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COVID-19 treatment: respiratory tract administration

• Direct treatment to the primary source of initial infection reduces progression and transmission

We do not provide medical advice. No treatment is 100% effective, and all may have side effects. Protocols combine multiple treatments. Consult a qualified physician for personalized risk/benefit analysis.
Naso/orophayngeal treatments
         
Over 9,000 compounds predicted to reduce COVID-19 risk. SARS-CoV-2 is easily disabled. SARS-CoV-2 infection and replication involves a complex interplay of over 100 host and viral proteins and other factors1-8, providing many therapeutic targets. Scientists have identified 9,177+ compounds9 potentially beneficial for COVID-19. Hundreds of compounds inhibit SARS-CoV-2 in vitro, including many with known pharmacokinetics and proven safety.
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Efficacy confidence - naso/oropharyngeal
Chlorpheniraminep<0.0000000001
Povidone-Iodinep<0.0000000001
Chlorhexidinep=0.0000000008
Alkalinizationp=0.000000004
Phthalocyaninep=0.0002
Nitric Oxidep=0.003 (exc. late)
Iota-carrageenanp=0.018
Hydrogen Peroxidep=0.024
Cetylpyridinium Chloridep=0.042
Efficacy confirmed February 2021 (PVP-I)(a),10
P-values indicate the confidence that studies show a significant effect. p=0.05 is the typical threshold for significance in scientific papers, with lower values indicating higher confidence. These treatments show lower risk for COVID-19. See the individual analyses for details of efficacy for specific outcomes and conditions.
Naso/oropharyngeal treatment is effective. Many compounds with existing safety records are expected to be beneficial within the upper respiratory tract. 70 clinical studies show lower risk for early treatment or prophylaxis with povidone-iodine, iota-carrageenan, nitric oxide, alkalinization, phthalocyanine, hydrogen peroxide, chlorhexidine, cetylpyridinium chloride, and chlorpheniramine11-88, confirmed in multiple additional meta analyses89-91. Studies show a degree of efficacy even with delayed treatment. Targeted administration to the respiratory tract has several advantages:
Direct treatment to the primary source of initial infection.
Rapid onset of action.
Higher local drug concentrations.
Reduced systemic side effects.
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Respiratory tract administration efficacy
Oral application38% [25‑49%]
Nasal application58% [49‑65%]
Nasal & Oral91% [74‑97%]
Meta analysis for early treatment/prophylaxis.
Studies use various administration methods including nasal and oral sprays, nasal irrigation, oral rinses, and inhalation. Combined nasal and oral application shows the highest efficacy. Efficacy depends on administration details, e.g., viscosity, mucoadhesion, sprayability, and the angle of administration for sprays92. 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(b).
Only 4% of studies applied treatment directly to the primary location of initial infection in the upper respiratory tract.
Despite the strong potential and advantages of directing treatment to the primary location of initial infection, only 4% of studies we cover did so. With focused research, safe, inexpensive, and effective naso/oropharyngeal treatments may be rapidly identified after discovery of new respiratory pathogens.
Many other treatments may be effective including azelastine93,94, astodrimer sodium95-98, benzalkonium chloride99, CDCM100,101, dequalinium chloride99, hypochlorous acid100, hexadecyl pyridinium chloride102, ethyl lauroyl arginate103, Sinomarin61, PCANS104, SA58105-108, ColdZyme109, pHOXWELL110, Panthexyl111, HH-120112,113, TriSb92114, IBIO123115, homoharringtonine116, A8G6117,118, STI-9167119, FSY-ACE2-NVs nanoSpray120, Sentinox121, and saline122.
Naso/oropharyngeal treatments experience regulatory challenges. For example the US FDA shut down a povidone-iodine treatment123 at a time when 7 RCTs indicated efficacy. The FTC sent warning letters to companies that referenced studies showing benefits of nasal/oral hygiene for COVID-19124-126. Similarly, the FDA has failed to approve SaNOtize127, although it is available in many other countries128.
Figure 1. Optimal spray angle may increase nasopharyngeal drug delivery 100x for nasal sprays, adapted from Akash et al.
Targeted treatment to the primary source of initial infection reduces transmission and progression. Clinical studies show that treatments applied to the upper respiratory tract via nasal/oral sprays, rinses, or inhalation can significantly reduce transmission and progression of COVID-19. 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 SanoTize128 (a nitric oxide generating nasal spray available in Israel, Indonesia, Thailand, Singapore, Hong Kong, South Africa, Malaysia, Cambodia, Germany, and India) and NoriZite129 (high viscosity nasal and oral sprays containing iota-carrageenan available in the United Kingdom).
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 acid18.
Protocols typically combine multiple treatments. No single treatment is guaranteed to be effective and safe for a specific individual. Leading evidence-based protocols combine multiple treatments.
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Combined treatments increase efficacy
Monotherapy33% [30‑36%]
Polytherapy68% [57‑77%]
Meta analysis of early treatment studies.
Complementary and synergistic actions. There are many complementary mechanisms of action across treatments, and studies show complementary and synergistic effects with polytherapy130-146. For example, Jitobaom et al.131 showed >10x reduction in IC50 with ivermectin and niclosamide, an RCT by Said et al.138 showed the combination of nigella sativa and vitamin D was more effective than either alone, and an RCT by Wannigama et al.147 showed improved results with fluvoxamine combined with additional treatments, compared to fluvoxamine alone. Treatment efficacy may vary significantly across SARS-CoV-2 variants. For example new variants may gain resistance to targeted treatments148-154, and the role of TMPRSS2 for cell entry differs across variants155. The efficacy of specific treatments varies depending on cell type156 due to differences in viral receptor expression, drug distribution and metabolism, cell-specific mechanisms, and the relevance of drug targets to specific cells. Efficacy may also vary based on genetic variants157-161. Variable efficacy across SARS-CoV-2 variants, cell types, different 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. Meta analysis of all early treatment trials shows 68% [57‑77%] lower risk for studies using combined treatments, compared to 33% [30‑36%] for single treatments.
SARS-CoV-2 evolution and the risk of escape mutants suggests treatments with broader mechanisms of action and polytherapy. SARS-CoV-2 can rapidly acquire mutations altering infectivity, disease severity, and drug resistance even without selective pressure162. Antigenic drift can undermine more variant-specific treatments like monoclonal antibodies and more specific antivirals. Treatment with targeted antivirals may select for escape mutations163. Less variant specific treatments and polytherapy targeting multiple viral and host proteins may be more effective.
Defined as ≥3 studies showing ≥10% improvement or >0% harm with statistical significance in meta analysis.
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.
Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.
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