Biological - SARS-CoV-2 - Medical Treatments

This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine.

Control of Contagion
A major goal of self-quarantine is the control of contagion.
Many sources of information suggest the main place of viral transmission occurs in the home.

Reduction of Self-Reinoculation
It is well-recognized that COVID-19 exists outside the human body in a bioaerosol of airborne particles and droplets. Because exhaled air in an infected person is considered to be “loaded” with inoculum, each exhalation and inhalation is effectively reinoculation.

Combination Antiviral Therapy
Rapid and amplified viral replication is the hallmark of most acute viral infections. By reducing the rate, quantity, or duration of viral replication, the degree of direct viral injury to the respiratory epithelium, vasculature, and organs may be lessened.

Zinc Lozenges and Zinc Sulfate
Zinc is a known inhibitor of coronavirus replication.

Antimalarials
Hydroxychloroquine (HCQ) is an antimalarial/anti-inflammatory drug that impairs endosomal transfer of virions within human cells.

Azithromycin
Azithromycin is a commonly used macrolide antibiotic that has antiviral properties mainly attributed to reduced endosomal transfer of virions as well as established anti-inflammatory effects.

Doxycycline
Doxycycline is another common antibiotic with multiple intracellular effects that may reduce viral replication, cellular damage, and expression of inflammatory factors.

Favipiravir
Favipiravir, an oral selective inhibitor of RNA-dependent RNA polymerase, is approved for ambulatory use in COVID-19 in Russia, India, and other countries outside of the United States.

Immunomodulators
In COVID-19, some of the first respiratory findings are nasal congestion, cough, and wheezing. These features are due to excess inflammation and cytokine activation. Early use of corticosteroids is a rational intervention for patients with COVID-19 with these features as they would be in acute asthma or reactive airways disease.

Colchicine
Because the short-term safety profile is well understood, it is reasonable to consider this agent along with corticosteroids in an attempt to reduce the effects of cytokine storm. A dosing scheme of 1.2 mg po, followed by 0.6 mg po bid for 3 weeks can be considered.

The autumn crocus is a source of colchicine, a secondary metabolite, and found in every part of the plant.  It is a bitter tasting alkaloid, which is Nature’s way of saying “don’t eat me.”  For centuries though, colchicine has been used to treat gout, an acute inflammatory arthritis afflicting (typically) the big toe.  Probably for this reason, generic colchicine was used off-label to treat gout.

Antiplatelet Agents and Antithrombotics
Based on this pathophysiologic rationale, aspirin 81 mg daily can be administered as an initial antiplatelet and anti-inflammatory agent. Ambulatory patients can be additionally treated with subcutaneous low-molecular-weight heparin or with short-acting novel anticoagulant drugs.

Delivery of Oxygen and Monitoring
A significant component of safe outpatient management is maintenance of arterial oxygen saturation on room air or prescribed home oxygen under direct supervision by daily telemedicine with escalation to hospitalization for assisted ventilation if needed.

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
Kory, Pierre MD1,*; Meduri, Gianfranco Umberto MD2; Varon, Joseph MD3; Iglesias, Jose DO4; Marik, Paul E. MD5Author Information
American Journal of Therapeutics: May Jun 2021 - Volume 28 - Issue 3 - p e299-e318

Therapeutic Advances:
A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large “natural experiments” occurred in regions that initiated “ivermectin distribution” campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns.

Conclusions:
Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

Wed May 26, 2021 - 5:10 pm EST
After Mexico City introduced ivermectin plan, COVID hospitalizations and deaths disappeared

An initiative in Mexico City to prescribe ivermectin to COVID-19 positive patients has resulted in a 52–76 percent reduction in hospitalizations.

“The Ministry of Health has identified that there is enough evidence to use in people positive for SARS-CoV-2, even without symptoms, some drugs such as ivermectin and azithromycin,” López confirmed in a press conference.
Local authorities created a home-treatment-kit, including ivermectin, for its 22 million-strong population on December 28, 2020, following a spike in cases of COVID-19.

Individuals testing positive for COVID from an antigen test, and who were experiencing at least mild symptoms, began receiving one of the government’s ivermectin-based treatment kits from December 29.

Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching
Published: January 15, 2022

. . . Hospitalization and mortality rates in ivermectin users and non-users in propensity score-matched analysis

As described in Table 2, after employing PSM, of the 6,068 subjects (3,034 in each group), there were 44 hospitalizations among ivermectin users (1.6% hospitalization rate) and 99 hospitalizations (3.3% hospitalization rate) among ivermectin non-users, a 56% reduction in hospitalization rate (RR, 0.44; 95% CI, 0.31-0.63). When adjustment for variables was employed, the reduction in hospitalization rate was 67% (RR, 0.33; 95% CI, 023-0.66; p < 0.0001).

There were 25 deaths among ivermectin users (0.8% mortality rate) and 79 deaths among non-ivermectin users (2.6% mortality rate), a 68% reduction in mortality rate (RR, 0.32; 95% CI, 0.20-0.49). When PSM was adjusted, reduction in mortality rate was 70% (RR, 0.30; 95% CI, 0.19-0.46; p < 0.0001).

. . . In a citywide ivermectin program with prophylactic, optional ivermectin use for COVID-19, ivermectin was associated with significantly reduced COVID-19 infection, hospitalization, and death rates from COVID-19.

Regular Use of Ivermectin as Prophylaxis for COVID-19 Led Up to a 92% Reduction in COVID-19 Mortality Rate in a Dose-Response Manner: Results of a Prospective Observational Study of a Strictly Controlled Population of 88,012 Subjects
Published: August 31, 2022 (see history)
DOI: 10.7759/cureus.28624
Cite this article as: Kerr L, Baldi F, Lobo R, et al. (August 31, 2022) Regular Use of Ivermectin as Prophylaxis for COVID-19 Led Up to a 92% Reduction in COVID-19 Mortality Rate in a Dose-Response Manner: Results of a Prospective Observational Study of a Strictly Controlled Population of 88,012 Subjects. Cureus 14(: e28624. doi:10.7759/cureus.28624

Abstract
Background

We have previously demonstrated that ivermectin used as prophylaxis for coronavirus disease 2019 (COVID-19), irrespective of the regularity, in a strictly controlled citywide program in Southern Brazil (Itajaí, Brazil), was associated with reductions in COVID-19 infection, hospitalization, and mortality rates. In this study, our objective was to determine if the regular use of ivermectin impacted the level of protection from COVID-19 and related outcomes, reinforcing the efficacy of ivermectin through the demonstration of a dose-response effect.
Methods

This exploratory analysis of a prospective observational study involved a program that used ivermectin at a dose of 0.2 mg/kg/day for two consecutive days, every 15 days, for 150 days. Regularity definitions were as follows: regular users had 180 mg or more of ivermectin and irregular users had up to 60 mg, in total, throughout the program. Comparisons were made between non-users (subjects who did not use ivermectin), and regular and irregular users after multivariate adjustments. The full city database was used to calculate and compare COVID-19 infection and the risk of dying from COVID-19. The COVID-19 database was used and propensity score matching (PSM) was employed for hospitalization and mortality rates.
Results

Among 223,128 subjects from the city of Itajaí, 159,560 were 18 years old or up and were not infected by COVID-19 until July 7, 2020, from which 45,716 (28.7%) did not use and 113,844 (71.3%) used ivermectin. Among ivermectin users, 33,971 (29.8%) used irregularly (up to 60 mg) and 8,325 (7.3%) used regularly (more than 180 mg). The remaining 71,548 participants were not included in the analysis. COVID-19 infection rate was 49% lower for regular users (3.40%) than non-users (6.64%) (risk rate (RR): 0.51; 95% CI: 0.45-0.58; p < 0.0001), and 25% lower than irregular users (4.54%) (RR: 0.75; 95% CI: 0.66-0.85; p < 0.0001). The infection rate was 32% lower for irregular users than non-users (RR: 0.68; 95% CI: 0.64-0.73; p < 0.0001). Among COVID-19 participants, regular users were older and had a higher prevalence of type 2 diabetes and hypertension than irregular and non-users. After PSM, the matched analysis contained 283 subjects in each group of non-users and regular users, between regular users and irregular users, and 1,542 subjects between non-users and irregular users. The hospitalization rate was reduced by 100% in regular users compared to both irregular users and non-users (p < 0.0001), and by 29% among irregular users compared to non-users (RR: 0.781; 95% CI: 0.49-1.05; p = 0.099). Mortality rate was 92% lower in regular users than non-users (RR: 0.08; 95% CI: 0.02-0.35; p = 0.0008) and 84% lower than irregular users (RR: 0.16; 95% CI: 0.04-0.71; p = 0.016), while irregular users had a 37% lower mortality rate reduction than non-users (RR: 0.67; 95% CI: 0.40-0.99; p = 0.049). Risk of dying from COVID-19 was 86% lower among regular users than non-users (RR: 0.14; 95% CI: 0.03-0.57; p = 0.006), and 72% lower than irregular users (RR: 0.28; 95% CI: 0.07-1.18; p = 0.083), while irregular users had a 51% reduction compared to non-users (RR: 0.49; 95% CI: 0.32-0.76; p = 0.001).
Conclusion

Non-use of ivermectin was associated with a 12.5-fold increase in mortality rate and a seven-fold increased risk of dying from COVID-19 compared to the regular use of ivermectin. This dose-response efficacy reinforces the prophylactic effects of ivermectin against COVID-19.

Virology Journal - Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Published: 22 August 2005
We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage

Dangerous pathogens found on children’s face masks BY JENNIFER CABRERA 06/16/2021
A group of parents in Gainesville, FL, sent 6 face masks to a lab at the University of Florida, requesting an analysis of contaminants found on the masks after they had been worn.

The resulting report found that five masks were contaminated with bacteria, parasites, and fungi, including three with dangerous pathogenic and pneumonia-causing bacteria. Although the test is capable of detecting viruses, including SARS-CoV-2, only one virus was found on one mask (alcelaphine herpesvirus 1).

The analysis detected the following 11 dangerous pathogens on the masks:

   Streptococcus pneumoniae (pneumonia)
   Mycobacterium tuberculosis (tuberculosis)
   Neisseria meningitidis (meningitis, sepsis)
   Acanthamoeba polyphaga (keratitis and granulomatous amebic encephalitis)
   Acinetobacter baumanni (pneumonia, blood stream infections, meningitis, UTIs—resistant to antibiotics)
   Escherichia coli (food poisoning)
   Borrelia burgdorferi (causes Lyme disease)
   Corynebacterium diphtheriae (diphtheria)
   Legionella pneumophila (Legionnaires’ disease)
   Staphylococcus pyogenes serotype M3 (severe infections—high morbidity rates)
   Staphylococcus aureus (meningitis, sepsis)

. . . The face masks studied were new or freshly-laundered before wearing and had been worn for 5 to 8 hours, most during in-person schooling by children aged 6 through 11. One was worn by an adult. A t-shirt worn by one of the children to school and unworn masks were tested as controls. No pathogens were found on the controls; samples from the front top and bottom of the t-shirt found proteins that are commonly found in skin and hair, along with some commonly found in soil.

Nicotine can selectively reduce the inflammatory response in various infection states, including Legionella pneumophila and Chlamydia pneumoniae infection, via the cholinergic anti-inflammatory pathway [6]. Nicotine is an agonist at the α7 subunit of nicotinic acetylcholine (α7-nACh) receptors on innate immune cells such as macrophages. These receptors respond to acetylcholine from different sources, including other immune cells and the vagus nerve, and their activation causes suppression of pro-inflammatory cytokines. Nicotine is able to suppress the production of pro-inflammatory cytokines by mimicking the binding of acetylcholine . . .
In the absence of any effective treatment for COVID-19, further research as to whether nicotine replacement offers protection against severe SAR-CoV-2 infection in smokers is clearly essential. If the mechanisms through which nicotine may interact with the virus remain speculative, the effects of route of administration, duration, dosing and frequency of use of nicotine on any such interaction are unknown.

Menthol Enhances the Desensitization of Human α3β4 Nicotinic Acetylcholine Receptors

Abstract - The α3β4 nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the peripheral and central nervous systems, including in airway sensory nerves. The nAChR subtype transduces the irritant effects of nicotine in tobacco smoke and, in certain brain areas, may be involved in nicotine addiction and/or withdrawal. Menthol, a widely used additive in cigarettes, is a potential analgesic and/or counterirritant at sensory nerves and may also influence nicotine’s actions in the brain.

Menthol has been tested in humans mainly for its pharmaceutical properties, such as enhancement of lung and airway volume.

Aside from its cold-inducing sensation capabilities, menthol exhibits cytotoxic effects in cancer cells, induces reduction in malignant cell growth, and engages in synergistic excitation of GABA receptors and sodium ion channels resulting in analgesia.

Griffithsin: An Antiviral Lectin with Outstanding Therapeutic Potential
Abstract - Griffithsin (GRFT), an algae-derived lectin, is one of the most potent viral entry inhibitors discovered to date. It is currently being developed as a microbicide with broad-spectrum activity against several enveloped viruses. GRFT can inhibit human immunodeficiency virus (HIV) infection at picomolar concentrations, surpassing the ability of most anti-HIV agents. The potential to inhibit other viruses as well as parasites has also been demonstrated.

High-level expression of the HIV entry inhibitor griffithsin from the plastid genome and retention of biological activity in dried tobacco leaves
Abstract - The potent anti-HIV microbicide griffithsin was expressed to high levels in tobacco chloroplasts, enabling efficient purification from both fresh and dried biomass, thus providing storable material for inexpensive production and scale-up on demand. The global HIV epidemic continues to grow, with 1.8 million new infections occurring per year. In the absence of a cure and an AIDS vaccine, there is a pressing need to prevent new infections in order to curb the disease. Topical microbicides that block viral entry into human cells can potentially prevent HIV infection. The antiviral lectin griffithsin has been identified as a highly potent inhibitor of HIV entry into human cells.

September 10, 2021
Drugs that mimic effects of cigarette smoke reduce SARS-CoV-2's ability to enter cells
by Hiroshima University

Researchers have identified a potential reason why lower numbers of COVID cases have appeared amongst smokers compared to non-smokers, even as other reports suggest smoking increases severity of the disease.

Researchers have identified two drugs that mimic the effect of chemicals in cigarette smoke to bind to a receptor in mammalian cells that inhibits production of ACE2 proteins, a process that appears to reduce the ability of the SARS-CoV-2 virus to enter the cell.

The findings appear in the journal Scientific Reports on 17 August.

3 existing drugs fight coronavirus with ‘almost 100%’ success in Jerusalem lab By Nathan Jeffay 20 July 2021, 12:59 pm

If medicines pass clinical test for COVID, they’re also likely to prove effective for new variants, scientists say, as they target proteins that barely change between mutations

Israeli scientists say they have identified three existing drugs that have good prospects as COVID-19 treatments, reporting that they illustrated high ability to fight the virus in lab tests.
. . .  Prof. Isaiah Arkin, the Hebrew University biochemist . . . “We have the vaccine, but we shouldn’t rest on our laurels, and I would like to see these drugs become part of the arsenal that we use to fight the coronavirus,” he said.
. . . The research that paved the way for the lab trial has been peer-reviewed and published, but the lab study itself has not yet been peer-reviewed.
. . . When confronting SARS‑CoV‑2, the drugs in question — darapladib, which currently treats atherosclerosis; the cancer drug Flumatinib; and an HIV medicine — don’t target the spike protein. Rather, they target one of two other proteins: the envelope protein and the 3a protein. These proteins — especially the envelope protein — hardly change between variants, and even between diseases from the coronavirus family. As such, drugs that target them are likely to remain effective in spite of mutations, Arkin said.

Some Herbal Compounds May be Effective Against Covid-19: Study . . . first published:November 18, 2020, 18:52 IST

A new study, published in the journal Frontiers of Pharmacology, suggests that such an effective treatment protocol may be at hand if we use certain natural and herbal compounds that can inhibit the SARS-CoV-2 virus. If these compounds are found to be effective against the virus then we could have a new treatment protocol or therapy for COVID-19.

Natural Products Modulating Angiotensin Converting Enzyme 2 (ACE2) as Potential COVID-19 Therapies
Published online 2021 May 3

The 2019 coronavirus disease (COVID-19) is a potentially fatal multisystemic infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Currently, viable therapeutic options that are cost effective, safe and readily available are desired, but lacking. Nevertheless, the pandemic is noticeably of lesser burden in African and Asian regions, where the use of traditional herbs predominates, with such relationship warranting a closer look at ethnomedicine.

Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data
Published online 2020 Aug 19
. . . Studies conducted in in-vivo and in-vitro test models clearly demonstrate antiviral potential of garlic and its OSCs against a wide range of viruses; for example from the Adenoviridae, Arteriviridae, Coronaviridae, Flaviviridae, Flaviviridae, Herpesviridae, Orthomyxoviridae, Picornaviridae, Paramyxoviridae, Poxvirus, Rhabdoviridae and Retroviridae family.

Study suggests honey and Nigella sativa expedites viral clearance in COVID-19 patients
By Susha Cheriyedath, M.Sc.Nov 8 2020
. . . The study results show that HNS (honey and Nigella sativa) helped with symptoms alleviation and viral clearance and reduced mortality in patients with moderate and severe disease. According to the team, HNS can be used as a safe and effective therapy in COVID-19 patients as it promotes quicker recovery and survival. Thus, they concluded that HNS represents an affordable therapeutic option and can be used alone or in combination with other therapies to fight COVID-19.

SARS-CoV-2 is steadily mutating during continuous transmission among humans. This might eventually lead the virus into evading existing therapeutic and prophylactic approaches aimed at the viral spike. We found effective inhibition of protein-protein interaction between the human virus cell entry receptor ACE2 and SARS-CoV-2 spike, including five relevant mutations, by water-based common dandelion (Taraxacum officinale) extracts. This was shown in vitro using human kidney (HEK293) and lung (A549) cells, overexpressing the ACE2 and ACE2/TMPRSS2 protein, respectively. Infection of the lung cells using SARS-CoV-2 pseudotyped lentivirus was efficiently prevented by the extract. The results deserve more in-depth analysis of dandelions’ effectiveness in SARS-CoV-2 prevention and now require confirmatory clinical evidence.

Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response
. . . Summary sentence: Cannabidiol from the cannabis plant has potential to prevent and inhibit SARS-CoV-2 infection

New study finds aspirin can significantly cut COVID risks — and even death
Sarah Taylor - October 11, 2021

New research from George Washington University has determined that treating COVID patients with aspirin reduced the risk of severe illness by nearly half.

The report noted that an aspirin regimen in more than 400 COVID-19 patients in hospitals across the United States cut the need for ventilation by 44%, slashed ICU admission by 43%, and reduced overall in-hospital mortality rates by 47%.

". . . Our research found an association between low-dose aspirin and decreased severity of COVID-19 and death."

. . . This isn't the only study professing the possible benefits of aspirin in COVID patients. Earlier in October, Medical Express reported that researchers from the University of Minnesota and Basel University in Switzerland came to the same conclusion.

May 27, 2021
N Engl J Med 2021; 384:1981-1990
DOI: 10.1056/NEJMoa2102137

. . . Conclusions

In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily.

Draft Recommendation Statement
Aspirin Use to Prevent Cardiovascular Disease: Preventive Medication
October 12, 2021

Adults ages 40 to 59 years with a 10% or greater 10-year cardiovascular disease (CVD) risk
The decision to initiate low-dose aspirin use for the primary prevention of CVD in adults ages 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one. Evidence indicates that the net benefit of aspirin use in this group is small. Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit.

Adults age 60 years or older
The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults age 60 years or older.

Why You Should Not Use Ivermectin to Treat or Prevent COVID-19
. . . There seems to be a growing interest in a drug called ivermectin for the prevention or treatment of COVID-19 in humans. Certain animal formulations of ivermectin such as pour-on, injectable, paste, and "drench," are approved in the U.S. to treat or prevent parasites in animals. For humans, ivermectin tablets are approved at very specific doses to treat some parasitic worms, and there are topical (on the skin) formulations for head lice and skin conditions like rosacea.

However, the FDA has received multiple reports of patients who have required medical attention, including hospitalization, after self-medicating with ivermectin intended for livestock.

Ivermectin
Last Updated: February 11, 2021

Ivermectin is a Food and Drug Administration (FDA)-approved antiparasitic drug that is used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies.1 It is also being evaluated for its potential to reduce the rate of malaria transmission by killing mosquitoes that feed on treated humans and livestock.2 For these indications, ivermectin has been widely used and is generally well tolerated.1,3 Ivermectin is not approved by the FDA for the treatment of any viral infection.

New Hampshire House Approves Over-the-Counter Ivermectin
By Alice Giordano
March 16, 2022 Updated: March 17, 2022

New Hampshire moved closer to becoming the first U.S. state to offer ivermectin without a prescription on March 16.

By a 183—159 vote, New Hampshire’s Republican-dominated House of Representatives approved HB1022, which would allow pharmacists to dispense ivermectin under a standing order, meaning that anyone could go to a pharmacist and get human-grade ivermectin.

. . . The legislation still has to win final approval from the Senate, which is also Republican-controlled, and thus far, its Republican lawmakers have shown they believe in the state’s “Live Free or Die” motto when it comes to treatment choices about COVID-19.

. . . In addition to ivermectin, Oklahoma Senate Bill 1525 also proposes making Hydroxychloroquine available over the counter.