COVID-19 treatment: respiratory tract administration
• Direct treatment to the primary source of initial infection reduces progression and transmission
Over 10,000
compounds predicted to reduce risk—SARS-CoV-2 easily
disabled
SARS-CoV-2 infection involves a complex interplay of over 400
host and viral proteins and other factors1-117, providing many therapeutic targets.
Scientists have identified 10,976+
compounds118 potentially beneficial
for COVID-19. Hundreds of compounds inhibit SARS-CoV-2 in vitro,
including many with known pharmacokinetics and proven safety.
Primary entry via the upper respiratory tract
Studies point to the upper respiratory tract, and specifically the nasal respiratory
epithelium as the primary source of infection and initial
replication50,119-121 (a).
The primary initial route for entry into the central nervous system
is thought to be the olfactory nerve in the nasal
cavity123-127.
c19early.org
Efficacy confidence - naso/oropharyngeal
p < 0.00000001
p < 0.00000001
p < 0.00000001
p < 0.00000001
p = 0.0002
p = 0.003
p = 0.003
p = 0.003 (exc. late)
p = 0.008
p = 0.018
p = 0.024
p = 0.048
P-values indicate the confidence that studies show a significant effect. p = 0.05 is the typical threshold for significance, with lower values indicating higher confidence. See the individual analyses for details of efficacy for specific outcomes and conditions.
•Direct treatment to the primary source of initial infection.
•Rapid onset of action.
•Higher local drug concentrations.
•Reduced systemic side effects.
Naso/oropharyngeal treatments may be effective via many mechanisms, e.g.:
inactivating virions, blocking attachment/entry, creating a physical barrier, mechanical
clearance, altering the environment to hinder fusion/replication, inhibiting spike-priming
proteases, enhancing mucociliary function, and priming local innate
immunity(b).
Studies use various administration methods including nasal/oral sprays,
rinses, and inhalation.
Combined nasal/oral application shows the highest efficacy.
Efficacy depends on administration details, e.g., viscosity, mucoadhesion,
sprayability, droplet size229,230, dispersion229, and the angle of administration for sprays230.
Some treatments may disrupt beneficial microbial populations, requiring care
to avoid side effects and suggesting a preference for more selective
treatments, especially with longer-term use(c).
c19early.org
| Respiratory tract administration efficacy | |
|---|---|
| Oral application | 38% [25‑49%] |
| Nasal application | 59% [50‑66%] |
| Nasal & oral | 88% [72‑95%] |
Naso/oropharyngeal treatments experience
regulatory challenges. For example the US FDA shut down a povidone-iodine
treatment257
when 7 RCTs showed efficacy, and
the FTC sent warning letters to companies that referenced studies showing
benefits of nasal/oral hygiene for
COVID-19258-260.
Naso/oropharyngeal treatment reduces
transmission Immediate or prophylactic naso/oropharyngeal treatment also
logically reduces transmission. A 621-patient RCT showed 92% reduction in transmission
with nasal and oropharyngeal sprays containing povidone-iodine and glycyrrhizic
acid135.
In contrast, the commonly recommended masking shows no significant efficacy in RCTs to date,
with 4 COVID-19 RCTs showing 2.2% [-25‑24%] improvement261.
Treatment at the source of initial infection
Studies show targeted treatment to the upper respiratory tract via nasal/oral sprays,
rinses, or inhalation can significantly reduce COVID-19 transmission and progression.
Several of these are widely available in most countries, including treatments with
povidone-iodine, chlorhexidine, alkalinizing agents, iota-carrageenan, and many
more.
In many cases, authorities prevent marketing for COVID-19, despite
evidence of efficacy. However, treatments specifically marketed for COVID-19
are becoming more widely available including
SanoTize262, a nitric
oxide generating nasal spray available in 10 countries(e),
and NoriZite263, nasal/oral sprays with iota-carrageenan available in the UK.
Nasopharyngeal/oropharyngeal treatments work via different methods.
The following tables summarize the primary mechanisms of action, mechanisms for specific
treatments, and the potential for disruption to the natural oral and nasal microbiomes.
c19early.org
Nasal/oral sprays and rinses—primary mechanisms
Primary mechanisms of action for nasopharyngeal/oropharyngeal sprays and rinses. Note: sequenced application is possible to maximize efficacy—for example, using a virucidal spray/wash first (to clean), followed by a barrier spray (to protect), with a 5-10 minute drying window in between.
| Virucidal action | Chemically inactivating or destroying the structure of viral particles |
| Blocking attachment | Binding to the virus or host cells to prevent viral attachment to host cells |
| Physical barrier | Forming a physical layer over the nasal mucosa preventing viral access to host cells |
| Physical removal | Mechanical washout/flushing of viral particles and mucus (e.g., large volume irrigation) |
| Mucociliary clearance | Stimulating the natural beating of nasal cilia to accelerate the clearing of trapped pathogens |
c19early.org
Nasal/oral sprays and rinses—mechanisms of action
Nasopharyngeal/oropharyngeal treatments have many different mechanisms of action. Specific treatments may have significant systemic effects or significantly alter the microbiome.
| Treatment | Mechanisms | Notes |
|---|---|---|
| Azelastine220 |
Antiviral: inhibits interaction between spike protein and ACE2 Antiviral: potential inhibition of viral protease (Mpro) Other: H1-receptor antagonist (antihistamine) Other: mast cell stabilizer |
Antihistamine. Designed to affect human receptors. Risks include dysgeusia, drowsiness, and nasal burning. |
| Cetylpyridinium Chloride211 |
Virucidal: disrupts viral lipid envelope Antiseptic: quaternary ammonium compound |
Chemical virucide. Common in mouthwashes. Can cause temporary staining of teeth or tongue irritation if used frequently. |
| Chlorhexidine198 |
Virucidal: disrupts viral lipid membranes Antiseptic: cationic polybiguanide |
Chemical virucide. May cause tooth staining and altered taste. |
| Chlorpheniramine215 |
Antiviral: binds to viral spike protein to block entry Antiviral: high affinity for viral transport proteins Other: H1-receptor antagonist (1st generation antihistamine) Other: anticholinergic activity |
Antihistamine. Stronger systemic risks than azelastine. Known to cause significant sedation/drowsiness and cognitive impairment. |
| Hydrogen Peroxide194 |
Virucidal: oxidizing agent that destroys viral parts Other: tissue debridement |
Chemical virucide. Can be toxic to healthy tissue if concentration is too high (>1%). Long-term safety on nasal mucosa is debated. |
| Inhaled Heparin224 |
Antiviral: acts as a decoy receptor (mimics heparan sulfate) Antiviral: anti-inflammatory effects on lung tissue Other: Anticoagulant |
Anticoagulant. Use requires caution regarding bleeding risks. |
| Iota-carrageenan180 |
Barrier: forms a viscous physical layer on mucosa Trap: electrostatistically traps virus particles (mimics cell surface) |
Physical barrier. High safety profile for daily use. |
| NaCl208 |
Cleaning: physically washes away viral particles Support: moisturizes mucosa to support natural immune barrier |
Physical wash. High degree of safety, reduces viral load via physical removal. |
| Nitric Oxide178 |
Virucidal: physically damages viral structure via nitrosylation Other: vasodilator (relaxes blood vessels) in systemic use |
Virucide/drug hybrid. In nasal spray form, it acts primarily as a topical disinfectant. Rapidly cleared, so systemic vasodilation risks are low but present. |
| Phthalocyanine185 |
Virucidal: generates reactive oxygen species (ROS) when exposed to light to kill virus Other: photosensitizer |
Chemical virucide. A synthetic compound often used in photodynamic therapy. Works by creating an oxidative environment hostile to the virus. |
| Povidone-Iodine150 |
Virucidal: oxidizes viral proteins and destabilizes membrane structures Antiseptic: broad-spectrum bacterial/fungal killer |
Chemical virucide. Highly effective but risk of thyroid absorption with chronic use. Can be irritating to mucous membranes. |
| Sodium Bicarbonate264 |
Environment: raises pH to inhibit viral fusion Cleaning: improves mucociliary clearance (washing) |
Physical/chemical environment. Changes the environment rather than attacking the virus directly. High degree of safety. |
c19early.org
Nasal/oral sprays and rinses may affect the microbiome
Nasopharyngeal/oropharyngeal treatments may significantly alter the microbiome. These effects may be more important with longer-term prophylaxis.
| Treatment | Microbiome disruption potential | Notes |
|---|---|---|
| Iota-carrageenan180 | Low | Primarily antiviral, however extended use may mildly affect the microbiome |
| Nitric Oxide178 | Low to moderate | More selective towards pathogens, however excessive concentrations or prolonged use may disrupt the balance of bacteria |
| Alkalinization165 | Moderate | Increases pH, negatively impacting beneficial microbes that thrive in a slightly acidic environment |
| Cetylpyridinium Chloride211 | Moderate | Quaternary ammonium broad-spectrum antiseptic that can disrupt beneficial and harmful bacteria |
| Phthalocyanine185 | Moderate to high | Photodynamic compound with antimicrobial activity, likely to affect the microbiome |
| Chlorhexidine198 | High | Potent antiseptic with broad activity, significantly disrupts the microbiome |
| Hydrogen Peroxide194 | High | Strong oxidizer, harming both beneficial and harmful microbes |
| Povidone-Iodine150 | High | Potent broad-spectrum antiseptic harmful to beneficial microbes |
Protocols combine multiple
treatments No single treatment is guaranteed to be effective and safe for a specific individual.
Leading evidence-based protocols combine multiple treatments.
c19early.org
| Combined treatments increase efficacy | |
|---|---|
| Monotherapy | 29% [26‑32%] |
| Polytherapy | 69% [57‑78%] |
Complementary/synergistic actions,
viral evolution, escape risk suggest polytherapy
There are many complementary mechanisms of action, and studies show complementary and
synergistic effects with polytherapy268-284.
For example, Jitobaom et al.269 shows >10x reduction in
IC50 with ivermectin and niclosamide, an RCT by Said et
al.276 showed the combination of nigella sativa and vitamin D was
more effective than either alone, and an RCT by Wannigama et
al.285 showed improved results with fluvoxamine combined with
additional treatments, compared to fluvoxamine alone.
SARS-CoV-2 can rapidly acquire mutations altering infectivity,
disease severity, and drug resistance even without selective
pressure286-293.
Antigenic drift can undermine more
variant-specific treatments like monoclonal antibodies and more specific
antivirals. Treatment with targeted antivirals may select for escape
mutations294.
The efficacy of treatments varies depending on cell
type295 due to differences in viral receptor expression, drug
distribution and metabolism, and cell-specific mechanisms.
Efficacy may also vary based on genetic
variants296-306.
Variable efficacy across variants, cell types, tissues, and
host genetics, along with the complementary and synergistic actions of different
treatments, all point to greater efficacy with polytherapy.
In many studies, the standard of care given to all patients includes other
treatments—efficacy seen in these trials may rely in part on
synergistic effects.
Less variant specific treatments and polytherapy targeting multiple viral and
host proteins may be more effective.
Meta-analysis of all early treatment trials shows 69% [57‑78%] lower risk
for studies using combined treatments, compared to 29% [26‑32%] for single
treatments.
c19early.org
Combined treatment is more effective
SARS-CoV-2 involves the complex interplay of 400+ host and viral proteins and factors, providing many therapeutic targets. Many compounds have antiviral activity for SARS-CoV-2, with many different mechanisms including blocking attachment, entry, and replication. Combinations of treatments, with careful attention to potential side effects, allows improved efficacy via complementary and synergistic mechanisms.
| Tissue and cell coverage | Different compounds have different tissue penetration profiles and efficacy across cell types |
| Variant coverage | Compounds with different viral resistance profiles |
| Intra/extracellular | Disabling and removing intracellular and extracellular viral particles |
| Resistance | Minimizing persistence and emergence of resistant variants |
| Genetics | Robustness against individual variations in efficacy based on genetics |
| Lower doses | Potentially lower doses of individual agents, reducing toxicity |
| Viral and host-directed | Antivirals targeting viral and host proteins |
| Immune system function | Supporting or enhancing natural immune system function |
| Disease phases | Addressing multiple disease phases (viral replication, inflammation, secondary complications) |
Contact.
Contact us on X at @CovidAnalysis.
Funding.
We have received no funding or
compensation in any form, and do not accept donations. This is entirely volunteer work.
Conflicts of interest.
We have no conflicts of interest.
We have no affiliation with any pharmaceutical companies, supplement companies, governments, political parties, or advocacy organizations.AI.
We use AI models (Gemini, Grok, Claude, and
ChatGPT) tasked with functioning as additional peer-reviewers to check for errors, suggest
improvements, and review spelling and grammar. Any corrections are verified and applied
manually. Our preference for em dashes is independent of AI.Dedication.
This work is dedicated to those who
risked their career to save lives under extreme censorship and persecution from
authorities and media that have not even reviewed most of the science. In alphabetical
order, those that paid the ultimate price: Dr. Thomas J. Borody, Dr. Jackie Stone, Dr.
Vladimir (Zev) Zelenko; and those that continue to risk their careers to save lives: Dr.
Mary Talley Bowden, Dr. Flavio Cadegiani, Dr. Shankara Chetty, Dr. Ryan Cole, Dr. George
Fareed, Dr. Sabine Hazan, Dr. Pierre Kory, Dr. Tess Lawrie, Dr. Robert Malone, Dr. Paul
Marik, Dr. Peter McCullough, Dr. Didier Raoult, Dr. Harvey Risch, Dr. Brian Tyson, Dr.
Joseph Varon, and the estimated over one million physicians worldwide that prescribed one
or more low-cost COVID-19 treatments known to reduce risk, contrary to authority beliefs.
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distributed in accordance with the Creative Commons CC0 1.0 Universal license, which
dedicates the work to the public domain by waiving all rights worldwide under copyright law.
You can distribute, remix, adapt, and build upon this work in any medium or format,
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See: https://creativecommons.org/publicdomain/zero/1.0/.
Entry via the eyes and gastrointestinal tract is possible, but less
common122, and entry via other routes is rare.
Nasal/oral sprays, rinses, etc. may be effective via multiple mechanisms:
directly inactivating virions: e.g., oxidizers, antiseptics, and cationic surfactants may
disrupt the viral envelope or proteins;
blocking attachment/entry: e.g., sulfated/negatively charged polymers can bind spike or its
heparan-sulfate co-receptor to prevent docking;
creating a physical barrier on the mucosa: e.g., mucoadhesive cellulose/carrageenan or
dendrimer polymers form a coating that traps particles and limits spread across the
epithelium;
mechanically removing viral particles: e.g., saline irrigation/gargling may physically
remove virus-laden mucus and reduce viral load;
altering the local environment to be less favorable for viral fusion/replication: e.g.,
altering the pH/osmolarity/ionic strength;
inhibiting host proteases needed for spike priming: e.g., topical protease inhibitors can
reduce entry activation;
providing antimicrobial nitric oxide (NO): e.g., NO-releasing nasal sprays provide direct
antiviral activity;
enhancing mucociliary function: e.g., improving ciliary beat frequency and mucus
transport, aiding in viral expulsion;
and priming local innate immunity: e.g., intranasal interferon-α may induce an antiviral
state in nasal epithelium.
Chlorhexidine, PVP-I, and hydrogen peroxide are broad-spectrum agents that do not discriminate between beneficial and harmful microbes—excessive use may significantly disrupt the microbiome. Cetylpyridinium chloride, a quaternary ammonium antiseptic, is less disruptive but may still alter microbial balance. Nitric oxide primarily attacks respiratory pathogens but high concentrations may also damage some commensal bacteria. Iota-carrageenan and alkalinization are expected to have more minimal impact on the natural microbiome.
Many additional compounds may be effective with nasopharyngeal/oropharyngeal treatment,
with promising but limited clinical data to date,
including astodrimer
sodium231-234, benzalkonium
chloride235, CDCM236,237, dequalinium
chloride235, hypochlorous acid236, hexadecyl pyridinium
chloride238, ethyl lauroyl arginate239,
Sinomarin162, PCANS240,
SA58241-244,
ColdZyme245,
Panthexyl246, HH-120247,248,
TriSb92249, IBIO123250,
homoharringtonine251,
A8G6252,253, STI-9167254,
FSY-ACE2-NVs nanoSpray255, and Sentinox256.
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