IL-18 secretion as a feedback mechanism controlling human MAIT-cell effector functions. Eur J of Immunology. 2015;45:2286-2298.
* Sheehan TP, Sims AC, Lesit SR, et.al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-Cov. Nature Communications. 2020.11:222https://doi.org/10.1038/s41467-019-13940-6.
* Shiow LR, Rosen DB, Brdickova N, et.al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature. 2006 Mar;440(7083):540-544.
* Skorvanova L, Svancarova P, Svetlikova D, Betakova T. Protective efficacy of IFN-? and IFN-?s against influenza viruses in induced A549 Cells. Acta Virol. 2015 Dec;59(4):413-417.
* Sommereyns C, Paul S, Staeheli P, Michiels T. IFN-lambda (IFN-?) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLOS Pathogens. 2008;4(3):e1000017.1-12.
* Stanifer ML, Pervolaraki K, Boulant S. Differential regulation of type I and type III interferon signaling. Intl J of Mol Sciences. 2019 Mar;20:1445.1-22.
* Tailor Prafullakumar, Tamura T, Ozato K. IRF family proteins and type I interferon induction in dendritic cells. Cell Research. 2006;16:134-140.
* Takaoka A, Yanai H. Interferon signaling network in innate defense. Cell Microbiol. 2006 Jun;8(6):907-922.
* Takashima K, Oshiumi H, Matsumoto M, Seya T, DNAJB1/HSP40 suppresses melanoma differentiation-associated gene t-mitochondrial antiviral signaling protein function in conjunction with HSP70. J of Innate Immunity. 2018;10:44-55.
* Tamura SI, Kurata T. Defense mechanisms against influenza virus infection in the respiratory tract mucosa. Jpn J Infect Dis. 2004;57:236-247.
* Tan JT, Dudl E, LeRoy E, et.al. IL-7 is critical for homeostatic proliferation and survival of naïve T cells. PNAS. 2001 Jul;98(15):8732-8737.
* Tanaka K, Ichiyama K, Hashimoto M, et.al. Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-? on STAT3 and Smads. The J of Immunology. 2008;180:3746-3756.
* Teijaro JR. Type I interferons in viral control and immune regulation. Curr Opin Virol. 2016 Feb;16:31-40.
* Teijaro JR, Turner D, Pham Q, et.al. Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol. 2011 Dec;187(11):5510-5514.
Teijaro JR, Verhoeven D, Page CA, et.al. Memory CD4 T cells direct protective responses to influenza virus in the lungs through helper-independent mechanisms. J of Virology. 2010 Sep;84(18):9217-9226.
* Tisoncik JR, Korth MJ, Simmons CP, et.al. Into the eye of the cytokine storm. Microbio and Mol Biol Reviews. 2012 Mar;76(1):16-32.
* To KKW, Lau CCY, Woo PCY, et.al. Human H7N9 virus induces a more pronounced pro-inflammatory cytokine but an attenuated interferon response in human bronchial epithelial cells when compared with an epidemiologically-linked chicken H7N9 virus. Virology Journal. 2016;13:42.1-7.
* Toledo KA, Fermino ML, del Cistia Andrade C, et.al. Galectin-1 exerts inhibitory effects during DENV-1 infection. PLOS One. 2014 Nov;9(11):e112474.1-11.
* Totura AL, Whitmore A, Agnihothram S, et.al. Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. mBio.ams.org. 2015 May/Jun;6(3):300638-18.1-14.
* Trinchieri R. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003 Feb;3(2):133-146.
* Ueki IF, Gundula MO, Kalinowski A, et.al. Respiratory virus-induced EGFR activation suppresses IRF1-dependent interferon ? and antiviral defense in airway epithelium. J Exp Med. 2013;210(10):1929-1936.
* Unkel B, Hoengner K, Clauson BE, et.al. Alveolar epithelial cells orchestrate DC function in murine viral pneumonia. The J of Clin Invest. 2012 Oct;122(10):3652-3664.
* Venkataraman T, Freiman MB. The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis. Antiviral Res. 2017 Jul;143:142-150.
* Vithoulkas, G. The Science of Homeopathy. 1980.
* von Steeg LG, Vermillion MS, Hall OJ, et.al. Age and testosterone mediate influenza pathogenesis in male mice. Am J of Physiology. 2016 Dec;311(6):L1234-L1244.
* Wang RF, Zhu YX, Lin X, et.al. Influenza M2 protein regulates MAVS-mediated signaling pathway through interacting with MAVS and increasing ROS production. Autophagy. 2019;15(7):1163-1181.
* Willenbring RC, Johnson AJ. Finding a balance between protection and pathology: the dual role of perforin in human disease. Intl J of Mol Sciences. 2017 Jul;18(1608).1-18.
* Xi Y, Kim T, Brumwell AN, et.al. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol. 2017 Aug;19(8):904-914.
* Yamaya M, Shimotai Y, Hatachi Y, et.al. The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells. Pulm Pharmacol Ther. 215 Aug;33:66-74.
* Yang ML, Chen YH, Wang SW, et.al. Galectin-1 binds to influenza virus and ameliorates influenza virus pathogenesis. J of Virology. 2011 Oct;85(19):10010-10020.
* Ye L, Ohnemus A, Ong LC, et.al. Type I and Type III interferons differ in their adjuvant activities for influenza vaccines. J Virol. 2019 Nov;93(23)pii:01262-19.
* Yeganeh B, Ghavami S, Rahim MN, et.al. Autophagy activation is required for influenza virus-induced apoptosis and replication. BBA – Molecular Cell Research 1865. 2018;364-378.
* Yoshimura A, Nishinakamura H, Matsumura Y, Hanada T. Negative regulation of cytokine signaling and immune responses by SOCS proteins. Arthritis Research & Therapy. 2005 Jun;7(3):100-110.
* Yoshimura A, Suzuki M, Sakaguchi R, et.al. SOCS, inflammation and autoimmunity. Frontiers in Immunology. 2012 Mar;3(20):1-8.
* Yu CF, Peng WM, Schlee M, et.al. SOCS1 and SOCS3 target IRF7 degradation to suppress TLR7-mediated Type I IFN production of human plasmacytoid dendritic cells. The J of Immunology. 2018;200:4024-4035.
* Zens KD, Farber DL. Memory CD4 T cells in influenza. Curr Top Microbiol Immunol. 2015;386:399-421.
* Zhang R, Chi Xj, Wang S, et.al. The regulation of autophagy by influenza A virus. Biomed Res Int. 2014;498053.PMID 24779013.
* Zhang RH, Zhang HL, Li PY, et.al. Autophagy is involved in the acute lung injury induced by H9N2 influenza virus. Int Immunopharmacol. 2019 Sep;74: PMID 31288152.
* Zhao JC, Zhao JX, Van Rooijen N, Perlman S. Evasion by stealth: inefficient immune activation underlies poor T cell response and severe disease in SARS-CoV-infected mice. PLOS Pathogens. 2009 Oct;5(10):e1222636.1-17.
* Zhao MM, Wang LY, Li ST. Influenza A virus-host protein interactions control viral pathogenesis. Intl J of Mol Sciences. 2017 Aug;18:1673-1688.
* Zheng J, Perlman S. Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host. Curr Opin Virol 2018 Feb;28:43-52.
* Zhimov OP, Klenk HD, Wright PF. Aprotinin and similar protease inhibitors as drugs against influenza. Antiviral Res. 2011 Oct;92(1):27-36.
* Zhou J, Chu H, Wong BH, et.al. Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implication for pathogenesis. J Infect Dis. 2014 May;209(9):1331-1342.
* Zoller V, Funcke JB, Roos J, et.al. Trail (TNF-related apoptosis-inducing ligand) induces an inflammatory response in human adipocytes. Nature. Scientific Reports. 2017 Jul;7:2691.1-12.
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Collaborator’s Comments and Clinical Experiences with these Medicines
As a physician in private practice for over 30 years, I have been aware of isoenergetic cell signaling™ medicines for over 25 of those years, having been introduced to them by the original researcher of this approach to healing (Barbara Brewitt, PhD, MDiv) in Seattle, WA who provided me with some of her first formulas to use with my patients. After Barbara died in 2009, I thought the formulas were no longer available, so I was unable to include them as part of my overall treatment approach until the fall of 2019 when I met the author of this white paper (Paul Opheim, MIM, MA and CEO/Research Director of Leptica Research, LLC). Since then, I have been able to re-introduce this highly-effective holistic medical therapy back into my practice, which has helped my patients tremendously on their journeys to optimal health. In addition, Mr. Opheim and I have also been able to collaborate together on some of my most complicated cases that were either minimally or unresponsive to other forms of therapy that I had tried with them. One patient in particular, whom I have been treating since 2006 for myriad chronic conditions – including breast cancer – is now finally starting to respond with the use of Paul’s formulas as part of her overall treatment protocol. Another patient, who had a TBI over 20 years ago, in addition to life-long anxiety and depression since childhood, has been finding significant relief from both of these conditions since starting the CTE and Anxiety and Depression formulas. I now use these formulas in conjunction with any and all other therapeutic modalities, in an effort to help patients reach their treatment goals sooner and more cost-effectively.
Mr. Opheim and I are also currently co-conducting a small clinical trial with veterans using his PTSD formula. Some of these vets have been suffering with this condition for more than 50 years. After just a short time on this formula, many of these vets’ longstanding symptoms began to ease and, for some, even dissipate (including horrific nightmares for one vet that had been a nightly occurrence for 40 years, after only two days on this formula). Within just 6 weeks, that same vet stated he felt that 80%of his PTSD symptoms were gone, which his wife corroborated; and, after 10 weeks on this formula, he stated that he now feels 93% recovered from the initial trauma he experienced in the Marine Corps that caused him to attempt suicide 30 times before his PTSD diagnosis was finally made in 2014. It took another vet in the study 8-10 weeks to reach 80-85% relief, after more than 50 years of debilitating nightmares and at least a 30-year loss of mental clarity. For me, as a physician caregiver, this kind and degree of clinical results is rare (though “miraculous” is the word both of these men have used to describe their results). To date, overall results of this study lie all along the 0-10 continuum, and I know that the resolution of such deeply-entrenched trauma patterns in chronic conditions like PTSD takes time. However, I feel hopeful for the vets in our study in a way that I haven’t felt hopeful for patients in a long time, and it often brings me to tears when I sit in their presence and witness their progress. They truly inspire me every day.
Because I am so encouraged with the results I have seen with the veterans in our PTSD study, as soon as Mr. Opheim completed his coronavirus research, I immediately sought funds to help them be able to participate in another clinical trial using the formulas outlined in this white paper. I did so mostly because I don’t want to lose any of them to this current pandemic, and also because prevention is EXTREMELY cost-effective (~17¢ per person per day), as is treatment for mild symptoms (~$1.75 per person per day), as well as severe symptoms ($3.00 per person per day). Mr. Opheim and I both feel that our veteran participants have NOTHING TO LOSE AND EVERYTHING TO GAIN (as do we ALL) by taking these Coronavirus Relief Signaling Formulas during this eerily quiet, sometimes chaotic and often surreal experience of being asked to home-quarantine and practice social distancing at a time when we really need each other the most. I am happy to say that, as of 4-16-20, more than 90% our PTSD Study veterans (and their families) have started the Prophylactic formula, and Mr. Opheim and I are committed to making this cost-effective option available to as many people as we can – as soon as possible – especially to those who are currently on the front lines, risking their lives 24/7 to take care of all who have already fallen prey to CoVID-19.
Ann B. McCombs DO, DABHM, DNM
American Board of Holistic Medicine Co-founder and Founding Diplomate
Leptica Research – the Founder’s Story
My name is Paul Opheim. I have always had an interest in health and wellness, so I became a pre-med student in my early college years. However, I couldn’t quite reconcile the allopathic approach to medicine and its primarily pharmacological focus without also including a holistic, integrative approach, so I did not apply to medical school and instead finished a BS degree in botany.
I sensed what I was looking for was out there, but where? In the late 1970s, I went to Taiwan where I became fluent in written and spoken Mandarin and later finished a master’s degree in Chinese Literature with a minor in Japanese. After Taiwan, I also did graduate studies in China and Japan. Equally important to me was the introduction and exposure I had to the various practices of Chinese Medicine, including acupuncture, and the understanding of the body’s qi (ki or chi) energy system as used in martial arts. I also decided to get another master’s degree in International Management (Thunderbird Graduate School of Global Management).
After coming back to the United States, I had the opportunity to work for a company that unified the western disciplines of endocrine research and isopathy with the eastern concepts of energy and wellness with its development of homeopathic Insulin-like Growth Factor-1 (IGF-1) and human Growth Hormone (hGH). Our first clinical study, using a set of growth factors for HIV, proved that loss of lean body mass could be prevented. The results were published in the Townsend Newsletter. After the passing of my mentor (Barbara Brewitt PhD, MDiv) in 2009, I acquired the company (including its patents and proprietary information) and began researching the cell signaling factors and pathways involved in the neurodegenerative afflictions of PTSD, Parkinson’s and dementia.
When doctors learned I was including the cell signaling factor called leptin for its neuroprotective attributes in my formulas, they asked that I create a formula for satiety, cravings and addictive eating. I agreed and, in December 2012, I finished the formula Naturally Leptin Signaling Complex and, in January 2013, I started doing the case studies. Now I’m happy to report that, after years of use by practitioners in their weight loss and weight management programs, this formula has proven to be safe and very effective – especially for controlling cravings – as it circumvents the issue of leptin impedance (resistance) at the blood brain barrier.
I am a member of The Endocrine Society and an invited member of the Society for Neuroscience, where cutting edge discoveries and research are presented every year. My fascination and passion for understanding how the cell signaling pathways in the body govern health motivates me to continue to develop additional isopathic formulas to address cell signaling challenges (including women’s health issues, healthy aging, addictions, immune suppression, anxiety & depression, dementia and Parkinson’s. These unique, highly effective and affordable formulas are now available to physicians for their patients through www.LepticaMedical.com (access is user-name and password-restricted for physicians).
Thank you for your time and interest in hearing a little about how I got into the fascinating world of neuroendocrine research and analysis, and how it has led to bringing these exclusive isoenergetic cell signaling™ Cell FunctionActivator™ formulas into the world of medicine, health and healing.
Paul E Opheim, MIM, MA
Research Director, CEO
Leptica Research, LLC
Ann B. McCombs DO, DABHM, DNM
Ann McCombs is an osteopathic and naturopathic physician (DO, DNM) who has been practicing Holistic Family Medicine as a general practitioner and specialist in WA State since 7-31-89. She is the Co-founder, Medical Director, CEO and President of the Center for Optimal Health, practicing in Bellevue, WA (1994-present), Sierra Vista, AZ (2018-present) and Benson, AZ (2019-present). She had successful careers in both teaching and marriage and family counseling before pursuing her first love: Holistic Medicine! Dr. McCombs served as a member of the Board of Trustees of the American Holistic Medical Association for 10 years (1992-2002) and the American Board of Holistic Medicine during its first 3 years (2000-2003), of which she was also a co-founder in 1995. She served on the Board of Directors for Dr. Devi Nambudripad’s Allergy Research Foundation (1995-2005) and has served as a consultant with Carbon-based Corporation/Lab Interpretation (a company specializing in the multi-variant analysis of biochemical, metabolic and environmental tests) since 1995.
Dr. McCombs was board-certified in Pain Management (1992) and now holds Diplomate status in Integrative Pain Management (2012) and Nutritional Pain Management (2018). She was also the first certified Neural Therapy/Neural Kinesiology Practitioner in the U.S. (1995). In addition, she has acquired post-graduate certifications from the American Boards of Neural Therapy (1996), Holistic Medicine (2000), Chelation Therapy (2003), Oxidative Medicine (2004), Heavy Metal Toxicology (2005) and Drugless Practitioners (2012), as well as in T3 Therapy (2013), Stem Cell Therapy (2018) and Emotional Freedom Technique (EFT Intermediate Practitioner 1) in 2019. Reiki (all levels), Nambudripad’s Allergy Elimination Technique (N.A.E.T.), Hellinger work (Systemic Family Therapy), Hendricks work (Body-centered Psychotherapy and Brief Relationship Therapy), Tennant Biomodulator treatment and HALO Biophotonic Light Therapy are some of Dr. McCombs’ other therapeutic skills and certifications.
As an educationally based, holistic medical practitioner, Dr. McCombs is actively engaged in clinical practice, teaching and mentoring. Her unique approach, utilizing Non-Protocol Diagnosis and Treatment, puts her on the cutting edge of those physicians who assist clients to achieve optimal health and healing. She has lectured both nationally and internationally on the use of this approach in treating both chronic pain (using a medical-dental-podiatry model without drugs and surgery) and chronic illness. She is currently co-authoring two books about these principles (both of which she expects will be published in 2020), where she and her two colleagues share personal and professional experiences from their own unique journeys towards optimal health as they assist their patients/clients to do the same. In addition, Dr. McCombs has been doing pro bono work in Benson, AZ as a Holistic Medicine Consultant, Medical Service Provider and Clinical Administrator with nationally-recognized Environmental Medicine specialist and Research Toxicologist, Dr. Michael Gray (MD, MPH, CIME). Through his not-for-profit Progressive Healthcare Group, they are exploring how to collaborate and navigate through our currently very broken disease care system to bring their combined approaches together to help patients heal more quickly from environmental illness caused by hypertoxicity and regain enough of their health to function effectively once again in their lives. Dr. McCombs and Dr. Gray have also been hired to share the Medical Director position for the new Sierra Vista-based Eden Health Hospice program, which will begin as soon as it is safe to do so following the CoVID-19 pandemic.
Dr. McCombs’ professional goals are: to be a part of creating a global health care system, including the best of both traditional and non-traditional medicine, that works for everyone (patients/clients, physicians and insurance companies); to provide a healing opportunity and environment for health care providers to heal themselves; to create an effective model of clinical practice that includes the physician-dentist team which can be duplicated locally, nationally and internationally; to create and teach a Living Medicine medical curriculum with Dr. Gladys McGarey that will include Non-Protocol Medicine; and, ultimately, to assist in founding clinical training, research and education at both the graduate and undergraduate levels which will utilize and train others to use this approach skillfully and with integrity (currently embodied in Dr. Gladys’ Village for Living Medicine concept being implemented in Scottsdale, AZ sometime in 2020 and in Colonel Tim Kirk (USAF, Ret)’s Warrior Healing Center in Sierra Vista, AZ since Dec 2018). Not-for-profit status was granted December 11, 2002 for Dr. McCombs’ own educational and research interests (the Optimal Health Foundation, founded in 1998), which was active until 2012.
Dr. McCombs currently serves on the Advisory Board of the Foundation for Living Medicine (2018-present) and as the On-site/On-call Urgent Care Service Provider and Medical Director for the Warrior Healing Center (2019-present) to assist her professional goals to come to fruition. In addition, Dr. McCombs is the Research Co-director (with Paul Opheim, Research Director/CEO of Leptica Research, LLC) of the PTSD and CoVID-19 clinical studies currently being conducted in Sierra Vista at the WHC (2020-present). She is also currently in partnership with Dr. Gladys and Colonel Kirk to do whatever it takes to bring into being their individual global visions for whole-person healing, an idea whose time has more than come. (For details of their individual visions, see www.thefoundationforlivingmedicine.org and www.visionheals.org.)
|The Center for Optimal Health|
|PO Box 6662||1838 Paseo San Luis, Ste 21|
|Bellevue, WA 98008||Sierra Vista, AZ 85635|
|Ph: 206-718-4343||Fax: 520-335-1874|