Classifications

• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
  • A23G4/00—Chewing gum
  • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
  • A23G4/08—Chewing gum characterised by the composition containing organic or inorganic compounds of the chewing gum base
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • 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
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/30—Zinc; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
  • A61K9/0058—Chewing gums

Definitions

• Embodiments of this disclosure relate generally to novel nitrate-based gum compositions useful for prolonging prebiotic nitrate exposure in the oral cavity of a subject resulting in a rapid and local increase in intraoral and nasopharynx nitric oxide gas.
• the embodiment also contributes to increasing systemic nitric oxide bioavailability.
• the mouth is teeming with bacteria, most of them harmless. Normally the body's natural defenses and good oral health care, such as daily brushing and flossing, can keep these bacteria under control. However, without proper oral hygiene, bacteria can reach levels that might lead to oral infections, such as tooth decay and gum disease. In addition, lifestyle activities, in particular smoking, or taking medications, such as decongestants, antihistamines, painkillers, antibiotics, and diuretics, or current oral hygiene practices, such as mouthwashes, can reduce saliva composition and flow as well as change the microbiome of the oral cavity, which in turn is detrimental to oral health. Saliva is important because it washes away food and neutralizes acids produced by bacteria in the mouth, helping to protect the mouth from microbial invasion or overgrowth that might lead to disease.
• Oral health is essential to general health and quality of life. It is a state of being free from mouth and facial pain, oral and throat cancer, oral infection and sores, periodontal (gum) disease, tooth decay, tooth loss, and other diseases and disorders that limit an individual’s capacity in biting, chewing, smiling, speaking, and psychosocial wellbeing.
• the most common oral diseases are dental cavities, periodontal (gum) disease, oral cancer, oral infectious diseases, trauma from injuries, and hereditary lesions.
• Tooth decay is one of the most common chronic conditions of childhood in the United States. Untreated tooth decay can cause pain and infections that may lead to problems with eating, speaking, playing, and learning. In the United States, about 1 of 5 (20%) children aged 5 to 11 years have at least one untreated decayed tooth; and about 1 of 7 (13%) adolescents aged 12 to 19 years have at least one untreated decayed tooth. The percentage of children and adolescents aged 5 to 19 years with untreated tooth decay is twice as high for those from low-income families (25%) compared with children from higher-income households (11%). There are threats to oral health across the lifespan. Nearly one-third of all adults in the United States have untreated tooth decay.
• Periodontitis is a set of inflammatory diseases affecting the periodontium, i.e., the tissues that surround and support the teeth. Periodontitis involves progressive loss of the alveolar bone around the teeth, and, if left untreated, can lead to the loosening and subsequent loss of teeth. Periodontitis is caused by microorganisms that adhere to and grow on the tooth's surfaces, along with an overly aggressive immune response against these microorganisms. Periodontitis manifests as painful, red, swollen gums, with abundant plaque. Symptoms may include redness or bleeding of gums while brushing teeth, using dental floss, or biting into hard food (e.g.
• Periodontitis also has been shown to have effects outside of the mouth. For example, periodontitis has been linked to increased inflammation as indicated by increased levels of C-reactive protein and Interleukin-6. In addition, periodontitis has been shown to increase the risk for a number of other diseases, including but not limited to, stroke, myocardial infarction, atherosclerosis, diabetes, and pre-term labor.
• Oral cancer constitutes another concern in oral health.
• the incidence of oral cancer ranges from one to 10 cases per 100,000 people in most countries.
• the prevalence of oral cancer is relatively higher in men, in older people, and among people of low education and low income.
• Tobacco and alcohol are major causal factor and contribute to disruption of the microbiome, specifically, nitrate reducing bacteria on the tongue. As such smoking reduces the health promoting microbiome on the tongue.
• Asymptomatic transmission of SARS-CoV-2 remains a concern and owing to the peripheral anatomical location and frequent exposure of oral tissues to the external environment. With that said, saliva plays a major role in the asymptomatic spread of SARS-CoV-2, hence, saliva actively participates in SARS-CoV-2 transmission.
• the burden of oral diseases and other chronic diseases can be decreased simultaneously by addressing common risk factors. These include: decreasing sugar intake and maintaining a well-balanced nutritional intake to prevent tooth decay and premature tooth loss; consuming fruit and vegetables that can protect against oral cancer; stopping tobacco use and decreasing alcohol consumption to reduce the risk of oral cancers, periodontal disease and tooth loss; using protective sports and motor vehicle equipment to reduce the risk of facial injuries; safe physical environments, and most importantly, ensuring proper oral hygiene.
• Dental cavities can be prevented by maintaining a constant low level of fluoride in the oral cavity, however, fluoride and chlorhexidine mouthwashes may also lower the healthy microbiome in the oral that contributes to antimicrobial nitric oxide.
• the nasopharynx is a primary site of colonization by respiratory pathogens and it constitutes a port of entrance to the respiratory tract.
• the nasopharynx often harbors bacterial and viral pathogens responsible for both middle ear and sinus infections.
• the most common condition that affects the nasopharynx is nasopharyngitis, otherwise known as the common cold. This swelling of the nasal passages and throat is sometimes called an upper respiratory infection, or rhinitis.
• nasopharyngitis a virus, often rhinovirus, infects the nasopharynx.
• the nose is the primary entry site and target of SARS-CoV- 2.
• Asymptomatic transmission of SARS-CoV-2 remains a concern owing to the peripheral anatomical location and frequent exposure of both the oral and nasopharynx tissues to the external environment. Therefore, the oral -nasopharynx plays a critical role in the asymptomatic spread of SARS-CoV-2, hence, saliva and exhaled aerosolize water-mucus droplets from the nose participates in SARS-CoV-2 transmission.
• Nitrite derived from nitrate through nitrate reducing bacteria on the tongue surface, is considered cytocidal and cytostatic to common oral pathogens involved in caries and in periodontal disease, especially when acidified. Therefore, an increase in nitrate secretion and a subsequent increase in salivary nitrite may contribute to the overall protective effect against those infections conditions, affecting both hard and soft oral tissues. It is known that salivary glands may respond to periodontitis by enhancing the protective potential of saliva. Thus, it is likely that the increment in salivary nitrate-nitrite concentration, in patients with periodontal disease, may be due to an increase in nitrate secretion as a response of salivary glands to the inflammatory process. In accordance with this hypothesis, it has been reported that patients with oral candidiasis have increased salivary nitrates and nitrites concentration.
• nitric oxide is formed in the mouth and its concentration is directly related to salivary nitrite, which in turn is related in part to dietary nitrate intake.
• nitrite via the bioconversion from nitrate, under acidic conditions had an inhibitory effect, through NO production, on Streptococcus mutans, Lactobacillus easel and Actinomyces naeslundii.
• S. mutans was inhibited by a more acid pH
• the addition of nitrite caused a marked, further dose-dependent reduction in bacterial numbers after 24 hours of exposure. Similar effects were observed with A. naeslundii and L.
• Salivary nitrate an ecological factor in reducing oral acidity. Li Hl, Thompson I, Carter P, Whiteley A, Bailey M, Leifert C, Killham K.) Along similar lines, Radcliffe (2002) suggests that exogenous nitrite acidified by metabolic products of acidogenic bacteria in the mouth will be converted to products which inhibit growth of Streptococcus mutans.
• Salivary nitrate and nitrite may also have antimicrobial effects on Desulfovibrio species. (Mitsui T, Fujihara M, Harasawa R. Biosci Biotechnol Biochem. 2013;77(12):2489)
• Nitrate concentrations are elevated in body with diet nitrate-rich plants, such as leafy greens and beetroots, and certain oral bacteria convert nitrate into nitrite and the human body can effectively convert nitrite into nitric oxide by certain enzymatic and non-enzymatic processes, resulting in beneficial outcomes, including, reducing blood pressure and inhibiting the spread of disease-causing pathogenic organisms.
• the dietary pathway or the L-arginine-independent, nitrate-nitrite-nitric oxide dietary pathway, coined, enterosalivary nitrate pathway, is when dietary nitrate is swallowed and absorbed in the proximal gastrointestinal tract and via the circulatory system is absorbed and concentrated in the salivary gland where it is secreted into the mouth and subsequently reduced by nitrate-reducing bacteria to nitrite after 30 to 90 minutes; nitrite is subsequently swallowed and is further reduced to nitric oxide and related intermediates in the stomach, blood stream, and tissue.
• nitric oxide from the upper airways is, thus, likely to be produced in the nasal cavity, since exhaled nitric oxide levels were also higher during nasal compared to oral breathing in all subjects, including healthy controls. Furthermore, direct nasal sampling yielded very high nitric oxide values and nitric oxide from the upper airways will follow the airstream with every inhalation and thus, continuously flush the lower airways.
• inhaled nitric oxide at concentrations as low as 100 ppb significantly decrease pulmonary vascular resistance in patients with pulmonary hypertension, indicating that nasally derived nitric oxide could be physiologically important in the lung and, thus, act as an airborne, or "aerocrine" factor.
• the author goes on to indicate that nasally produced nitric oxide gas is bacteriostatic and exhibits antiviral properties, hence, participate in the unspecific primary mucosal defense line against infections.
• compositions and methods that bypass the enterosalivary nitrate circuit, and enable subjects to intermittently and rapidly augment intraoral and nasal nitric oxide.
• the present disclosure relates to the use of a nitrate-based formulation delivered in a compression-type chewing gum to prolong prebiotic nitrate exposure in the oral cavity.
• Use of the chewing gum by a subject enables a rapid and local increase in intraoral and nasopharynx nitric oxide gas.
• the chewing gum of the present disclosure also contributes to improved systemic nitric oxide bioavailability resulting from the subsequent swallowing of nitrate and bioconversion via the enterosalivary nitrate-nitrite-nitric oxide pathway.
• the chewing gum composition is designed to enable nitric oxide levels to be below the acceptable daily intake of 3.7 milligrams per kilogram of body weight per day (mg/kg bw/day).
• the design and composition of the gum allows for intermittent administration of the nitrate-based chewing gum throughout the day to immediately and locally increase oral-nasopharynx nitric oxide production and prolong the delayed systemic nitric oxide bioavailability.
• the novel gum compositions claimed herein uniquely enable subjects to achieve optimal nitric oxide levels both locally and systemically.
• the chewing gum compositions of the present disclosure uniquely contribute to a bi-phasic nitric oxide response: first by providing an instantaneous local increase in the oral and nasal cavity, and second as a response after swallowing, wherein followed by absorption in the gut, nitrate is concentrated in the salivary gland as a result of enterosalivary circulation.
• the invention further utilizes information about nitric oxide levels and acidity-alkalinity in an individual's oral cavity, specifically, monitoring real-time pH and nitric oxide metabolites, nitrate and nitrite, with rapid self-testing saliva test strips to make adjustment as to the dosing of the nitrate-formulated chewing gum.
• the gum composition of the present disclosure is thought to act by shifting the oral microbiome to a higher abundance of the nitric oxide promoting bacteria with the corresponding increase the in ratio of salivary nitrite-to-nitrate (>1) and an increase in the pH (>7).
• This shift in the oral microbiome corresponds to a decrease in bacteria associated with disease related to pathogens that contribute to gum inflammation, tooth decay, halitosis, and cardiometabolic complications.
• the disclosure herein comprises a novel chewing gum composition that rapidly increases intraoral-nasal cavity nitric oxide levels thereby bypassing the L-arginine- independent, nitrate-nitrite-nitric oxide dietary pathway.
• nitric oxide supplement products as well as prior art and publications, are exclusively based on improving nitric oxide levels by depending on the L-arginine- independent, nitrate-nitrite-nitric oxide dietary pathway.
• the invention provides a methodology for optimizing oral -nasal health by coupling or bundling a novel nitrate-formulated chewing gum with a saliva self-test to gain real-time information concerning the levels of salivary nitric oxide analytes in the oral cavity.
• This information may be utilized to maximize the antimicrobial activity of such analytes and consequently improve oral, nasopharyngeal and sinus health with intermittent chewing of nitrate-formulated gum.
• rapid saliva testing that may be used at-will and directly in the oral cavity for monitoring nitric oxide status enables regular monitoring and can be incorporated into a routine for improving oral and nasopharynx health.
• the present disclosure provides real-time feedback through the detection of saliva analytes and a biomarker of nitric oxide, to enables individuals to make realtime adjustments to oral hygiene regimens and to optimize oral health.
• users can rapidly, in a real-time fashion, evaluate nitric oxide levels in their oral cavities, and determine a corrective course for improving and maintaining oral hygiene.
• the invention provides a novel programmatic approach to oral hygiene comprising a nitrate-formulated chewing gum to extend nitrate exposure in the oral cavity to enhance or shift the microbiome from an acid or cariogenic microflora, to a nitrate-reducing microbiome.
• the chewing gum composition claimed herein provides a unique advantage by both prolonging exposure of the oral cavity to nitrate, while stimulating salivary secretion to contribution to downstream nitrate-nitrite-nitric oxide pathway with the subsequent ingestion of nitrate provided by the gum (which would not be the case for toothpaste or mouth rinse).
• the invention comprises the use of a nitric oxide generating chewing gum used in conjunction with intra-daily self-monitoring with a saliva test strip for promoting consumer compliance behavior.
• Colorimetric test strip outcomes may be recorded and tracked on electronic devices such as wearables or mobile phones providing reminders and updates to both user and dentist or healthcare provider through wireless messaging capabilities as to compliance and adherence to oral healthcare.
• the present disclosure provides systematic approaches for improving oral and sinus health.
• Nitric oxide decreases inflammation and pathogenic microbes and accordingly, use of the novel gum compositions as disclosed herein enables the decrease in the incidence of health issues related to oral health and the upper respiratory system, including but not limited to, dental cavities, tooth decay, gum disease, periodontitis, oral cancer and viral infections or virus sequestered in saliva and sinus, including nasopharyngitis.
• the gum compositions also decrease the viral load of nitric oxi de- sensitive coronavirus, including SARS CoV-1 and SARS-CoV-2.
• Figure 1 provides a schematic summary of nitric oxide bioavailability comparison of a nitrate-based chewing gum (thick line) versus an equal amount of nitrate-derived from an ingested capsule or beverage (thin line) as measured with MYFITSTRIP® saliva test strips for nitrite, the surrogate marker for nitric oxide, over the course of time.
• Figure 2 provides a graph showing intraoral nitric oxide gas formation (A), saliva nitrate (B), and saliva nitrite (C) at various times after chewing two (2) plant-derived, nitrate- formulated gum for 5 mins at 0 minutes and 45 minutes and then discarded.
• ARROW(S) represents the time point of administering chewing gum for 5 min and the number of ARROW(S) indicates the number of pieces.
• Figure 3 provides a graph showing intraoral nitric oxide gas formation (A), saliva nitrate (B), and saliva nitrite (C) at various times after chewing one (1) potassium nitrate- formulated gum for 5 minutes at 0 minutes and then discarded.
• ARROW(S) represents the time point of administering chewing gum for 5 min and the number of ARROW(S) indicates the number of pieces.
• Figure 4 provides a graph showing intraoral nitric oxide gas formation (A), saliva nitrate (B), and saliva nitrite (C) at various times after chewing three (3) potassium nitrate- formulated gum for 5 minutes at 0 minutes for 5 minutes and then discarded.
• ARROW(S) represents the time point of administering chewing gum for 5 min and the number of ARROW(S) indicates the number of pieces.
• Figure 5 provides a graph showing intraoral nitric oxide gas formation (A), saliva nitrate (B), and saliva nitrite (C) after chewing potassium nitrate-formulated gum at two different points for 5 minutes.
• A intraoral nitric oxide gas formation
• B saliva nitrate
• C saliva nitrite
• ARROW(S) represents the time point of administering chewing gum for 5 min and the number of ARROW(S) indicates the number of pieces.
• Figure 6 provides a graph showing intraoral nitric oxide gas (A) and nasal exhaled nitric oxide at various times after chewing potassium nitrate-formulated gum. In this example, 1 piece is administered at 0 minutes for a duration of 5 min discarded.
• Figure 7 shows the relative abundance of the bacterial species before and after chewing potassium nitrate-formulated gum.
• Whole genome metagenomic sequencing or Shotgun sequencing was used to look at all the DNA present in a microbiome sample.
• Saliva samples were in subjects with low nitrite-to-nitrate ratio with Probiotic Nitric Oxide Tests by MyFitStrip® and low saliva pH (below 7) as detected with Oral Health Strips by MyFitStrips®.
• Saliva was collected according to the methodology provided by Bristle Oral Health Labs. Upon collection, subject chewed potassium-ascorbic acid formulated gum for for 5-10 min twice over a period 3-4 hours.
• nitrite-to-nitrate and pH were measure and a second saliva sample was collected for Shotgum sequencing analysis according to the procedures of Bristle Labs.
• improving oral and nasopharynx health by enhancing nitric bioavailability by increasing the relative abundance of Rothia aeria, Rothia mucilaginosa, Neisseria flavescens, Neisseria subflava, Haemophilus parainfluenzae within saliva after 6 hrs from chewing 3 pieces at 0, 2 and 4 hrs at of said gum during this period with corresponding reduction of disease associated bacteria Tannerella forsythia, Treponema socranskii, Fusobacterium periodonticum, Porphyromonas gingivalis, Streptococcus constellatus, Fusobacterium nucleatum, Parvimonas micra, Prevotella melaninogenica, Prevotella histicola, Candida albicans.
• nitric oxide is a short-lived, endogenously produced gas that acts as a signaling molecule in the body. Signal transmission by a gas, produced by one cell, which penetrates membranes and regulates the function of other cells was recognized for the first time as an entirely new principle for signaling in the human organism.
• Related research proved the crucial role that nitric oxide plays in such fundamental biological processes as regulation of blood pressure, functioning and malfunctioning of the immune system, and activation of mechanisms in the central nervous system affecting everything from gastric motility to memory to behavior.
• nitric oxide has antimicrobial activity in the oral cavity: more specifically, the inventors herein have observed that oxides of nitrogen produced non-enzymatically and enzymatically from the serial chemical reduction of nitrate to nitrogen oxides, in particular nitric oxide, are potently antimicrobial.
• the inventors have recognized the need to deliver nitric oxide locally as well as systemically. Further the need to create, sustain and monitor a threshold level of the appropriate precursor within the oral cavity is accomplished by the use of salivary test strips.
• compositions and that enable the optimization of nitrate metabolites to maintain a healthy and antimicrobial environment in the oral and nasal cavity of a subject may be accomplished by the use of chewing gum to slowly release a nitrate- formula to increase the exposure of the critical oral microbiome to the nitrate, which behaves as a prebiotic to both shift the cariogenic and acid promoting bacteria to a health beneficial nitrate-reducing bacterium.
• nitric oxide In the case of coronavirus disease (COVID-19), the inventor previously established that restoring nitric oxide improves endothelial dysfunction and contributes to pulmonary vasodilation, antithrombotic, and direct antiviral activity (Microbes and Infection, Volume 22, Issues 4-5, 2020, p.149-150). Nitric oxide interferes with the interaction between coronavirus viral S-protein and its cognate host receptor, ACE-2. Nitric oxide- mediated S-nitrosylation of viral cysteine proteases and host serine proteases, TMPRSS2, which are both critical in viral cellular entry, appear to be nitric oxide sensitive. Based on a report of improved lung function during the 2003 SARS outbreak, FDA’s emergency expanded use of nitric oxide gas is now underway for treating COVID- 19.
• the phrase “about 8” preferably refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase “about 8%” preferably (but not always) refers to a value of 7.2% to 8.8%, inclusive.
• all ranges are inclusive and combinable.
• the recited range should be construed as including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, “2-5”, and the like.
• a list of alternatives is positively provided, such a listing can be interpreted to mean that any of the alternatives may be excluded, e.g., by a negative limitation in the claims.
• the recited range may be construed as including situations whereby any of 1, 2, 3, 4, or 5 are negatively excluded; thus, a recitation of “1 to 5” may be construed as “1 and 3-5, but not 2”, or simply “wherein 2 is not included.” It is intended that any component, element, attribute, or step that is positively recited herein may be explicitly excluded in the claims, whether such components, elements, attributes, or steps are listed as alternatives or whether they are recited in isolation.
• nitrate-rich source holds potential effects against dental caries via bioconversion of nitrate to nitrite to nitric oxide resulting in elevating pH levels which is predictably a reduction of acidogenic cariogenic bacteria.
• persistent anti- cariogenic effect which is likely due to the clearance of nitrate which needs to be periodically replenished based on test strip outcomes.
• the current example demonstrates an immediate production of nitric oxide gas (A) with a corresponding reduction of nitrite (C) from nitrate (B) within 3 to 5 min of chewing gum.
• a subsequent chewing of gum at 45 min resulted in a similar response as the 3-5 min timepoint although at a slightly elevated and persistent elevation of gas, nitrate and nitrite that persisted for a minimum of an additional hour.
• the intermittent chewing was found to be additive and persistent in elevating antimicrobial levels of nitric oxide in the oral cavity and as such it resulted in maintaining and improving oral hygiene: 1.
• dietary nitrate source in a delivery format that optimizes immediate local levels of nitrate, including but not limited to nitrate-rich gum or slow releasing gummy or chewy or lozenge and the like and 2.
• a saliva test strips to both ensure, indirectly, nitrate content and validate bioconversion of nitrate to antimicrobial nitrite.
• Example 2 shows both an immediate increase in antimicrobial nitric oxide gas (A) with the increase in the corresponding precursor and metabolite, nitrate (B) and nitrite (C), respectively, with the chewing of one potassium nitrate-based chewing gum piece for 5 minutes and then discarded.
• ARROW(S) represents the time point of administering chewing gum for 5 min of chewing. Methods for detecting nitric oxide gas and salivary metabolites are described above.
• Example 2 demonstrates an immediate production of nitric oxide gas (A) with a corresponding reduction of nitrite (C) from nitrate (B) within 3 to 5 min of chewing gum and that persisted for a minimum of an additional hour with antimicrobial nitric oxide levels with an associated pH of >7.5 during this time period.
• Example 3 shows an immediate and sustain elevation of intraoral nitric oxide gas formation (A), saliva nitrate (B), and saliva nitrite (C) at various times after chewing three (3) potassium nitrate-formulated gum for 5 minutes at 0 minutes and then discarded.
• ARROW(S) represents the time point of administering chewing gum for 5 min and the number of ARROW(S) indicates the number of pieces.
• Example 3 demonstrates an immediate and sustained production of nitric oxide for 3 hours with an associated pH of >7.5 during this time period.
• Example 4 shows intraoral nitric oxide gas formation (A), saliva nitrate (B), and saliva nitrite (C) at various times after chewing one (1) potassium nitrate-formulated gum at intermittent time points.
• gum is administered at 0 time for 5 minutes and 150 min later and in both cases discarded after 5 min of chewing.
• ARROW(S) represents the time point of administering chewing gum for 5 min and the number of ARROW(S) indicates the number of pieces.
• Example 4 is the best example of an immediate local increase in nitric oxide which in turn contributed in an additive fashion with the intermittent addition of another gum to increase both the local and systemic nitric oxide level.
• the unique and novel aspect of this example is that the duration of nitric oxide bioavailability was extended to 5 hours with a cumulative lower amount when administrated over time in comparison to a single high dose as shown in Example 3.
• Bioconversion of nitrate chewing gum increases intraoral and nasal exhaled nitric oxide
• NObreath® (NOB; Bedfont, Kent, UK) was used to measure oral nitric oxide gas and modified with a nose piece to capture exhaled air from a nostril where the opposing nostril is press closed during the 10 second exhalation.
• NOB was used to measure nitric oxide gas. These devices were assessed based on the National Institute for Health and Clinical Excellence (NICE) guideline. NOB is designed to measure fractional exhaled nitric oxide (FeNO) in the human breath and a normal FeNO test is any number less than 25 parts per billion (ppb) in adults. Levels above this value have been used to assess inflammatory response in the lung where inducible nitric oxide synthase is activated in immune cells in response to an inflammatory response. NOB is used to evaluate nitric oxide gas generated locally in the mouth.
• NeNO fractional exhaled nitric oxide
• ppb parts per billion
• Participants were screened in advance, excluding asthmatics, individuals with respiratory infections and healthy individuals with levels about 35 ppb which was due to nitraterich beet or leafy green diets or excessive nasal breathing within 6-18 hour prior to testing. All included healthy subjects consistently exhaled between 10-30 ppb which was influenced with exercise and diet, especially, nitrate-rich plant-based foods and diets and excessive nasal breathing.
• a total of 4-6 subjects were evaluated 2-4 time over the course of 2 weeks.
• the Figures are measurements from a single individual and representative of the other 4-6 subjects. Participates underwent the measurement in a sitting position, always holding the monitor upright. After inhaling to total lung capacity, participants then exhaled through the mouthpiece, ensuring that the visual indicator marker was held in the middle of the bands for proper measurement. The exhalation time was approximately 10 seconds. All participants were asked to repeat the measurement 3 times to verify the repeatability of the device.
• the baseline values ranging between 10-35 ppb is reflective of lung and respiratory tract sourced nitric oxide prior to chewing gum.
• Example 5 shows intraoral (A-E) and nasal (B-F) exhalation for 10 seconds at 4 time points including 0 (pre-gum chewing) and 5, 10, 30 min after chewing one (1) piece of potassium-ascrobate-zinc gum for 5 min beginning at 0 time point.
• Example 5 shows an immediate increase in both intraoral and nasal cavity nitric oxide gas formation.
• Figure 6 represents 3 healthy subjects wherein oral and nasal nitric oxide measurements were taken at 4 time points; subjects 1, 2, 3 results are shown as A and B, C and D, and E and F, respectively.
• Baseline level of exhaled nasal nitric oxide gas was found to be l-2x higher than oral and the magnitude of the exhaled in nitric oxide gas was found to be consistently higher in nasal compared to oral in absolute terms by 2-4x higher. Further, the ‘hang time’ of nasal nitric oxide appeared to persistent longer than that of the mouth.
• Example 5 understates the importance of nitric oxide chewing gum in improving local nasal nitric oxide, especially in subject with low nasal sinus nitric oxide production, since most of the nitric oxide from the upper airway is produced in the nasal cavity.
• Lundberg et al (1996) reminds us recent studies have shown that inhaled NO (typically from a external device) at concentrations as low as 100 ppb significantly decrease pulmonary vascular resistance in patients with pulmonary hypertension indicating that nasally derived nitric oxide is physiologically important in the lung and, thus, act as an airborne, or "aerocrine" factor.
• Nitric oxide also has bacteriostatic and antiviral properties, and nasally derived nitric oxide can participate in the mucosal defense line against infections.
• the invention herein is a new and unique composition and method to provide nitric oxide to the nasal cavity as exemplified in Figure 6, thereby, supporting a source for antimicrobial nitric oxide to the nasopharynx and respiratory tract to combat both infections and manage pulmonary hypertension.
• Nitrate chewing gum shifts oral microbiome to high NO bioavailability
• Figure 7 shows the relative abundance of the bacterial species before and after chewing potassium nitrate-formulated gum.
• Whole genome metagenomic sequencing or Shotgun sequencing was used to looks at all the DNA present in a microbiome sample.
• Saliva samples were in subjects with low nitrite-to-nitrate ratio with Probiotic Nitric Oxide Tests by MyFitStrip® and low saliva pH (below 7) as detected with Oral Health Strips by MyFitStrips®.
• Saliva was collected according to the methodology provided by Bristle Oral Health Labs.
• nitrite-to-nitrate and pH were measure and a second saliva sample was collected for Shotgum sequencing analysis according to the procedures of Bristle Labs.
• Nitrate-reducing bacteria Rothia and Neisseria are consistently found at higher levels in individuals free of oral disease in comparison to individuals with caries, periodontitis, and halitosis and increase when nitrate-rich diets are consumed.
• bacteria normally associated with disease such as Veillonella -- which is often found with high caries — and Prevotella - associated with periodontal diseases and halitosis — decrease in the presence of nitrate-rich foods and diet.
• nitrate as an ecological factor stimulating health-associated species and functions.
• Figure 7 demonstrates that chewing gum can replace nitrate-rich diets and foods which works through the enterosalivary loop at relatively high ADI or concentrations of dietary nitrate whereas chewing gum delivers prebiotic nitrate directly, independent of the enterosalivary loop, to enhance health associated microbiome while reducing disease associate bacterial among other nitric oxide-sensitive infectious disease, including Helicobacter and Candida.
• the present disclosure has been discussed in terms of certain embodiments, it should be appreciated that the present disclosure is not so limited, hence, to include, restoring nitric oxide deficiency in smokers, ex-smokers, and secondhand smokers, especially among the previous smokers in their later years where nitric oxide deficiency is most pronounced with associated saliva acidity and diminished immune function.
• the composition can be modified to enhance bioactivity with the addition of specific vitamin Bs, specifically, thiamine mononitrate, nicotinamide riboside, N-acylcysteine (NAC).
• NAC N-acylcysteine
• 50 mg of caffeine to synergize in the enhancement of nitric oxide-mediated activities.

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• 2023
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