WO2021214547A1 - Compositions and methods for treating upper respiratory infections - Google Patents
Compositions and methods for treating upper respiratory infections Download PDFInfo
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B21/00—Nitrogen; Compounds thereof
- C01B21/20—Nitrogen oxides; Oxyacids of nitrogen; Salts thereof
- C01B21/24—Nitric oxide (NO)
Definitions
- the present disclosure relates to methods of treating a subject with an infection. Accordingly, this invention involves the fields of chemistry, pharmaceutical sciences, medicine, and other health sciences. BACKGROUND
- Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a strain of Severe Acute Respiratory Syndrome Coronavirus (SARSr-CoV).
- SARS-CoV-2 is a single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). This virus is highly contagious in humans and causes, among other symptoms, respiratory illness that can ultimately result in death. The virus is primarily spread between people through close contact and via respiratory droplets produced from coughs or sneezes. People may also become infected by touching a contaminated surface and then touching their eyes, nose, or mouth. The virus mainly enters human cells by binding to the receptor angiotensin converting enzyme 2 (ACE2). New mechanisms of preventing and treating the COVID-19 condition and other respiratory conditions are being sought.
- ACE2 angiotensin converting enzyme 2
- NO nitric oxide
- FIG. 1 illustrates the difference in the change from baseline in SARS-CoV-2 RNA between the active nitric oxide nasal spray (NONS) group and the placebo (saline) group from day 1 to day 6 in accordance with an example;
- FIG. 2 depicts a total of 80 subjects (40 NONS, 40 Placebo) randomized into the trial and receiving study treatments in accordance with an example;
- FIG. 3 shows a graphical representation of the (log) viral load change from baseline to Days 2, 4, and 6 in accordance with an example;
- FIG. 4 displays a Kaplan Meier curve for the time-to SARS-CoV-2 (log) viral load reduction for threshold 3 achievement at day 2, day 4 and day 6 (ITT Population) in accordance with an example;
- FIG. 5a shows the droplet size distribution for samples 1 to 3 in accordance with an example;
- FIG. 5b shows the droplet size distribution for samples 4 to 6 in accordance with an example
- FIG. 5c shows the droplet size distribution for samples 1 and 4 in accordance with an example
- FIG. 5d shows the droplet size distribution for sample 1 in accordance with an example
- FIG. 5e shows the droplet size distribution for sample 4 in accordance with an example
- FIG. 6a depicts a study dosage regimen in accordance with an example
- FIG. 6b shows a change in total modified Lund Kennedy (MLK) endoscopic score pre and post treatment in accordance with an example
- FIG. 6c shows a change in disease-specific quality of life Sino-Nasal Outcome Test (SNOT-22) pre and post treatment with NOSi in accordance with an example.
- SNOT-22 Sino-Nasal Outcome Test
- subject refers to a mammal that may benefit from the administration of a nitric oxide releasing solution (NORS).
- NORS nitric oxide releasing solution
- NONS nitric oxide nasal spray
- the mammal may be a human.
- the terms “treat,” “treatment,” or “treating” when used in conjunction with the administration of NORS, including when administered as a NONS, including compositions and dosage forms thereof, refers to administration to subjects who are either asymptomatic or symptomatic.
- “treat,” “treatment,” or “treating” can be to reduce, ameliorate or eliminate symptoms associated with a condition present in a subject, or can be prophylactic, (i.e. to prevent or reduce the occurrence of the symptoms in a subject).
- prophylactic treatment can also be referred to as prevention of the condition.
- formulation and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules.
- the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with a carrier or other excipients.
- Compositions can take nearly any physical state, including solid, liquid (i.e. solution), or gas.
- the term “dosage form” can include one or more formulation(s) or composition(s) provided in a format for administration to a subject.
- a composition can be a solution that releases nitric oxide.
- a “kit” can mean a package or container that includes a composition or dosage form along with instructions regarding application or administration of the composition or dosage form according to a given regimen or within specified time and amount parameters to treat one or more specific indications.
- a kit could include a NORS composition in a specific volume or amount along with a set of instructions on appropriate administration of the NORS to a subject in order to treat a given condition (e.g., indication). Instructions may include direction for a single type of administration or indication, or for multiple types of administration or indications.
- the amount and form of the NORS composition in the kit can be suitable for a single administration for treatment of a single indication, multiple administrations creating a regimen for one indication, or single or multiple administrations for multiple indications.
- a composition or dosage form of a NORS composition can be provided as a NONS in the kit along with instructions for applying the dosage form in terms of amount and volume that is suitable to treat a plurality of indications, such as improving immunity in the sinus and throat areas against a viral or bacterial infection, or infections therewith, or associated symptoms.
- NORS refers to a nitric oxide (NO) releasing solution, composition or substance.
- NO released from NORS may be a gas.
- NORS refers to a NORS in the form of a nasal spray (e.g. a nitric oxide nasal spray).
- a “therapeutic agent” refers to an agent that can have a beneficial or positive effect on a subject when administered to the subject in an appropriate or effective amount.
- NO can be a therapeutic agent.
- therapeutic agents can include non-NORS agents with physiologic activity, such as antibiotics, antihistamines, antivirals, antimicrobials, biological molecules, such as siRNA, cDNA, steroids, vasodilators, vasoconstrictors, analgesics, anti-inflammatories, etc.
- therapeutic agent can be used interchangeably with “active agent” or “drug”.
- an “effective amount” of an agent is an amount sufficient to accomplish a specified task or function desired of the agent.
- a “therapeutically effective amount” of a composition, drug, or agent refers to a non-toxic, but sufficient amount of the composition, drug, or agent, to achieve therapeutic results in treating or preventing a condition for which the composition, drug, or agent is known to be effective. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an “effective amount” or a “therapeutically effective amount” may be dependent in some instances on such biological factors.
- a “dosing regimen” or “regimen” such as “treatment dosing regimen,” or a “prophylactic dosing regimen” refers to how, when, how much, and for how long a dose of a composition can or should be administered to a subject in order to achieve an intended treatment or effect.
- daily dose refers to the amount of active agent administered to a subject over a 24-hour period of time.
- the daily dose can be administered in one or more administrations during the 24-hour period.
- the daily dose provides for 2-6 administrations in a 24-hour period.
- an “acute” condition refers to a condition that can develop rapidly and have distinct symptoms needing urgent or semi-urgent care.
- a “chronic” condition refers to a condition that is typically slower to develop and lingers or otherwise progresses over time.
- Some examples of acute conditions can include without limitation, an asthma attack, bronchitis, a heart attack, pneumonia, and the like.
- Some examples of chronic conditions can include without limitation, arthritis, diabetes, hypertension, high cholesterol, and the like.
- release and “release rate” are used interchangeably to refer to the discharge or liberation, or rate thereof, of a substance, including without limitation a therapeutic agent, such as NO, from the dosage form or composition containing the substance.
- a therapeutic agent such as NO
- a therapeutic agent may be released in vitro.
- a therapeutic agent may be released in vivo.
- immediate release or “instant release” can be used interchangeably and refer to immediate or near immediate (i.e. uninhibited or unrestricted) release of an agent or substance, including a therapeutic agent, such as NO, from a composition or formulation.
- a therapeutic agent such as NO
- controlled release refers to non-immediate release of an agent or substance, including a therapeutic agent, such as NO, from a composition or formulation.
- a therapeutic agent such as NO
- Examples of specific types of controlled release include without limitation, extended or sustained release and delayed release. Any number of control mechanisms or components can be used to create a controlled release effect, including formulation ingredients or constituents, formulation properties or states, such as pH, an environment in which the formulation is placed, or a combination of formulation ingredients and an environment in which the formulation is placed.
- extended release can include release of a therapeutic agent at a level that is sufficient to provide a therapeutic effect or treatment for a non-immediate specified or intended duration of time.
- module refers to any change in biological state, i.e. increasing, decreasing, and the like.
- baseline refers to a level or concentration of the substance in a subject prior to administration of an active agent.
- baseline level of viral RNA load in a subject would the subject’s viral RNA load prior (e.g. just prior) to the commencement of NORS administration or therapy.
- the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
- an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
- the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
- the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result.
- compositions that is “substantially free of” particles would either completely lack particles, or so nearly completely lack particles that the effect would be the same as if it completely lacked particles.
- a composition that is “substantially free of” an ingredient or element may still actually contain such item as long as there is no measurable effect thereof.
- the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. Unless otherwise stated, use of the term “about” in accordance with a specific number or numerical range should also be understood to provide support for such numerical terms or range without the term “about”. For example, for the sake of convenience and brevity, a numerical range of “about 50 ml to about 80 ml” should also be understood to provide support for the range of “50 ml to 80 ml.” Furthermore, it is to be understood that in this specification support for actual numerical values is provided even when the term “about” is used therewith. For example, the recitation of “about” 30 should be construed as not only providing support for values a little above and a little below 30, but also for the actual numerical value of 30 as well.
- comparative terms such as “increased,” “decreased,” “better,” “worse,” “higher,” “lower,” “enhanced,” “improved,” “maximized,” “minimized,” and the like refer to a property of a device, component, composition, biologic response, biologic status, or activity that is measurably different from other devices, components, compositions, biologic responses, biologic status, or activities that are in a surrounding or adjacent area, that are similarly situated, that are in a single device or composition or in multiple comparable devices or compositions, that are in a group or class, that are in multiple groups or classes, or as compared to an original (e.g. untreated) or baseline state, or the known state of the art.
- a composition that “decreases” viral load provides a viral load in a subject that is lower as compared to a viral load at a previous point in time, such as a baseline level (e.g. prior to treatment), or as compared to an earlier treatment with a different dose (e.g. lower dose).
- a baseline level e.g. prior to treatment
- a different dose e.g. lower dose
- COVID-19 coronavirus disease 2019 (COVID-19) is wide, ranging from no symptoms, mild signs of upper respiratory tract infection, to severe pneumonia and death.
- COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. It is a single-stranded, positive-sense, RNA virus, which has a similar receptor-binding domain structure to that of SARS-CoV and MERS- CoV. The virus is transmitted via airborne droplets to the nasal mucosa. Rapid viral reproduction occurs within these cells and viral shedding into nasal secretions and sputum causes disease of the lower respiratory tract potentially causing fatal viral pneumonia.
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- MERS- CoV MERS- CoV
- Sputum may continue to contain the virus for almost 2 weeks after recovery and the disease can spread before onset of symptoms, during the symptomatic period and even after recovery.
- Infection of epithelial cells by the SARS-CoV-2 virus uses angiotensin converting enzyme 2 (ACE-2) as a receptor for cellular entry which is highly expressed in the nose.
- ACE-2 angiotensin converting enzyme 2
- the binding affinity of the Spike protein to its cognate receptor ACE-2 is a major determinant of the SARS-CoV replication rate and disease severity.
- Nitric oxide is a free radical gas molecule that plays a major role in innate immunity, mammalian host defense against infection, modulation of wound healing, vasodilation, neurotransmission and angiogenesis. NO has been reported to have antimicrobial activity against bacteria, yeast, fungi, and viruses both in vitro and in vivo in animal studies. NO also prevents the fusion between the Spike protein and ACE-2. Together, the antiviral and ACE-2 inhibitory effects of NO qualify it for a potential molecule to prevent and/or to minimize the severity of COVID-19 infections.
- NORS provides antimicrobial chemical characteristics (in a solution) that can be equivalent to hours of exposure of 160 ppm NO gas.
- the NORS formulation has been developed and evaluated to enable a safe dose for host cells and can have a rapid microbicidal effect (within seconds) against bacterial, fungal and viral pathogens.
- the present disclosure relates to the discovery that a liquid nitric oxide releasing solution (NORS) is effective in killing or otherwise deactivating SARS-CoV-2 and upper respiratory tract infections. Accordingly, it is thought that NORS can be used for the purpose of treating, preventing, or reducing its infection of individuals.
- NNS liquid nitric oxide releasing solution
- a method of treating a subject for infection with a Severe Acute Respiratory Syndrome Coronavirus can include administering a therapeutically effective amount of a nitric oxide releasing solution (NORS) to the subject.
- a method of minimizing subject-to-subject transmissibility for a pathogen can include administering a therapeutically effective amount of a nitric oxide releasing solution (NORS) to the subject.
- a method of treating a subject for infection of a pathogen in an upper respiratory tract can include administering a therapeutically effective amount of a nitric oxide releasing solution (NORS) to the subject as a spray having an average droplet volume which contains treatment within the upper respiratory tract.
- a nitric oxide releasing solution can include at least one nitric oxide releasing compound and at least one acidifying agent.
- the NORS can release a therapeutically effective amount as a spray having an average droplet volume which contains treatment within the upper respiratory tract
- a nitric oxide releasing solution can include at least one nitric oxide releasing compound and at least one acidifying agent.
- the NORS can be released as a spray having an average droplet volume which contains treatment within the upper respiratory tract or airway.
- the NORS can provide release (e.g. an extended release) of gaseous nitric oxide (gNO) when administered to a situs.
- extended release it is meant that an effective amount of NO gas is released from the formulation at a controlled rate such that therapeutically beneficial levels (but below toxic levels) of gNO are maintained over an extended period of time, ranging from, e.g., about 5 seconds to about 24 hours, thus, providing, for example, a 30 to 60 minute, or several hour, dosage form.
- the NO gas is released over a period of at least 30 minutes. In a further embodiment, the NO gas is released over a period of at least 1 hour, or from about 1.5 hours to about 3 hours. In another embodiment, the NO gas is released over a period of at least 8 hours. In another embodiment, the NO gas is released over a period of at least 12 hours. In another embodiment, the NO gas is released over a period of at least 24 hours.
- An extended release NORS is beneficial in that the solution can be administered to a situs over a short period of time, while the release of NO from the solution continues following administration.
- the solution of the present invention becomes active when the nitrites and acids mix in saline or water in which the pH of the solution is below about 4.0 and exhibits an increased or enhanced production level of nitric oxide gas over an extended period of time.
- the pH of the active state of the nitric oxide releasing solution is between a pH of about 1.0 and a pH of about 4.0.
- the pH of the active state of the nitric oxide releasing solution is between a pH of about 3.0 and a pH of about 4.0.
- the pH is about 3.2.
- the pH is about 3.4.
- the pH is about 3.5.
- the pH is about 3.6.
- the pH is about 3.7.
- the pH is about 4.0.
- the pH is below about 4.0.
- the nitric oxide releasing solution of the present invention is not active until the acid interacts with the nitrites in liquid, the nitrite solution can be pre-made, transported and set up for administration while in its dormant state (pH greater than 4.0), without producing any appreciable nitric oxide gas or without losing its ability to produce an effective amount of nitric oxide gas. Then, when a user is ready to deliver or administer the solution for treatment of a human subject, the solution can be activated immediately prior to administration to the human subject by the addition of an acid (pH driven below 4.0), thereby maximizing the amount of nitric oxide gas produced by the administered dosage of solution.
- an acid pH driven below 4.0
- the pH of the solution can be lowered via addition of at least one acidifying agent into the solution.
- Introduction of the acidifying agent drives the solution reaction towards the reactants, thus reducing the pH (creating more acid), which in turn creates more nitric oxide gas.
- an acidifying agent for example an acid
- the nitric oxide releasing solution includes the use of a water or saline-based solution and at least one nitric oxide releasing compound, such as nitrite or a salt thereof.
- the solution is a saline-based solution.
- the nitric oxide releasing compound is a nitrite, a salt thereof, and any combinations thereof.
- Non-limiting examples of nitrites include salts of nitrite such as sodium nitrite, potassium nitrite, barium nitrite, and calcium nitrite, mixed salts of nitrite such as nitrite orotate, and nitrite esters such as amyl nitrite.
- the nitric oxide releasing compound is selected from the group consisting of sodium nitrite and potassium nitrite, and any combinations thereof. In another embodiment, the nitric oxide releasing compound is sodium nitrite. In one embodiment, the solution is comprised of sodium nitrite in a saline solution. In another embodiment, the solution is comprised of potassium nitrite in a saline solution.
- the concentration of nitrites in the solution is between 0.07% w/v and about 0.5% w/v. In one embodiment, the concentration of nitrites in the solution is no greater than about 0.5% w/v. In another embodiment, the concentration of nitrites in the solution is about 0.41% w/v. In another embodiment, the concentration of nitrites in the solution is between about 0.07-0.5% w/v. As used herein, the term "w/v" refers to the (weight of solute/volume of solution) x 100%.
- the acidifying agent can be any suitable acidifying agent. As described elsewhere here, the addition of at least one acidifying agent to the solution of the present invention contributes toward increased production of NO.
- the acidifying agent is an acid, such as an inorganic or an organic acid.
- acids include ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, and phosphoric acid acetic acid and the like.
- the acid is selected from the group consisting of ascorbic acid, citric acid, malic acid, hydrochloric acid, and sulfuric acid, and any combinations thereof.
- the acid is citric acid.
- the amount of acidifying agent present in the solution can affect the rate of the reaction to produce NO.
- the amount of acidifying agent is no greater than about 0.5% w/v.
- the amount of acidifying agent is about 0.5% w/v.
- the amount of acidifying agent is about 0.2% w/v.
- the amount of acidifying agent is about 0.07% w/v.
- the amount of acidifying agent is between about 0.07-0.5% w/v.
- the acidifying agent can provide a low pH-level that reduces viral load (e.g., viral load of the SARS-CoV-2 virus).
- the increase in NO compared to baseline levels before treatment can also block viral access (e.g., SARS-CoV-2 viral access) to the host cell by enveloping epithelial cells with a physical barrier.
- the NO can further block viral access (e.g., SARS-CoV-2 access) to host cells through the ACE-2 receptors.
- the NORS may release an effective or therapeutically effective concentration of NO.
- the concentration of NO is between about 100 ppb and about 1000 ppm.
- the concentration of NO is between about 120 ppb and about 400 ppb.
- the therapeutically effective concentration of NO can be about 160 ppb.
- the concentration of NO is between about 100 ppb and 1000 ppb.
- the concentration of NO is between about 100 ppb and 500 ppb.
- the concentration of NO is between about 100 ppb and 300 ppb.
- the nitric oxide releasing solution can comprise a thickener, such as polyacrylic acids (e.g. Carbopols, for example), gelatin, pectin, tragacanth, methyl cellulose, hydroxylethylcellulose, hydroxypropylcellulose, HPMC, CMC, alginate, starch, polyvinyl alcohol, polyvinyl pyrrolidone, co-polymers of polyoxyethylene and polyoxypropylene, polyethylene glycol, the like, or combinations thereof.
- the thickener can comprise hydroxypropyl methylcellulose (HPMC).
- the nitric oxide releasing solution can comprise a preservative.
- preservatives can include ascorbic acid, acetylcysteine, bisulfite, metabisulfite, monothioglycerol, phenol, meta-cresol, benzyl alcohol, methyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, benzethonium chloride, butylated hydroxyl toluene, myristyl gamma-picolimium chloride, 2-phenoxyethanol, phenyl mercuric nitrate, chlorobutanol, thimerosal, tocopherols, the like, or combinations thereof.
- the nitric oxide releasing solution can comprise a tonicity agent.
- tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, mannitol, sorbitol, dextrose, glycerin, propylene glycol, ethanol, trehalose, phosphate-buffered saline (PBS), Dulbecco’s PBS, Alsever’s solution, Tris-buffered saline (TBS), water, balanced salt solutions (BSS), such as Hank’s BSS, Earle’s BSS, Grey’s BSS, Puck’s BSS, Simm’s BSS, Tyrode’s BSS, and BSS Plus, the like, or combinations thereof.
- PBS phosphate-buffered saline
- BSS balanced salt solutions
- the tonicity agent can have sufficient NaCl to create an isotonic saline solution (e.g., 0.9% NaCl).
- the tonicity of the composition can be from about 250 to about 350 milliosmoles/liter (mOsm/L). In another aspect, the tonicity of the composition can be from about 277 to about 310 mOsm/L.
- the NORS may be administered in a variety of forms.
- the NORS may be administered as a liquid, a spray, a vapor, micro-droplets, mist, gargle, lavage, aerosol, or any form which provides the release of nitric oxide from the solution.
- the NORS is administered as a spray.
- the amount or dosing volume of administered nitric oxide releasing solution may be varied in order to maximize the duration of nitric oxide production and delivery.
- the amount of nitric oxide releasing solution administered is between about 0.1 mL and 5000 mL.
- the amount of nitric oxide releasing solution administered is between about 10 mL and 1000 mL.
- the nitric oxide releasing solution may be readministered one or more times, as used to effectively treat the situs.
- the amount of administered nitric oxide releasing solution can be from about 100 ⁇ l to about 1000 ⁇ l for each actuation of a spray device.
- the amount of administered nitric oxide releasing solution can be actuated from 1 to 6 times for each administration to provide a total amount per administration of from about 100 ⁇ l to about 5000 ⁇ l.
- the amount of administered nitric oxide releasing solution can be from about 100 ⁇ l to about 200 ⁇ l for each actuation of a spray device.
- 100 ⁇ l to about 200 ⁇ l of NORS can be actuated 1 to 4 times for each administration to provide a total amount per administration of from about 100 ⁇ l to about 800 ⁇ l.
- the amount of administered nitric oxide releasing solution can be from about 120 ⁇ l to about 140 ⁇ l for each actuation of a spray device.
- 120 ⁇ l to about 140 ⁇ l of NORS can be actuated 2 to 4 times for each administration to provide a total amount per administration of from about 240 ⁇ l to about 560 ⁇ l.
- the amount of administered nitric oxide releasing solution can be from about 50 mL to about 500 mL. In one aspect, the amount of administered nitric oxide releasing solution can be from about 100 mL to about 400 mL. In another aspect, the amount of administered nitric oxide releasing solution can be from about 150 mL to about 350 mL.
- the amount of administered nitric oxide releasing solution can be from about 5 mL to about 50 mL. In one aspect, the amount of administered nitric oxide releasing solution can be from about 10 mL to about 40 mL. In another aspect, the amount of administered nitric oxide releasing solution can be from about 10 mL to about 30 mL.
- the NORS can be administered according to various dosage regimens.
- the NORS can be administered to the subject according to a dosage regimen of 1 to 6 times per day for a duration of from about a single day to about 2 weeks.
- the NORS can be administered to the subject according to a dosage regimen of 4 to 6 times per day for a duration of from about a single day to about 2 weeks.
- the NORS can be administered to the subject according to a dosage regimen of 5 to 6 times per day for a duration of from about a single day to about 2 weeks.
- the NORS can be administered to the subject according to a dosage regimen of 5 to 6 times per day for a duration of from about 1 day to about 9 days.
- the NORS can be administered to a subject in varying dosage amounts.
- the NORS can be administered to the subject at a single dose of from about 300 ⁇ l of NORS to about 700 ⁇ l of NORS.
- the NORS can be administered to the subject at a single dose of from about 400 ⁇ l of NORS to about 600 ⁇ l of NORS.
- the NORS can also be administered to a subject at a daily dose.
- the NORS can be administered to the subject at a daily dose of from about 1500 ⁇ l of NORS to about 4200 ⁇ l of NORS.
- the NORS can be administered to the subject at a daily dose of from about 2000 ⁇ l of NORS to about 3600 ⁇ l of NORS.
- the nitric oxide releasing solution is prepared just prior to administration to the situs through the administration of an acidifying agent to a dormant solution.
- administration of the acidifying agent to the dormant solution results in the lowering of the pH of the dormant solution, thereby activating the nitric oxide releasing solution to be administered to the treatment site.
- the nitric oxide releasing solution provides for extended production of nitric oxide.
- the nitric oxide releasing solution produces nitric oxide for a period of between 1 minute and 24 hours. In one embodiment, the nitric oxide releasing solution produces nitric oxide for a period of between 10 and 45 minutes. In one embodiment, the nitric oxide releasing solution produces nitric oxide for at least 15 minutes. In one embodiment, the nitric oxide releasing solution produces nitric oxide for at least 30 minutes. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 1 hour. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 4 hours.
- the nitric oxide releasing solution produces nitric oxide for at least 8 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 12 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 24 hours.
- the NORS can be administered to an afflicted situs.
- the afflicted situs can be an upper respiratory tract or upper airway of the subject. In another aspect, the afflicted situs can be a mucosal membrane.
- the NORS can be administered to a subject’s nasal passage or sinus and the NORS can be administered as a sprayed solution or as a lavage.
- the mucosal membrane is a conjunctival mucosa of the subject
- the NORS can be administered as an ophthalmic solution.
- the afflicted situs is a mucosal membrane and the mucosal membrane is a subject’s mouth or throat
- the NORS can be administered to the afflicted situs as a gargle solution.
- NORS can be administered to a site that is different from, including distal from, an afflicted situs, but which location still allows NO to reach the intended treatment site or afflicted situs to have a therapeutic effect.
- the NORS when administered as a spray, a lavage, or a gargle, the NORS may not be administered to the upper airway of a subject, but can reach the upper airway to have a therapeutic effect.
- nitric oxide releasing solution is directly administered into the upper respiratory tract of a subject.
- the nitric oxide releasing solution is sprayed into the upper respiratory tract of the subject.
- the solution may be administered into the upper respiratory tract of the subject once an hour, once a day, once a week, once every two weeks, once a month, once every two months, once a year, and any and all ranges therebetween as used to treat the subject.
- the solution is sprayed once a week.
- the solution is sprayed once a week for four consecutive weeks.
- the nitric oxide releasing solution provides for extended nitric oxide production, thereby providing continuous delivery of therapeutic nitric oxide to the upper respiratory infection of the subject.
- a nitric oxide releasing solution can include at least one nitric oxide releasing compound and at least one acidifying agent.
- the NORS can release a therapeutically effective amount as a spray having an average droplet volume which contains treatment within an upper respiratory tract.
- the spray can have a median droplet size (Dv50) of greater than one or more of 100 ⁇ m , 150 ⁇ m , 200 ⁇ m , 250 ⁇ m , 300 ⁇ m , 350 ⁇ m , 400 ⁇ m , 450 ⁇ m , 500 ⁇ m , 550 ⁇ m , or 600 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv50 median droplet size
- the spray can have a percentage of spray by volume at droplet sizes of less than 10 ⁇ m (% ⁇ 10 ⁇ m ) of less than one or more of: 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% when measured a 30 mm or 60 mm distance from actuation.
- the spray can have a percentage of spray by volume at droplet sizes of less than 5 ⁇ m (% ⁇ 5 ⁇ m ) of less than one or more of: 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% when measured a 30 mm or 60 mm distance from actuation.
- the spray can have a 10 th percentile by volume of spray (Dv(10)) of greater than one or more of 100 ⁇ m , 150 ⁇ m , 200 ⁇ m , 250 ⁇ m , 300 ⁇ m , 350 ⁇ m , or 400 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv(10) 10 th percentile by volume of spray
- the spray can have a 90 th percentile by volume of spray (Dv(90)) of greater than one or more of 500 ⁇ m , 550 ⁇ m , 600 ⁇ m , 650 ⁇ m , 700 ⁇ m , 750 ⁇ m , 800 ⁇ m , 850 ⁇ m , 900 ⁇ m , 950 ⁇ m , or 1000 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- the spray can have a droplet size distribution of about 0.5 to about 2.0 (the droplet size distribution can be defined as (Dv(90) - Dv(10))/Dv(50)).
- the duration of administering the nitric oxide releasing solution to the subject may be varied in order to maximize delivery.
- the nitric oxide releasing solution is administered over a time period of less than 5 seconds.
- the nitric oxide releasing solution is administered over a time period of about 5 seconds.
- the nitric oxide releasing solution is administered over a time period of about 30 seconds.
- the nitric oxide releasing solution is administered over a time period of about 1 minute to about 20 minutes.
- Acute Respiratory Syndrome Coronavirus can include administering a therapeutically effective amount of a nitric oxide releasing solution (NORS) to the subject.
- NORS nitric oxide releasing solution
- the NORS can be administered to the subject when the subject is asymptomatic.
- the NORS can be administered to the subject when displaying mild symptoms of SARS-CoV-2 infection.
- the NORS can be administered to the subject when displaying moderate symptoms of SARS-CoV-2 infection.
- the NORS can be administered to the subject when displaying severe symptoms of SARS-CoV-2 infection.
- the NORS can be administered to the subject when displaying critical symptoms of SARS-CoV-2 infection.
- a subject can be asymptomatic when the subject does not display mild, moderate, severe, or critical symptoms.
- a subject can display mild symptoms when the subject has non-pneumonia or mild pneumonia with no chest pain or shortness of breath, where pneumonia is defined as ‘inflammation of one or both lungs.’ Mild symptoms could include but were not limited to fever (>37.2 C), dry cough, tiredness, sore throat, malaise, headache, muscle pain, lack of taste or smell, and gastrointestinal symptoms.
- a subject can display moderate symptoms when there is clinical or radiographic evidence of lower respiratory tract disease and when oxygen saturation is greater than or equal to 94%.
- a subject can display server symptoms when oxygen saturation is less than 94%, the respiratory rate is greater than or equal to 30 breaths -minute, and the lung has been infiltrated by greater than 50%.
- a subject can display critical symptoms when there is respiratory failure, shock, or multiorgan dysfunction or failure.
- administering a therapeutically effective amount of NORS to the subject can reduce the duration and severity of symptoms compared to the duration of the symptoms when NORS is not administered to a subject.
- administering the therapeutically effective amount of NORS can provide these benefits by reducing the viral load of the subject.
- the NORS can be administered to the subject within a selected number of days of an identified first-person exposure. In another aspect, the NORS can be administered to the subject without an identified first-person exposure.
- the NORS can be administered to the subject when displaying acute symptoms of SARS-CoV-2 infection. In another aspect, the NORS can be administered to the subject when displaying chronic symptoms of SARS-CoV-2 infection.
- Treatment of a respiratory disease by way of the present invention can comprise the delivery of a nitric oxide releasing solution into the upper respiratory tract of the subject to be treated.
- the nitric oxide releasing solution may be injected, sprayed, inhaled, or instilled into the respiratory tract of the subject.
- the nitric oxide releasing solution may be administered to the respiratory tract of the subject using a nitric oxide nasal spray (NONS) via the nasal cavity or oral cavity of the subject.
- NONS nitric oxide nasal spray
- the nitric oxide releasing solution is sprayed into the upper respiratory tract of the subject. In one embodiment, the solution is administered to the subject intranasally. In one embodiment, the solution is administered to the sinuses.
- the nitric oxide releasing solution provides for extended nitric oxide production, thereby providing continuous delivery of therapeutic nitric oxide to the upper respiratory tract of the subject.
- the method can comprise the treatment, prevention, or reduction of incidence of a virally induced condition.
- the virally induced condition can be caused by or associated with one or more of: adenovirus, influenza, enteroviruses, human metapneumoviruses, astrovirus, rhinovirus, respiratory syncytial virus, parainfluenza, severe acute respiratory syndrome (SARS), coronavirus, H1N1, H2N2, H3N2, H1N1pdm09, or combinations thereof.
- the virally induced condition can be caused by or associated with one or more of human coronavirus 229E, human coronavirus OC43, human coronavirus HKU1, human coronavirus NL63, MERS- coronavirus, human respirovirus 1, human rubulavirus 2, human respirovirus 3, human rubulavirus 4, human enterovirus, human respiratory virus, rhinovirus A, rhinovirus B, rhinovirus C, or combinations thereof.
- influenza can be any of Influenza A, Influenza B, Influenza C, or Influenza D.
- the method can comprise the treatment, prevention, or reduction of incidence of a bacterial condition.
- the bacterial condition can be one or more of: Bacillus, Bartonella, Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Corynebacterium, Enterococcus, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Ureaplasma, Vibrio, Yersinia, the like, and combinations thereof.
- the method can comprise the treatment, prevention, or reduction of incidence of a fungal condition.
- the fungal condition can be caused by a fungus selected from a genus including: Aspergillus, Histoplasma, Pneumocystis, Stachybotrys , the like, and combinations thereof.
- the method comprises the treatment, prevention, or reduction of incidence of a Severe Acute Respiratory Syndrome Coronavirus (SARSr- CoV).
- administration of NORS can treat, prevent, or reduce the incidence of SARS-CoV-2 or a variant thereof.
- the SARS-CoV-2 virus can be one or more of: Lineage A (also termed as the sequence WIV04/2019), Cluster 5 (also termed as the ⁇ FVI-spike by the Danish State Serum Institute), Lineage B.1.1.7 (also termed as the UK variant, the variant under investigation (VUI) 202012/01, or 20I/501Y.V1), B.1.1.7 with E484K (also termed as the variant of concern 202102/02 (VOC 202102/02), Lineage B.1.1.207 , Lineage B.1.1.317, Lineage B.1.1.318 (VUI- 202102/04), Lineage B.1.351 (also termed as the 501.V2 variant, 20H/501Y.V2, or variant of concern (VOC-202012/02), Lineage B.1.429/CAL.20C, Lineage B.1.525 (also termed as VUI-202102/03 and formerly termed as UK 1188), Lineage P.1 (VOC 202101/02), Lineage B.1.427
- administration of NORS can provide a treatment, prevention, or reduction of incidence of SARS-CoV-2 or a variant thereof that can be substantially equally effective for treating one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage P.l, Lineage B.1.427, Lineage B.1.526, Lineage P.2, or a combination thereof.
- administration of NORS can be substantially equally effective in treating SARS-CoV-2 or a variant thereof when the viral load of SARS-CoV-2 or the variant is reduced by more than 80%, 90%, or 95%, or 99% in a subject within 24 hours, or 48 hours, or 72 hours, or 96 hours, or 120 hours, or 148 hours of treatment compared to a baseline viral load of SARS-CoV-2 or the variant before the commencement of treatment for SARS-CoV-2 or for the variant.
- the NORS can reduce the viral load compared to a baseline level.
- the therapeutically effective amount of the NORS can reduce a viral RNA load compared to a baseline level by greater than one or more of: 80%, 90%, 95%, or 99% after a treatment duration of one or more of: 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days.
- the NORS can reduce the viral load through various mechanisms.
- the NORS can provide a low pH (e.g., a pH of about 3.5) that can reduce the viral load (e.g., SARS-CoV-2 viral load).
- the NORS can provide a physical barrier over epithelial cells of the subject that can prevent access of the virus to the host cells of the subject.
- the NORS can provide a physical barrier that prevents the SARS-CoV-2 virus from accessing host cells of the subject.
- the NORS can provide an angiotensin- converting enzyme 2 (ACE-2) receptor blocking agent.
- ACE-2 an angiotensin- converting enzyme 2
- NORS can also be used in a method of minimizing subject-to-subject transmissibility for a pathogen.
- a therapeutically effective amount of a nitric oxide releasing solution (NORS) can be administered to a subject.
- the NORS can be administered to the subject before or after exposure of the subject to the pathogen.
- the NORs can also be administered to the subject before or after exposure of the subject to a person displaying symptoms of the pathogen.
- the pathogen can include any pathogen disclosed herein.
- the pathogen can be a Severe Acute Respiratory Syndrome Coronavirus (SARSr-CoV) or a variant thereof.
- SARSr-CoV can be a SARS-CoV-2 virus including one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage P.1, Lineage B.1.427, Lineage B.1.526, Lineage P.2, the like, or a combination thereof.
- the therapeutically effective amount of the NORS can be substantially equally effective for minimizing subject-to-subject transmissibility for a a Severe Acute Respiratory Syndrome Coronavirus (SARSr-CoV) or a variant thereof including one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage P.1, Lineage B.1.427, Lineage B.1.526, Lineage P.2, the like, or a combination thereof.
- SARSr-CoV Severe Acute Respiratory Syndrome Coronavirus
- the NORS can minimize subject-to-subject transmissibility by reducing the viral load of the pathogen.
- the therapeutically effective amount of the NORS can reduce a viral RNA load compared to a baseline level by greater than one or more of: 80%, 90%, 95%, or 99% after a treatment duration of one or more of: 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days.
- the NORS can reduce the viral load through various mechanisms discussed herein including a low pH, a physical barrier over epithelial cells of the subject that prevents viral access to host cells of the subject, or an ACE-2 receptor blocking agent.
- method of treatment can involve NORS that can be constrained to an upper airway of a subject.
- a method of treating a subject for infection of a pathogen in an upper respiratory tract can comprise administering a therapeutically effective amount of a nitric oxide releasing solution (NORS) to the subject as a spray (e.g. from aNONS) having an average droplet volume which contains treatment within the upper respiratory tract.
- NORS nitric oxide releasing solution
- Droplet size can be controlled by employing specific structures with the NONS.
- the NORS can remain in the nasal cavity and upper airways without substantial dispersion into the lungs of the subject. In such a case, there may be no detectable systemic increase in NO metabolites (e.g., methemoglobin) when NORS has been administered to the subject.
- the method can comprise providing a median droplet size (Dv50) of greater than one or more of 100 ⁇ m , 150 ⁇ m , 200 ⁇ m , 250 ⁇ m , 300 ⁇ m , 350 ⁇ m , 400 ⁇ m , 450 ⁇ m , 500 ⁇ m , 550 ⁇ m , or 600 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv50 median droplet size
- the distribution of droplet size can be minimal below a certain value.
- the method can comprise providing a percentage of spray by volume at droplet sizes of less than 10 ⁇ m (% ⁇ 10 ⁇ m ) of less than one or more of:
- the method can comprise providing a percentage of spray by volume at droplet sizes of less than 5 ⁇ m (% ⁇ 5 ⁇ m ) of less than one or more of:
- the distribution of droplet size can be bounded at the 10 th percentile and the 90 th percentile.
- the method can comprise providing a 10 th percentile by volume of spray (Dv(10)) of greater than one or more of 100 ⁇ m , 150 ⁇ m , 200 ⁇ m , 250 ⁇ m , 300 ⁇ m , 350 ⁇ m , or 400 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv(10) 10 th percentile by volume of spray
- the method can comprise providing a 90 th percentile by volume of spray (Dv(90)) of greater than one or more of 500 ⁇ m , 550 ⁇ m , 600 ⁇ m , 650 ⁇ m , 700 ⁇ m , 750 ⁇ m , 800 ⁇ m , 850 ⁇ m , 900 ⁇ m , 950 ⁇ m , or 1000 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- the span of the distribution of the droplet size can be calculated from the 90 th percentile droplet size, the 10 th percentile droplet size, and the median droplet size.
- the method can comprise providing a droplet size distribution of about 0.5 to about 2.0, wherein the droplet size distribution is: (Dv(90) - Dv(10))/Dv(50).
- a composition for use in treating a subject for infection with a Severe Acute Respiratory Syndrome Coronavirus (SARSr-CoV) can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject.
- a composition for use in minimizing subject-to-subject transmissibility for a pathogen can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject.
- NNS nitric oxide releasing solution
- a composition for use in treating a subject for infection of a pathogen in an upper respiratory tract can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject as a spray having an average droplet volume which contains treatment within the upper respiratory tract.
- NOS nitric oxide releasing solution
- the use of a pharmaceutical composition for the manufacture of a medicament for treating a subject for infection with a Severe Acute Respiratory Syndrome Coronavirus can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject.
- a pharmaceutical composition for the manufacture of a medicament for minimizing subject-to-subject transmissibility for a pathogen can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject.
- a pharmaceutical composition for the manufacture of a medicament for treating a subject for infection of a pathogen in an upper respiratory tract can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject as a spray having an average droplet volume which contains treatment within the upper respiratory tract.
- NNS nitric oxide releasing solution
- a method of treating a SARS-CoV-2 virus can comprise administering an effective amount of a nitric oxide releasing solution (NORS) to a location where the SARS-CoV-2 virus resides.
- NNS nitric oxide releasing solution
- the SARS-CoV-2 virus can reside on an exposed surface of an object.
- the SARS-CoV-2 virus can reside on an exterior surface of a subject. [00117] In one example, the SARS-CoV-2 virus can reside within a tissue of a subject.
- the tissue can be a mucosal tissue.
- the SARS-CoV-2 virus can be one or more of: Lineage A,
- the effective amount of the NORS can be substantially equally effective for treating one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage P.1, Lineage B.1.427, Lineage B.1.526, Lineage P.2, or a combination thereof.
- a method of treating a subject for infection with a Severe Acute Respiratory Syndrome Coronavirus can comprise administering a therapeutically effective amount of a nitric oxide releasing solution (NORS) to the subject.
- SARSr-CoV Severe Acute Respiratory Syndrome Coronavirus
- the method can comprise administering the NORS to the subject when the subject is asymptomatic.
- the method can comprise administering the NORS to the subject within a selected number of days of an identified first-person exposure.
- the method can comprise administering the NORS to the subject without an identified first-person exposure.
- the method can comprise administering the NORS to the subject when displaying mild symptoms of SARS-CoV-2 infection.
- the method can comprise administering the NORS to the subject when displaying moderate symptoms of SARS-CoV-2 infection.
- the method can comprise administering the NORS to the subject when displaying severe symptoms of SARS-CoV-2 infection.
- the method can comprise administering the NORS to the subject when displaying critical symptoms of SARS-CoV-2 infection.
- the method can comprise administering the NORS to the subject according to a dosage regimen of 1 to 6 times per day for a duration of from about a single day to about 2 weeks.
- the method can comprise administering the NORS to the subject at a single dose of from about 300 ul of NORS to about 700 ul of NORS. [00131] In one example, the method can comprise administering the NORS to the subject at a single dose of from about 400 ul of NORS to about 600 ul of NORS.
- the method can comprise administering the NORS to the subject at a daily dose of from about 1500 ul of NORS to about 4200 ul of NORS.
- the method can comprise administering the NORS to the subject at a daily dose of from about 2000 ul of NORS to about 3600 ul of NORS.
- the therapeutically effective amount of the NORS can reduce a viral RNA load compared to a baseline level by greater than one or more of: 80%, 90%, 95%, or 99% after a treatment duration of one or more of: 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days.
- the therapeutically effective amount of the NORS can: provide a low pH that reduces SARS-CoV-2 viral load, or provide a physical barrier over epithelial cells of the subject that prevents SARS-CoV-2 access to host cells of the subject, or provide an angiotensin-converting enzyme 2 (ACE-2) receptor blocking agent.
- ACE-2 an angiotensin-converting enzyme 2
- the NORS can be administered to an afflicted situs.
- the afflicted situs can be an upper respiratory tract of the subject.
- the afflicted situs can be a mucosal membrane.
- the mucosal membrane can be a subject's nasal passage or sinus and the NORS is administered as a sprayed solution or as a lavage.
- the mucosal membrane can be a subject's mouth or throat and the NORS is administered as a gargle solution.
- the virus can be a SARS-CoV-2 virus or a variant thereof.
- the SARS-Co-V-2 virus or the variant thereof can be one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage Rl, Lineage B.1.427, Lineage B.1.526, Lineage P.2, or a combination thereof.
- the therapeutically effective amount of the NORS can be substantially equally effective for treating one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage P.1, Lineage B.1.427, Lineage B.1.526, Lineage R2, or a combination thereof.
- a method of minimizing subject-to-subject transmissibility for a pathogen can comprise administering a therapeutically effective amount of a nitric oxide releasing solution (NORS) to the subject.
- NNS nitric oxide releasing solution
- the method can comprise administering the NORS to the subject before or after exposure of the subject to the pathogen.
- the method can comprise administering the NORS to the subject before or after exposure of the subject to a person displaying symptoms of the pathogen.
- the pathogen can be a Severe Acute Respiratory Syndrome Coronavirus (SARSr-CoV) or a variant thereof.
- SARSr-CoV Severe Acute Respiratory Syndrome Coronavirus
- the Severe Acute Respiratory Syndrome Coronavirus can be a SARS-CoV-2 virus including one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage P.1, Lineage B.1.427, Lineage B.1.526, Lineage P.2, or a combination thereof.
- SARSr-CoV-2 virus including one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage P.1, Lineage B.1.427, Lineage B.1.526, Lineage P.2, or a combination thereof.
- the therapeutically effective amount of the NORS can be substantially equally effective for minimizing subject-to-subject transmissibility for a a Severe Acute Respiratory Syndrome Coronavirus (SARSr-CoV) or a variant thereof including one or more of: Lineage A, Cluster 5, Lineage B.1.1.7, B.1.1.7 with E484K, Lineage B.1.1.207, Lineage B.1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429/CAL.20C, Lineage B.1.525, Lineage P.1, Lineage B.1.427, Lineage B.1.526, Lineage P.2, or a combination thereof.
- SARSr-CoV Severe Acute Respiratory Syndrome Coronavirus
- the therapeutically effective amount of the NORS can reduce a viral RNA load compared to a baseline level by greater than one or more of: 80%, 90%, 95%, or 99% after a treatment duration of one or more of: 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days.
- the therapeutically effective amount of the NORS can: provide a low pH that reduces SARS-CoV-2 viral load, or provide a physical barrier over epithelial cells of the subject that prevents SARS-CoV-2 access to host cells of the subject, or provide an angiotensin-converting enzyme 2 (ACE-2) receptor blocking agent.
- ACE-2 angiotensin-converting enzyme 2
- NORS can be administered to a mucosal membrane.
- the mucosal membrane can be a subject's nasal passage or sinus and the NORS is administered as a sprayed solution or as a lavage.
- the mucosal membrane can be a subject's mouth or throat and the NORS is administered as a gargle solution.
- a method of treating a subj ect for infection of a pathogen in an upper respiratory tract can comprise administering a therapeutically effective amount of a nitric oxide releasing solution (NORS) to the subject as a spray having an average droplet volume which contains treatment within the upper respiratory tract.
- NNS nitric oxide releasing solution
- the method can comprise providing a median droplet size (Dv50) of greater than one or more of 100 ⁇ m , 150 ⁇ m , 200 ⁇ m , 250 ⁇ m , 300 ⁇ m , 350 ⁇ m , 400 ⁇ m , 450 ⁇ m , 500 ⁇ m , 550 ⁇ m , or 600 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv50 median droplet size
- the method can comprise providing a percentage of spray by volume at droplet sizes of less than 10 ⁇ m (% ⁇ 10 ⁇ m ) of less than one or more of:
- the method can comprise providing a percentage of spray by volume at droplet sizes of less than 5 ⁇ m (% ⁇ 5 ⁇ m ) of less than one or more of: 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% when measured a 30 mm or 60 mm distance from actuation.
- the method can comprise providing a 10th percentile by volume of spray (Dv(10)) of greater than one or more of 100 ⁇ m , 150 ⁇ m , 200 ⁇ m , 250 ⁇ m , 300 ⁇ m , 350 ⁇ m , or 400 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv(10) 10th percentile by volume of spray
- the method can comprise providing a 90th percentile by volume of spray (Dv(90)) of greater than one or more of 500 ⁇ m , 550 ⁇ m , 600 ⁇ m , 650 ⁇ m , 700 ⁇ m , 750 ⁇ m , 800 ⁇ m , 850 ⁇ m , 900 ⁇ m , 950 ⁇ m , or 1000 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv(90) 90th percentile by volume of spray
- the method can comprise providing a droplet size distribution of about 0.5 to about 2.0, wherein the droplet size distribution is: (Dv(90) - Dv(10))/Dv(50).
- a nitric oxide releasing solution can comprise at least one nitric oxide releasing compound and at least one acidifying agent, wherein the NORS releases a therapeutically effective amount as a spray having an average droplet volume which contains treatment within an upper respiratory tract.
- the NORS can provide a median droplet size (Dv50) of greater than one or more of 100 ⁇ m , 150 ⁇ m , 200 ⁇ m , 250 ⁇ m , 300 ⁇ m , 350 ⁇ m , 400 ⁇ m , 450 ⁇ m , 500 ⁇ m , 550 ⁇ m , or 600 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv50 median droplet size
- the NORS can provide a percentage of spray by volume at droplet sizes of less than 10 ⁇ m (% ⁇ 10 ⁇ m ) of less than one or more of: 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% when measured a 30 mm or 60 mm distance from actuation.
- the NORS can provide a percentage of spray by volume at droplet sizes of less than 5 ⁇ m (% ⁇ 5 ⁇ m ) of less than one or more of: 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% when measured a 30 mm or 60 mm distance from actuation.
- the NORS can provide a 10th percentile by volume of spray (Dv(10)) of greater than one or more of 100 ⁇ m , 150 ⁇ m , 200 ⁇ m , 250 ⁇ m , 300 ⁇ m , 350 ⁇ m , or 400 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- Dv(10) 10th percentile by volume of spray
- the NORS can provide a 90th percentile by volume of spray (Dv(90)) of greater than one or more of 500 ⁇ m , 550 ⁇ m , 600 ⁇ m , 650 ⁇ m , 700 ⁇ m , 750 ⁇ m , 800 ⁇ m , 850 ⁇ m , 900 ⁇ m , 950 mm, or 1000 ⁇ m when measured a 30 mm or 60 mm distance from actuation.
- the NORS can provide a droplet size distribution of about 0.5 to about 2.0, wherein the droplet size distribution is: (Dv(90) - Dv(10))/Dv(50).
- the at least one nitric oxide releasing compound can be selected from the group consisting of a nitrite, a salt thereof, and any combinations thereof.
- the at least one acidifying agent can be an acid.
- Severe Acute Respiratory Syndrome Coronavirus can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject.
- a composition for use in minimizing subject-to-subject transmissibility for a pathogen can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject.
- a composition for use in treating a subject for infection of a pathogen in an upper respiratory tract can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject as a spray having an average droplet volume which contains treatment within the upper respiratory tract.
- NOS nitric oxide releasing solution
- use of a pharmaceutical composition for the manufacture of a medicament for treating a subject for infection with a Severe Acute Respiratory Syndrome Coronavirus can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject.
- NNS nitric oxide releasing solution
- use of a pharmaceutical composition for the manufacture of a medicament for minimizing subject-to-subject transmissibility for a pathogen can comprise: administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject.
- use of a pharmaceutical composition for the manufacture of a medicament for treating a subject for infection of a pathogen in an upper respiratory tract can comprise administering a therapeutically effective amount of nitric oxide releasing solution (NORS) to the subject as a spray having an average droplet volume which contains treatment within the upper respiratory tract.
- NNS nitric oxide releasing solution
- Testing was performed to determine if liquid samples inactivate virus when exposed for a contact time of 2 minutes or 8 minutes. Virus solution was mixed with samples for the liquid contact period, then surviving infectious virus was quantified by standard endpoint dilution and compared with untreated controls.
- SARS-CoV-2 stocks were prepared prior to testing by growing in Vero 76 cells in MEM supplemented with 2% FBS and 50 ug/mL gentamicin (test media).
- Product G (nitrite) and Product H (acidifying agent) were mixed together at a 1 : 1 ratio prior to testing (G+H).
- the Product G + H produced a NO concentration of about 0.7 ppm to about 4 ppm with the area under the curve (AUC) after two minutes of from 0.7 ppm to about 2.0ppm*min.
- Product J (nitrite) and Product K (acidifying agent) were likewise mixed (J+K).
- the Product J + K produced a NO concentration of from about 1.4 ppm to about 8 ppm with an area under the curve after two minutes of from about 1.4 ppm to about 4.0 ppm*min.
- virus solution was added to the mixed samples at a 1:9 ratio (10 ⁇ L of virus in 90 ⁇ L of pre- mixed test samples). The mixtures were incubated together for 2 minutes or 8 minutes at room temperature. An untreated virus control of water and a positive control of EtOH (63%) were tested in parallel. For toxicity controls, media (no virus) was added to each sample. The test was performed in triplicate tubes. Following the contact period, samples were diluted 1/10 in test media and then stored at -80°C until time of virus quantification.
- Virus controls were tested in water and the reduction of virus in test wells compared to virus controls was calculated as the log reduction value (LRV). Toxicity controls were tested with media not containing virus to see if the samples were toxic to cells. Neutralization controls were tested to ensure that virus inactivation did not continue after the specified contact time, and that residual sample in the titer assay plates did not inhibit growth and detection of surviving virus. This was done by adding toxicity samples to titer test plates then spiking each well with a low amount of virus that would produce an observable amount of CPE during the incubation period.
- Table 1 shows results for SARS-CoV-2 titers and LRV after contact with G+H and J+K liquid samples.
- G+H reduced virus by from 3.9 to 1.8 log CCID50 per 0.1 mL (>99%).
- G+H reduced virus below the limit of detection ⁇ 0.7 CCID50 per 0.1 mL (>99.9%).
- J+K reduced virus below the limit of detection of 0.7 CCID50 per 0.1 mL (>99.9%).
- Residual test sample did not inhibit virus growth and detection in the endpoint titer assays.
- Ethanol was cytotoxic in culture after the 1/10 dilution in media and therefore the lower limit of detection of virus was 1.7 CCID50 per well.
- Virus controls and positive controls performed as expected.
- Table 1 Virucidal activity of G+H and J+K against SARS-CoV-2 after contact period at 22 2 C.
- NORS accelerated clearance of SARS-CoV-2 by a factor of 16-fold versus the placebo, and it presents supporting evidence for the emergency use ofNORS for prevention or treatment of patients with recent or established SARS-CoV-2 RNA infection.
- the study also concluded that patients with a self- administered nasal spray ofNORS were found to have reduced SARS-CoV-2 log viral load by more than 95% in infected participants within 24 hours of treatment, and by more than 99% in 72 hours.
- Eligible participants were men and women aged 18 to 70 years with mild COVID-19 infection within 5 days of symptom onset and confirmed by a laboratory SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) nasal and throat swab within the 48 hours prior to randomization. It is intended that patients over 70 years of age will be tested in a further sub-analysis.
- RT-PCR reverse transcription polymerase chain reaction
- Mild symptoms could include but were not limited to: fever (>37.2 C), dry cough, tiredness, sore throat, malaise, headache, muscle pain, lack of taste or smell, and gastrointestinal symptoms.
- Exclusion criteria included asymptomatic infection with COVID-19, current tracheostomy or laryngectomy, pregnancy or current lactation, hypersensitivity to the active substance or to any of the excipients, concomitant respiratory therapy (e.g., oxygen or ventilator support) and any clinical signs indicative of moderate, severe or critical COVID-19 symptoms as defined by FDA COVID-19 Guidance Document.
- Written consent was obtained from all participants.
- Nasal and throat swabs were taken at presentation for baseline, and treatment commenced on day 1. Participants were already in isolation and advised to ensure using the spray and taking swabs was performed in isolation of others. Participants took self- sampled swabs on days 2, 4 and 6 and these were taken in the morning prior to treatment to avoid interference with the swab results. Quantitative RT-PCR was performed at the Berkshire Surrey Pathology Services Virology laboratory at ASPHFT to determine SARS-CoV-2 RNA levels. SARS-CoV-2 sequencing for variants was performed at the Public Health England Colindale. Participants completed daily self-reporting questionnaires on symptoms, compliance and tolerance of treatment. Follow-up was carried out for a total of 18 days.
- the outcome measure was the difference in SARS-CoV-2 viral load from baseline through day 6 between NONS and control arms, as measured on quantitative RT- PCR. It was originally intended to study the cycle threshold (ct) value and the viral load though as the viral load is derived from the ct value and represents a more reliable measure of quantity then the load was solely analyzed.
- the analysis utilized a linear mixed effect model for log (10)SARS-CoV-2 RNA.
- a random (Gaussian) intercept for subject was included to account for multiple observations.
- Parameter estimation was performed using maximum likelihood (not restricted / REML) and inference was based on a likelihood ratio test of the full model, versus a null model excluding the main and interaction effects involving arm.
- least-square mean log (10) SARS-CoV-2 RNA estimates for each time point were generated from the full model accompanied by 95% confidence.
- a second model was constructed using random effects for treatment group.
- the analysis used R (2020 version), while simple exploratory analyses were accomplished using MedCalc version 19.7. Results:
- Table 3A-1 Characteristics of the Patients at Baseline
- Table 3A-2 Change from Baseline in SARS-CoV-2 RNA
- One patient in each of the NONS and placebo group sought care due to COVID-19.
- the patient in the NONS group seeking care was aged 37 years old, had a medical history of asthma and did not have hospitalization beyond 24 hours.
- a patient in the placebo group had emergency hospitalization and was aged 65 years old. Insufficient numbers of patients completed the symptom scores for statistical analysis.
- an agent with antiviral and viricidal properties towards SARS-CoV-2 should shorten or prevent the course of disease, reduce immune mediated pathological damage and reduce progression to severe disease.
- Inhaled NO treatment in severe illness has been observed to improve arterial oxygenation in patients with SARS- CoV beyond termination of NO suggesting a direct effect on the disease.
- reducing the transport of viruses towards the acinar airways could provide an opportunity for the prevention of pneumonia.
- a delayed viral clearance for instance can be observed in patients with more severe disease.
- the nasopharyngeal viral load has not been validated as a predictor of clinical disease course in COVID-19. Consequently, further study is needed though to fully understand the dynamics of SARS-CoV-2 including the duration of shedding and causal association with clinical progression and severity.
- SARS-CoV-2 neutralizing antibody LY-CoV555 revealed a relative SARS-CoV-2 RNA decrease versus placebo of -0.64 and -0.45 log10 copies/ml at days 3 and 7 respectively.
- Oseltamivir is available for influenza virus infection and has been shown to be independently associated with an accelerated decrease in viral RNA concentration -1.19 [0.43] and -0.68 [0.33] log10 copies/mL for patients treated on day 1 and days 2-3, respectively (P ⁇ 05).
- the lower levels SARS-CoV-2 RNA loads in patients with NONS may also be beneficial in the prevention of SARS-CoV-2 transmission. It has been described that the higher viral loads in patients with SARS-CoV-2 earlier than SARS-CoV may have contributed to the greater difficulty in reducing the onward transmission. Furthermore, it has been observed that the risk of symptomatic COVID-19 was associated with the SARS-CoV-2 RNA levels of contacts and incubation time was shortened in a dose- dependent manner. It is therefore proposed that NONS could reduce the spread of infection by reducing the period of infectivity in contacts. If NONS were also to be used prophylactically, then it could potentially reduce the dose in those exposed. It is envisaged though that the greatest benefit of treatment would be demonstrated by treating as early as possible and potentially before onset of symptoms
- NONS is portable and can be self- administered at home which would reduce the risk of healthcare associated infections.
- the risk of adverse events would be significantly lower with localized application of NONS than by systemic usage of NO at higher dosage requiring specialized gas cylinders and inhalation technologies.
- NONS could be a safe and well tolerated treatment for SARS-CoV-2 and other infections as well.
- the accelerated clearance of SARS-CoV-2 by NONS could be used to prevent the spread of SARS-CoV-2.
- NONS accelerated reduction of SARS-CoV-2 by a mean factor of 16.2 versus placebo at days 2 and 4. Advancing the clearance of SARS-CoV-2 could lead to shorter duration of symptoms and reduced progression to severe infection. The reduction of SARS-CoV-2 could decrease the period of infectivity and prevent transmission.
- interventions recommended for sever SARS-CoV-2 including remdesivir and dexamethasone. However, there are currently no available agents for mild COVID-19 infection so NONS could become a useful treatment for emergency use.
- the objective was to evaluate the efficacy of NONS compared to placebo to shorten the duration of COVID-19 viral infectivity through day 6 from randomization on treatment (Days 1 to 6).
- the secondary objective was to assess the virucidal effect of NONS compared to placebo in the nasal cavity on Days 2, 4 and 6. Additional secondary objectives include an assessment of the efficacy of NONS in the prevention of the progression of COVID-19, an assessment of the reduction in subjects’ COVID-19 clinical symptom score, an assessment of the tolerability of NONS in subjects with COVID-19, and the safety of NONS in subjects with COVID-19.
- each subject administered 2 sprays per nostril using a metered dose nasal spray pump repeated 5-6 times daily while awake, with a cleansing procedure every morning before the first treatment.
- Subjects collected and entered daily symptom result scores in their diary, including symptom relief medications, through an on-line portal (monitored by study staff for deterioration of condition) to the end of the study (Day 18).
- Subjects were pre-scheduled to have a nasal swab obtained at their COVID-19 test center or via a home self-test on Days 2, 4 and 6 for viral load analysis. A telephone follow-up occurred on Days 2, 4, 6, 9 and 18.
- Adverse events, discomfort, pain, discontinuation of treatment, urgent care, emergency room, and hospitalizations were recorded.
- Mild COVID/FLU symptoms which may include fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, lack of taste or smell without shortness of breath or dyspnea, or no symptoms.
- Concomitant respiratory therapy such as oxygen or ventilator support (however, positive airway pressure for obstructive sleep apnea was permitted if treatment was established with good compliance at least 3 months before enrollment);
- the investigational medicinal product (IMP) for nasal irrigation i.e., NONS was provided in two, 5 mL tubes which was added to the nasal spray bottle (10 mL) solution and replaced every 3 days with fresh solution.
- the IMP contained sufficient NaCl to create an isotonic (0.9% NaCl) saline solution.
- NONS Nitric Oxide Nasal Spray
- Matching placebo was provided in two, 5 mL tubes (sodium chloride [NaCl] designed to create an isotonic saline solution), which was added to the nasal spray bottle (10 mL) and replaced every 3 days with fresh solution. Placebo nasal spray was administered in the same dose and fashion as active treatment.
- sodium chloride [NaCl] designed to create an isotonic saline solution
- Each subject participated in the study for up to 20 days, including a screening period of up to 2 days (Day -2 to Day 0), 9 continuous treatment days (Day 1 to Day 9), and 8 days for follow up (Day 10 to Day 18). Over the course of the study, 41.7% of the NONS doses and 46.3% of placebo doses were recorded as having been administered; 4.3% of the NONS doses and 4.8% of placebo doses were recorded as having been missed.
- One efficacy variable and endpoint for this study is difference in SARS-CoV- 2 viral load (Cycle threshold [Ct]) from baseline through Day 6 between NONS and control arms.
- the Ct value is inversely related to the viral load and for every 3.3 increase in the Ct value reflects a 10-fold reduction in COVID-19 starting material.
- a secondary efficacy variable assessment included multiple evaluations. An assessment of the virucidal effect of NONS was compared to placebo in the nasal cavity on Days 2, 4, and 6. An assessment of the proportion of subjects requiring hospitalization or an emergency department visit(s) for COVID-19 flu-like symptoms by Day 18. An assessment of efficacy in the reduction of COVID-19 subject clinical symptom (modified Jackson) scores between NONS and placebo control at Days 2, 4, 6, 9 and 18. Safety
- Descriptive statistics for continuous monitoring data include the number of subjects with data to be summarized (n), mean, standard deviation and median. All categorical and qualitative data are presented using counts and percentages. Summary statistics were presented by treatment group and overall, unless stated otherwise.
- Baseline was defined as the last non-missing value before the dose of study drug.
- the efficacy analysis was conducted using the intent-to-treat (ITT) population and utilized a linear mixed effect model for Ct with fixed effects for randomized treatment group (NONS, control), age (continuous), presence of comorbidities at randomization (no/yes), and study day (0, 2, 4, 6) was included in the model along with an interaction between treatment group and study day.
- a random (Gaussian) intercept for subject was included to account for multiple observations.
- Parameter estimation were performed using maximum likelihood (not restricted / REML) and inference was based on a likelihood ratio test of the full model (above) versus a model excluding the main and interaction effects involving arm.
- Thresholds (1, 2 and 3) at Day 2, Day 4 and Day 6 - Time to Ct threshold (unmeasurable viral load) was modeled using a Cox proportional hazards model including fixed effects for treatment group, age, and baseline co-morbidity. Individuals who did not achieve threshold were considered censored at the last available Ct measurement time. Median time and 95% confidence intervals were calculated.
- Modified Jackson Scores Modeled on the Endpoint Analysis (ITT) were modeled as in the analysis of the endpoint, but all days from randomization through Day 6 were used each with an indicator for whether on or prior to treatment. Symptom scores on the day treatment was initiated were considered prior to treatment unless times of NONS administration and questionnaire completion indicated the opposite. Scores that were missing due to hospitalization, or death, were imputed with the maximum possible score. If scores were missing and a subject subsequently died or was hospitalized prior to Day 18, they were also imputed with the maximum possible score. All other missingness were treated as missing at random and all available data for the subject included in the model.
- One objective was to demonstrate the efficacy of NONS to shorten COVID- 19 infectivity duration in mild COVID-19 patients. Fifty-four (54) nasal spray treatments were administered 6 times per day for 9 continuous days. [00239] Each treatment considered of 4 sprays (560 ⁇ L total), 2 sprays per nostril, for a total dosage regimen of approximately 30 mL. The mean baseline SARS-CoV-2 viral load was 2.415 x10 13 RNA copies per cm 3 (mL) across all study subjects.
- the efficacy variable was the change from baseline reduction through Day 6 of treatment in ‘Cycle Threshold’, i.e., the difference in SARS-CoV-2 viral load.
- the efficacy endpoint for this trial was the comparison of the mean (log)viral load reduction change from baseline between treatment groups.
- the analysis performed utilized a generalized linear mixed effect model for (log 10 ) viral load with fixed effects for randomized treatment group (NONS, control), age (continuous), presence of comorbidities at randomization, study day (0, 2, 4, 6), and interaction between treatment group and each study day.
- SARS-CoV-2 (log)viral load was significantly decreased over the first 6 days of NONS treatment compared to placebo: The treatment difference between NONS and placebo was statistically significant for all three days (p ⁇ 0.05 at Day 2, 4 and 6 for NONS treatments compared to placebo). Viral load observed in subjects randomized to placebo was significantly higher over the first 6 days compared to those allocated to NONS active treatment.
- the nasal cavity is the major route for host entry and infectivity of the COVID-19 virus.
- An effective COVID-19 antiviral therapy that could shorten or prevent the course of the disease, reduce immune mediated pathological damage and lower disease severity is currently lacking.
- Nitric oxide has antimicrobial activity against bacteria, yeast, fungi, and viruses both in vitro and in vivo animal studies. NO also prevents the fusion between the SARS-CoV-2 Spike protein and its cognate receptor, ACE-2.
- NONS Nitric Oxide Nasal Spray
- NONS treatment started on or before day 5 of COVID-19 symptom onset was independently associated with an accelerated decrease in SARS-CoV-2 RNA concentration of -1.21 and -1.21 log 10 copies/mL on days 2 and 4 compared to placebo.
- Mean SARS-CoV-2 RNA concentration was lower on NONS treatment by a factor of 16.2 at both day 2 and 4.
- Day 6 equated to at least 10 days since symptom onset when a reduction of SARS-CoV-2 viral load with or without treatment was expected. Nevertheless, the SARS-CoV-2 RNA concentration was still lower on NONS treatment at day 6.
- the area under the curve analysis revealed a mean difference of -5.22 log 10 copies/mL with NONS treatment compared to placebo over the first 6 days of treatment.
- SARS-CoV-2 neutralizing antibody LY-CoV555 revealed a relative SARS-CoV-2 RNA concentration decrease versus placebo of -0.64 and -0.45 log 10 copies/mL at days 3 and 7, respectively.
- Oseltamivir has been shown to be independently associated with an influenza RNA concentration decrease of -1.19 and -0.68 log 10 copies/mL on days 2 and 4, respectively.
- Nasal deliver of NONS is effective in reducing COVID-19 viral load as are systemic therapies under investigation or currently being used to treat viral infections.
- Nitric oxide therapy is often overlooked as a COVID-19 treatment when potential beneficial treatments and pathogenic new insights are reviewed.
- NONS could be used across the population for prevention or early treatment if new variants reduce the efficacy of the current vaccines. NONS could also provide antiviral treatment to those infected who may not yet have been fully vaccinated, those who are unable to be vaccinated or those with infection despite vaccination.
- the objective was to demonstrate the efficacy of NONS to shorten COVID- 19 infectivity duration in mild COVID-19 patients (ITT Population).
- the efficacy variable was the change from baseline reduction through Day 6 of treatment in ‘Cycle Threshold’, i.e., the difference in SARS-CoV-2 viral load.
- the analysis performed utilized a linear mixed effect model for (log 10 ) viral load with fixed effects for the randomized treatment groups.
- the mean baseline SARS-CoV-2 viral load was 2.415 x10 13 RNA copies per cm 3 (mL) across all study subjects.
- SARS-CoV-2 (log)viral load reduction and the likelihood ratio test using sensitivity analyses with random effects for treatment groups was comparable to the fixed effects assessment.
- Thresholds None of the differences between the NONS treatments and placebo at each of the thresholds were statistically significant for the ITT population. No analyses were conducted on the PP population.
- NORS Newcastle disease virus
- H1N1 and H3N2 The dosage regimen of NORS proposed for this study has been tested in vitro against H1N1 and H3N2.
- NORS eradicated HINland H3N2 within 30-60 seconds of exposure using very high viral titers (>10 6 PFU/mL).
- Recent tests confirm NORS inactivates more than 99.9% (to below the limit of detection) of SARS-CoV-2, within two minutes in laboratory tests using recent clinical isolates of titers of >10 4 PFU/mL.
- NORS has been previously administered topically to 21 individuals at the same concentration as the nitric oxide nasal spray (NONS) proposed for this study in a Health Canada approved clinical trial to treat Tenia Pedis. The treatment was tolerated, with no SAEs and a small number of mild adverse events (AEs) reported. In addition, environmental and user safety were evaluated and NORS was deemed to be safe.
- NONS nitric oxide nasal spray
- the NORS can be used as a sinus irrigation therapy for treating sinusitis, including individuals with recalcitrant chronic sinusitis (CRS).
- CRS chronic sinusitis
- a dose escalation study was conducted to identify the maximum tolerated dose for a single daily treatment in subjects with CRS. The study identified the maximum tolerated dose as 4X the current study proposed dose. It was also noted that no severe adverse events were recorded and that all 5 subjects had a significant improvement in their quality of life (measured by SNOT-22) and sinusitis severity (measured by endoscopy evaluation).
- the dosage range for treating sinusitis can vary, including the dosage ranges based on the NORS compositions recited herein.
- the dosage range from a 50 mL sinus irrigation to a 500 mL sinus irrigation. In some embodiments, the dosage range can be a 240 mL sinus irrigation. In some embodiments, the irrigation amount can be from 100 mL to 240 mL and the NORS used can be any specific NORS recited herein.
- the objective was to evaluate the efficacy of NONS compared to placebo to shorten the duration of COVID-19 viral infectivity through day 6 from randomization on treatment (Days 1 to 6).
- the secondary objective was to assess the virucidal effect of NONS compared to placebo in the nasal cavity on Days 2, 4 and 6. Additional secondary objectives include an assessment of the efficacy of NONS in the prevention of the progression of COVID-19, an assessment of the reduction in subjects’ COVID-19 clinical symptom score, an assessment of the tolerability of NONS in subjects with COVID-19, and the safety of NONS in subjects with COVID-19.
- each subject administered 2 sprays per nostril using a metered dose nasal spray pump repeated 5-6 times daily while awake, with a cleansing procedure every morning before the first treatment.
- Subjects collected and entered daily symptom result scores in their diary, including symptom relief medications, through an on-line portal (monitored by study staff for deterioration of condition) to the end of the study (Day 18).
- Subjects were pre-scheduled to have a nasal swab obtained at their COVID-19 test center or via a home self-test on Days 2, 4 and 6 for viral load analysis. A telephone follow-up occurred on Days 2, 4, 6, 9 and 18.
- Adverse events, discomfort, pain, discontinuation of treatment, urgent care, emergency room, and hospitalizations were recorded.
- the Daily Treatment Questionnaire recorded treatment compliance, tolerance, ease of use, and adverse events. A discomfort/pain scale was included, and used.
- EQ5D5L A PRO EuroQol five dimensions questionnaire (EQ5D5L) was used which defines health in terms of 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety /Depression. Each dimension has 5 levels of response categories corresponding to no problems, slight problems, moderate problems, severe problems and extreme problems. The instrument is designed for self-completion.
- Subjects rated their overall health at the end of the questionnaire on a 0-100 vertical (hash-marked), visual analogue scale.
- the follow-up telephone calls conducted by the study staff requested subjects to confirm their current health status including the presence of any COVID-19 symptoms such as fever, cough, dyspnea, sneezing, ageusia, anosmia, headache, major fatigue, loss of appetite, general muscle pain, diarrhea, sore throat and loss of smell/taste. Subjects were reminded about their daily treatment regimen and were asked about any challenges with the administration or any adverse events they may have experienced.
- Follow-up questionnaires were emailed on Days 9 and 18, which took 2-5 minutes to complete.
- Mild COVID/FLU symptoms which may include fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, lack of taste or smell without shortness of breath or dyspnea, or no symptoms.
- Concomitant respiratory therapy such as oxygen or ventilator support (however, positive airway pressure for obstructive sleep apnea was permitted if treatment was established with good compliance at least 3 months before enrollment);
- EXAMPLE 3-E Treatments [00297] The nitric oxide nasal spray (NONS) and placebo solutions were delivered to individuals every three days over the nine days of treatment.
- NONS nitric oxide nasal spray
- the investigational medicinal product (IMP) for nasal irrigation i.e., NONS was provided in two, 5 mL tubes which was added to the nasal spray bottle (10 mL) solution and replaced every 3 days with fresh solution.
- Placebo was provided in two, 5 mL tubes (sodium chloride [NaCl] designed to create an isotonic saline solution), which was added to the nasal spray bottle (10 mL) and replaced every 3 days with fresh solution.
- the IMP contained sufficient NaCl to create an isotonic (0.9% NaCl) saline solution, as depicted in Table 3E-1.
- the NONS Package Kit contained 3 tubes labelled A, 3 tubes labelled B, 1 empty nasal spray botle, and labelled secondary packaging.
- the Placebo package Kit containing 3 tubes labelled C, 3 tubes labelled D, 1 empty nasal spray botle, and labelled secondary packaging. Active investigational product and placebo were delivered in identical packaging with unique identification codes for each package.
- NORS nitric oxide releasing solution
- the objective was to provide a NO gas formulation equivalent using a nitric oxide releasing solution (NORS) without the need for gas cylinders or high pressure.
- NORS nitric oxide releasing solution
- the benefit of NORS includes its ability to release the fast-acting viricidal dose of NO for a sustained period of time (at least 5 minutes), at the target site (nasal mucosa/lungs), while producing insignificant oxidative insult to respiratory epitheba, and minimal systemic methemoglobin levels.
- Nitric Oxide Nasal Spray was self-administered daily, by the participant throughout each day, for 9 continuous treatment days. A cleansing procedure was performed every morning before the first treatment (two sprays, then nose blown after 30 seconds to clear mucous/debris from the epithelial cell surfaces). Video instructions for the preparation and use of the spray pump were available online for subjects.
- Concomitant medications were recorded at each visit. All subjects could continue their usual daily medications, including ACE inhibitors. Intranasal steroids, antihistamines and anticholinergics could be continued. Intranasal rescue medications could be used as prescribed for migraine, etc. Prescribed nasal sprays could not be used less than one hour before or one hour after each treatment. Asthma inhalers could be taken as previously prescribed and as needed.
- Acetaminophen, naproxen sodium and ibuprofen could be used for pain and fever according to package labelling BUT needed to be linked to symptoms and recorded in the Daily Treatment Questionnaire. Guaifenesin and dextromethorphan could be used orally for cough according to package labelling. Pseudoephedrine could be used orally for nasal congestion.
- Study personnel monitored compliance by reviewing study medication dispensed in the pharmacy drug accountability log. Subjects were asked to return completed, partially used and unused treatment packs to the trial center. In the follow-up call after 18 days subjects were asked for their (honest) assessment of how much of the investigational treatment had been used and subsequently recorded.
- cycle threshold a whole number to quantitate changes in viral load from nasal swabs without the need for viral cultures.
- the cycle threshold (Ct) correlates inversely to live virus and viral load and was used in this study as the endpoint measure to determine the antiviral effectiveness of NONS.
- the secondary objectives were to assess the degree of NONS virucidal effect, prevention of COVID-19 progression, reduction of COVID-19 symptoms, and assess to the tolerability and safety of NONS in subjects with COVID-19.
- Table 3F-2 Study Schedule for Screening, Qualification (Baseline), Procedures and follow-up
- the efficacy variable and endpoint for this study is difference in SARS-CoV-2 viral load (Cycle threshold [Ct]) from baseline through Day 6 between NONS and control arms.
- Ct SARS-CoV-2 viral load
- the SARS-CoV-2 RT-qPCR test provides real-time quantification by first reverse transcribing SARS- CoV-2 RNAinto DNA (RT operation), and then performing qPCR where a fluorescence signal increases proportionally to the amount of amplified nucleic acid, enabling accurate quantitation of the RNA in the sample. If the fluorescence reaches a specified threshold within a certain number of PCR cycles (Ct value), the sample is considered a positive result.
- the Ct value is inversely related to the viral load and for every 3.3 increase in the Ct value reflects a 10-fold reduction in COVID-19 starting material.
- Secondary efficacy variable assessments include multiple endpoints.
- a tolerability endpoint which assessed AEs for each treatment and discontinuation of NONS in subjects with COVID-19 during treatment Days 1-9.
- a safety endpoint which assessed AEs over the entire clinical execution of the study, i.e., Days 1 to 18.
- the efficacy analysis was conducted using the intent-to-treat (ITT) population and utilized a linear mixed effect model for Ct with fixed effects for randomized treatment group (NONS, control), age (continuous), presence of comorbidities at randomization (no/yes), and study day (0, 2, 4, 6) was included in the model along with an interaction between treatment group and study day.
- a random (Gaussian) intercept for subject was included to account for multiple observations.
- Parameter estimation were performed using maximum likelihood (not restricted/REML) and inference was based on a likelihood ratio test of the full model (above) versus a model excluding the main and interaction effects involving arm.
- Thresholds (1.00, 2.00 and 3.00) at Day 2, Day 4 and Day 6 - Time to Ct threshold (unmeasurable viral load) was modeled using a Cox proportional hazards model including fixed effects for treatment group, age, and baseline co-morbidity. Individuals who did not achieve threshold were considered censored at the last available Ct measurement time. Median time and 95% confidence intervals were calculated.
- Subjects will be modeled using a logistic regression with fixed effects as in the analysis (arm, age, co-morbidity) for this assessment. Point estimates and 95% confidence intervals will be provided. Subjects for whom hospitalization or ER/ED visits cannot be definitively determined for day 18 will be imputed as having a visit. This may include some blinded data review by the sponsor for subjects who are deemed recovered, and withdrew consent or were lost to follow-up prior to day 18.
- Baseline ⁇ 5 or Reduction to Zero at Days 2, 4, 6, 9 and 18 - Modified Jackson scores were modeled as in the analysis of the endpoint, but all days from randomization through Day 6 were used each with an indicator for whether on or prior to treatment. Symptom scores on the day treatment was initiated were considered prior to treatment unless times of NONS administration and questionnaire completion indicated the opposite. Scores that were missing due to hospitalization, or death, were imputed with the maximum possible score. If scores were missing and a subject subsequently died or was hospitalized prior to Day 18, they were also imputed with the maximum possible score. All other missingness were treated as missing at random and all available data for the subject included in the model.
- Baseline ⁇ 5 or Reduction to Zero at Days 2, 4, 6, 9 and 18 - Proportion of subjects experiencing modified Jackson score (or COVID-19 PRO Score) change of ⁇ 5 from baseline or reduction to zero were modeled using a logistic regression as described for other secondary endpoints at Day 2, 4, 6, 9, and 18. Scores that were missing due to hospitalization, or death, were imputed with the maximum possible score. Scores that were missing and a subject subsequently died or was hospitalized were also imputed with the maximum possible score. All other missingness were treated as missing at random.
- sample size for the study was based on the endpoint, however there was insufficient information available regarding the correlation of the Ct results over time within-subjects, precluding a sample size calculation involving unfounded assumption. Instead, the sample size was justified using a single-timepoint and assumed to be a lower bound on power considering the inclusion of additional time-points in the analysis.
- a sample size of 50 subjects (25 per arm) was determined to have 91% power to demonstrate superiority of treatment versus control if the true underlying mean Cts were 31 versus 26, respectively, using a two-sided 0.05- level Wilcoxon-signed rank test and assuming a common standard deviation of 5 for both groups.
- Safety Population The safety population included all subjects who received at least 1 dose of study treatment. Participants were analyzed, according to the intervention, they actually received. Safety results are to be separated into events on-treatment (Day 1- 9) and off-treatment (Day 10-18).
- ITT Intent-to-treat
- Per-Protocol (PP) Population The PP population consisted of all subjects who were enrolled in the study, had been randomized, received at least one dose of their assigned study treatment and had no major protocol deviations, were not lost-to-follow-up for reasons unrelated to treatment, and had documented test article administration on a minimum of 80% of their on-study days while enrolled in the study. All subject data was analyzed according to their received treatment.
- Demographics and other baseline characteristics were summarized for the safety population by treatment group and overall, with descriptive statistics including n, mean, and SD for numeric variables and frequency and percentage for categorical variables.
- Demographics included age, gender, and race.
- Medical history included comorbidities (any, or chronic heart, liver, and lung disease; diabetes; and hypertension) and presenting symptoms (dry cough, fever, loss or sense of smell, or none).
- Disposition was summarized by efficacy for the NONS treatment, placebo and overall. The number and percentage of subjects discontinuing, along with the reasons for discontinuation, were summarized for subjects in the safety population. The analysis of the efficacy endpoint was carried out on the observed data, i.e., a complete case analysis. All analyses of demographics, secondary endpoints, and safety data were based on the observed data.
- Subjects had mild COVID-19 infection defined by non-pneumonia or mild pneumonia with no chest pain or shortness of breath, where pneumonia was defined as ‘inflammation of one or both lungs’. Mild symptoms included, but were not limited to fever (>37.2° C), dry cough, tiredness, sore throat, malaise, headache, muscle pain, lack of taste or smell and gastrointestinal symptoms.
- the ITT population consisted of all subjects that had been enrolled and randomized irrespective of adherence to study protocol or study treatments received. This population was used for the efficacy analyses. No subject was excluded from the ITT population data.
- the per protocol (PP) population includes all study subjects that had been enrolled, randomized, and received a minimum of 80% of on-study treatments. In addition, no subject had been lost-to-follow-up, withdrew consent, and had no major protocol deviations while enrolled in the study.
- the safety population consisted of all subjects who were enrolled in the clinical trial and had received at least 1 dose of study treatment. Safety results are separated into events occurring on-treatment (Day 1-9) and off-treatment (Day 10-18). [00345] Demographics for the safety population are presented in Table 3J-1. Overall,
- Table 3J-1 Demographics and Baseline Characteristics (Safety Population)
- Treatment compliance was recorded by subjects via the daily treatment questionnaire, i.e., nasal sprays administered or missed per day. Returned completed, partially used, and unused treatments for each subject were summarized by the trial center. Verification of subjects’ treatment compliance from the end of study follow-up call were summarized by the trial center.
- the objective was to demonstrate the efficacy of NONS to shorten COVID-19 infectivity duration in mild COVID-19 patients.
- Fifty -four (54) nasal spray treatments were administered 6 times per day for 9 continuous days. Each treatment considered of 4 sprays (560 ⁇ L total), 2 sprays per nostril, for a total dosage regimen of approximately 30 mL.
- the efficacy variable was the change from baseline reduction through Day 6 of treatment in ‘Cycle Threshold’, i.e., the difference in SARS-CoV-2 viral load.
- the efficacy endpoint for this trial is the comparison of the mean (log 10 ) viral load reduction change from baseline between treatment groups.
- the analysis performed utilized a linear mixed effect model for (log)viral load with fixed effects for randomized treatment group (NONS, control), age (continuous), presence of comorbidities at randomization (no/yes), study day (0, 2, 4, 6), and interaction between treatment group and each study day.
- Subjects missing all four (log)viral load measurements baseline, Day, 2, 4 and 6) were imputed with the highest (log)viral load observed in either group for the analysis.
- a random (Gaussian) intercept for subject was included to account for multiple observations (full model).
- the mean baseline SARS-CoV-2 viral load was 2.415 x10 13 RNA copies per cm 3 (mL) across all study subjects.
- the SARS-CoV-2 viral load was significantly decreased over the first 6 days of treatment.
- the viral load observed in subjects randomized to placebo was significantly higher over the first 6 days compared with subjects allocated to the NONS active treatment group.
- the treatment difference between NONS and placebo was statistically significant for all three days (p ⁇ 0.05 at Day 2, 4 and 6 for NONS treatments compared to placebo).
- Table 3J-3 Summary of Treatment Difference for SARS-CoV-2 (log)Viral Load Change from Baseline at Day 2, Day 4 and Day 6 (Generalized Linear Model with Fixed Effect for Treatment Group; ITT Population) aThe analysis was performed utilizing a generalized linear mixed effect model for (log 10 ) viral load with fixed effects for randomized treatment group (NONS, control), age (continuous), presence of comorbidities at randomization (no/yes), study day (0, 2, 4, 6), interaction between treatment group and study day. Subjects missing all four Viral Load measurements (baseline, Day, 2, 4, and 6) were imputed with the highest (log)viral load observed in either group. A random (Gaussian) intercept for subject was included to account for multiple observations. bParameter estimation were performed using maximum likelihood (not restricted / REML) and inference was based on the full model versus a null model excluding the main and interaction effects involving arm.
- null model was performed excluding the main covariate and the interaction effect between the main covariate and the study day.
- the full model and the null model were compared using a likelihood ratio test.
- FIG. 3 A graphical representation of the (log)viral load change from baseline to Days 2, 4 and 6 is shown in FIG. 3.
- a rapid reduction (95%) in the high SARS-CoV-2 viral load was observed within 24 hours, and a 99% reduction within 72 hours, with NONS treatments.
- a second model will be constructed using random effects for treatment group.
- a further scenario will repeat the analysis using the per protocol population, excluding any patients with missing data.
- the efficacy results for the intent-to-treat (ITT) population are comparable to the efficacy results (fixed effect).
- the likelihood ratio test also suggests that the full model significantly differs from the null model.
- the secondary efficacy endpoint analyses broadly support the efficacy of nitric oxide nasal spray administration in mild COVID-19 patients.
- Ct is reported as a whole number to quantitate changes in viral load from nasal swabs without the need for viral cultures. Ct correlates inversely to live virus and viral load and was used as the endpoint measurement to determine the antiviral effectiveness of the treatments.
- b 95% Cl 95% confidence interval.
- the survival probabilities for the time to SARS-CoV-2 (log 10 ) viral load reduction at Day 2, Day 4 and Day 6 are displayed as Kaplan Meier curves for each of the thresholds as shown in FIG. 4.
- the Kaplan Meier curve for the time to (log)viral load threshold 3 achievement is displayed in FIG. 4.
- the threshold 3 median time was the same for both the NONS treatment and Placebo (6 hours), while the mean time was 4 hours on NONS treatment and 6 hours for Placebo.
- Modified Jackson scores i.e., COVID-19 Patient Reported Outcome (PRO) Scores were derived from data collected on twelve symptom questions asked each day (Day 1 - 9) regarding: nasal congestion/runny nose, new loss of smell/taste, muscle or body aches, sore/scratchy throat, cough, sneezing, headache, malaise, fever/chills, shortness of breath, nausea/vomiting, and diarrhea. For each, the subject was to provide an answer of absent (0), mild (1), moderate (2) or severe (3). Total symptom scores could range from 0 to 36.
- AUC analysis was also carried out on the serial measurements assessment from baseline to day 9 to evaluate the impact of all intermediate data points.
- the baseline values for each curve was set to zero, in order to take into account differences in starting symptom scores.
- the DMC extend the study, since the original power calculation used a number of assumptions including a clear lack of understanding of the clinical behavior of early-stage COVID-19 at the time the study was designed.
- the protocol describes the endpoint population and analysis. A slight adjustment was made for the endpoint. The analyses as documented in the protocol as originally plan was predicated on having semi-quantitative metrics for viral load (Ct).
- the evaluable efficacy population consisted of the full analysis ITT population.
- the PP population consisted of the group of subjects that were not lost-to-follow-up, had not withdrawn consent, and had no major protocol violations that could influence efficacy. Results were generally consistent for the two populations.
- the objective was to demonstrate the efficacy of NONS to shorten COVID-19 infectivity duration in mild COVID-19 patients (ITT Population).
- the efficacy variable was the change from baseline reduction through Day 6 of treatment in ‘Cycle Threshold’, i.e., the difference in SARS-CoV-2 viral load.
- the analysis performed utilized a linear mixed effect model for (log)viral load with fixed effects for the randomized treatment groups.
- the mean baseline SARS-CoV-2 viral load was 2.415 x10 13 RNA copies per cm 3 (mL) across all study subjects.
- VOC B.1.1.7 infection is associated with an increased risk of mortality compared to infection with non-VOC viruses.
- the nasal cavity is the major route for host entry and infectivity of the COVID-19 virus.
- An effective COVID-19 antiviral therapy that could shorten or prevent the course of the disease, reduce immune mediated pathological damage and lower disease severity is currently lacking.
- Nitric oxide has antimicrobial activity against bacteria, yeast, fungi, and viruses both in vitro and in vivo animal studies. NO also prevents the fusion between the SARS-CoV-2 Spike protein and its cognate receptor, ACE-2.
- NONS Nitric Oxide Nasal Spray
- NONS treatment started on or before day 5 of COVID-19 symptom onset was independently associated with an accelerated decrease in SARS-CoV-2 RNA concentration of -1.21 and -1.21 log 10 copies/mL on days 2 and 4 compared to placebo.
- Mean SARS-CoV-2 RNA concentration was lower on NONS treatment by a factor of 16.2 at both day 2 and 4.
- Day 6 equated to at least 10 days since symptom onset when a reduction of SARS-CoV-2 viral load with or without treatment was expected. Nevertheless, the SARS-CoV-2 RNA concentration was still lower on NONS treatment at day 6.
- the area under the curve analysis revealed a mean difference of -5.22 log 10 copies/mL with NONS treatment compared to placebo over the first 6 days of treatment.
- a rapid reduction (95%) in the high SARS-CoV-2 viral load occurred within 24 hours, and 99% reduction within 72 hours, on NONS treatments.
- Nasal deliver of NONS is effective in reducing COVID-19 viral load as are systemic therapies under investigation or currently being used to treat viral infections.
- Nitric oxide therapy is often overlooked as a COVID-19 treatment when potential beneficial treatments and pathogenic new insights are reviewed.
- NONS could be used across the population for prevention or early treatment if new variants reduce the efficacy of the current vaccines. NONS could also provide antiviral treatment to those infected who may not yet have been fully vaccinated, those who are unable to be vaccinated or those with infection despite vaccination.
- Test Set 1 6 total samples tested; Sample hand actuated at 30mm distance from measurement zone.
- Test Set 2 6 total samples tested; Sample hand actuated at 60mm distance from measurement zone.
- Test Set 3 2 samples tested (sample 1 and sample 4 were selected);
- Beam Steering - Beam steering is a phenomenon in droplet size testing of aerosols where propellant causes false peaks of very large droplets to be apparently measured. From a measurement standpoint, this is caused by a change in the refractive index of the measurement zone. It is observed by the instrument’s inner detectors. These detectors, when testing aerosols similar to the sample submitted, can be ignored in the analysis.
- FIGS. 6a and 6b the overlay plots for the triplicate analysis of each individual sample with all samples represented. The goal of these plots is to assess consistency both within a sample bottle as well as from sample to sample. In this case, the same individual sprayed each sample and did so in a consistent manner. The first 250ms was determined to be the stable fully developed phase of the spray throughout the testing. This was utilized in all of the data averaging to ensure the spray is most properly characterized.
- FIG. 5a the results of samples 1-3 are shown. There appears to be a fairly consistent plot trace in the center of the plot with a few outlier plot traces.
- Sample 2 was found to be larger than the other plots in terms of droplet size. This plot was used to determine sample 1 would be used in the hand study to be conducted with several different operators. Overall, the differences involved in this plot may be significant and indicate a difference from bottle to bottle in terms of output. The droplet size distributions output were large in comparison with the traditional nasal delivery systems.
- Sample 4 was selected for the hand study due to its similarity to Sample 1 results at the same testing. [00419] The 60mm results also mimic the results above and the data can be seen on the tables on the prior page tables.
- the droplet size output in general of this device is fairly large in terms of droplet size. There was almost no material under 5um and 10um respectively. The atomization of the material was minimal leaving large droplets. In one bottle, sample 5, there was no atomization at all present and instead just a stream of material coming out of the spray tip.
- RCRS Recalcitrant chronic rhinosinusitis
- NO Nitric Oxide
- This study aimed to determine the tolerance and safety of escalating dose treatments of NO sinus irrigation (NOSi) in RCRS adults.
- Recalcitrant CRS was defined as continued symptoms of colored nasal discharge, post-nasal drip, nasal congestion, decreased sense of smell, and mucosal edema as indicated on nasal endoscopy for at least 3 months despite appropriate medical therapy including topical irrigation with corticosteroids and well-executed endoscopic sinus surgery.
- Individuals who presented with sino-nasal tumors, nasal polyps, autoimmune disorders with sino-nasal manifestations, pregnancy, history or presence of cardiovascular disease, stroke history, drug use that could induce methemoglobinemia or had used any investigational drug within the past 30 days were excluded from the study. All participants were asked to undergo a wash-out period of 30 days if using concurrent medications that may improve sinus symptoms (betadine irrigation, topical antibiotic treatment, systemic steroids etc.).
- Tolerability was evaluated using patient reported visual analogue scores (VAS) for pain and discomfort after each treatment.
- VAS included five 10 cm horizontal lines and participants were instructed to evaluate prickling, stinging, throbbing, cramping and stabbing pain post-irrigation. A total VAS score out of 50 including all pain descriptors was used to evaluate patient reported tolerability. Additionally, tolerability was determined by the participant’s willingness to tolerate treatments of a maximum of two or minimum of one NOSi treatments for up to 6 consecutive days.
- Safety was evaluated by close monitoring of methemoglobin, oxygen saturation and environmental NO 2 levels because of the known potential for NO/NO 2 to impact these parameters if exposed to vascular surfaces; as well adverse events were recorded. Vital signs, including blood pressure, respiratory rate and heart rate were measured pre- and post- each dose escalation in clinic. Ciliary function was measured by the saccharin time test and histopathology test. Olfaction was measured using the
- Efficacy was evaluated by performing routine endoscopy and assessed with the modified Lund Kennedy (MLK) score for chronic rhinosinusitis. Bacterial load in the sinuses was obtained with swab samples sent to the laboratory for semi-quantitative culturing & sensitivity. Patient reported quality of life was assessed using the validated disease-specific Sinonasal Outcomes Test (SNOT-22). This clinical evaluation was intended to identify tolerance of NOSi in this patient population. Mean values and standard deviations were reported. Results:
- VAS Visual Analogue Scale
- This prospective pilot study provided preliminary data of NOSi dose tolerance and short-term safety. This study provides a concrete base for the initiation of a phase II randomized controlled trial that will evaluate the efficacy and long-term safety of NOSi.
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ELS KEYAERTS, LEEN VIJGEN, LUNI CHEN, PIET MAES, GÖRAN HEDENSTIERNA, MARC VAN RANST: "Inhibition of SARS-coronovirus infection in vitro by S-nitroso-N- acetylpenicillamine, a nitric oxide donor compound", INT J INFECT DIS ., vol. 8, no. 4, 1 July 2004 (2004-07-01), pages 223 - 226, XP055868410 * |
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