WO2021209998A1 - Composition for the treatment of respiratory symptoms and methods thereof - Google Patents

Abstract

The present invention relates to a composition and method for the treatment of respiratory symptoms in mammals. More specifically, this invention relates to a novel composition, comprising a combination of at least one pyrazine, at least one cannabinoid, in a specific enhancing formulation. The enhancing formulation is configured to increase the effectiveness of the pyrazine and/ or the cannabinoid; and to enhance their binding and/or molecular docking to specific receptors of the targeted mammal.

Description

COMPOSITION FOR THE TREATMENT OF RESPIRATORY SYMPTOMS AND METHODS THEREOF

FIELD

The present invention relates to a composition and method for the treatment of respiratory symptoms in mammals. More specifically, this invention relates to a novel composition, comprising a synergic combination of at least one pyrazine, at least one cannabinoid, in a specific enhancing formulation. The enhancing formulation is configured to increase the effectiveness of the pyrazine and/ or the cannabinoid; and to enhance their binding and/or molecular docking to specific receptors of the targeted mammal.

BACKGROUND

Respiratory symptoms are common symptoms of lung or heart conditions, emotions, or injury. In some cases, respiratory symptoms may be a symptom of a serious or life-threatening condition that should be immediately evaluated in an emergency setting. These include: Asthma, Pneumonia, Anaphylaxis, Chest trauma, Choking on a foreign object in airway, Epiglottitis, Myocardial infarction (heart attack), Pneumothorax (collapsed lung), Pulmonary embolism (blockage of a pulmonary artery due to blood clot), Chronic obstructive pulmonary disease, or COPD, lung cancer or Acute respiratory distress syndrome (ARDS).

One of the recent causes for respiratory symptoms are coronaviruses. Coronaviruses are an extremely common cause of colds and other upper respiratory infections.

Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were subsequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of COVID-19 have been implemented to control the current outbreak. Special attention and efforts to protect or reduce transmission should be applied in susceptible populations including children, health care providers, and elderly people (see Rothan HA, Byrareddy SN The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak [published online ahead of print, 2020 Feb 26] . J Autoimmun. 2020; 109: 102433. ) “Novel coronavirus” SARS-CoV-2 is rapidly spreading worldwide with a significant mortality rate. There is real threat of a global pandemic of an easily transmissible disease, with a significant morbidity and mortality, from this epidemic. The disease which is now called COVID-19 is caused by a novel coronavirus, labelled as SARS-CoV-2, which was discovered through whole-genome sequencing, polymerase chain reaction (PCR) and culture of bronchoalveolar lavage fluid obtained from affected patients. This virus, which is the seventh coronavirus that has been proven to infect humans, has 75- 80% genomic similarity to the severe acute respiratory syndrome coronavirus (SARS-CoV), 50% to the Middle East Respiratory syndrome coronavirus (MERS-CoV) and 96% to a bat coronavirus and uses the same cell receptor, angiotensin-converting enzyme II (ACE2), that is used by SARS-CoV. (see Arabi, Y.M., Murthy, S. & Webb, S. COVID-19: a novel coronavirus and a novel challenge for critical care. Intensive Care Med (2020).)

As a novel infectious disease, there is an urgent unmet need to conduct research to determine optimal treatment modulation of the immune system, and how best to provide support for failed organ systems.

At present, there are no specific drugs or vaccine against COVID-19 infection for potential therapy of humans.

SUMMARY OF THE INVENTION

One object of the invention is to disclose a composition for the treatment of respiratory symptoms in a mammalian subject, wherein said composition comprising a combination of at least one pyrazine, at least one cannabinoid, in a specific enhancing formulation.

Another object of the invention is to disclose the composition as defined in any of the above wherein said composition further comprising a pH controlling agent.

Another object of the invention is to disclose the composition as defined in any of the above wherein said enhancing formulation is configured to increase the effectiveness of said at least one pyrazine and/ or said at least one cannabinoid; and to enhance their binding and/or molecular docking to specific protein receptors of the said mammal.

Another object of the invention is to disclose the composition as defined in any of the above wherein said respiratory symptoms are selected from a group consisting of dyspnea, tachypnea, hypopnea, hyperpnea, apnea, pneumonia , acute bronchitis, chronic obstructive pulmonary disease, (COPD), acute respiratory distress syndrome (ARDS), emphysema, chronic bronchitis, pleuritis, COVID-19, SARS , MERS and any combination thereof.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said respiratory symptoms are selected from a group consisting of cardiovascular symptoms accompanying respiratory symptoms. Another object of the invention is to disclose the composition as defined in any of the above, said symptoms are selected from a group consisting of asystole, angina, arrhythmia, bradycardia, tachycardia and any combination thereof.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said mammal is human or animal.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said respiratory symptoms are caused by COVID-19 infection.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said pyrazine is pyrazinamide.

Another object of the invention is to disclose the composition as defined in any of the above,, wherein said pyrazine is nicotinamide.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said cannabinoid is selected from a group consisting of Tetra-hydro-cannabinoids (d9- THC), Tetra-hydro-cannabinoids (d8- THC), Tetra-hydro-cannabinolic acid (THCA- d9), Tetra-hydro-cannabivarin (THCV/THC-C3), Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabigerolic acid (CBGA), Cannabinol (CBN), Cannabidiolic acid (CBNA), Cannabichromene (CBC), Cannabichromenic acid (CBCA), and any combination thereof.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said specific enhancing formulation comprises of two groups: a. cannabinoid system receptors enhancers/ligands; b. pH regulator for enhancing activity said pyrazine and/ or said cannabinoid.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said cannabinoid system receptors enhancers/ligands comprises terpenes .

Another object of the invention is to disclose the composition as defined in any of the above, wherein said pH controlling agent is selected from a group consisting of acid, base, buffer and any combination thereof.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said composition is configured to be administrable in a manner selected from a group consisting of a tablet, a capsule, a pill, lyophilized, powder, emulsion, granulated powder, liquid, a solution, a patch, nebulizer, inhaler, nasal spray, aerosol and any combination thereof. Another object of the invention is to disclose the composition as defined in any of the above, wherein said composition is configured to be administrable in a manner selected from a group consisting of intravenous, buccal, sublingual, depository, inhalation and orally.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said composition is configured to be administrable in a manner selected from a group consisting of fast release, slow release, sustained release, controlled release and any combination thereof.

Another object of the invention is to disclose the composition as defined in any of the above, wherein said composition additionally comprising ingredients selected from a group consisting solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancer s/reducers, surfactants, chelating agents, adjuvants and any combination thereof.

Another object of the invention is to disclose the composition as defined in any of the above, additionally comprising at least one additional compound selected from a group consisting of binders, excipients, stabilizers, anti-adherents, disintegrants, sorbents and preservatives.

One object of the invention is to disclose a method for treating of respiratory symptoms in a mammalian subject, comprising administrating a composition comprising a combination of at least one pyrazine, at least one cannabinoid, in a specific enhancing formulation.

BRIEF DESCRIPTION OF FIGURES

Figure 1: The systemic and respiratory disorders caused by COVID-19 infection;

Figure 2: Chemical structures of selected pyrazines;

Figure 3: Mode of action for pyrazinamide; and

Figure 4: The chemical constituents of one embodiment composition of the current invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The current invention discloses a novel composition for the treatment of respiratory symptoms, The composition comprises a synergic combination of at least one pyrazine and at least one cannabinoid, in a specific enhancing formulation. The enhancing formulation comprises acidic or basic solutions configured to increase the effectiveness of the pyrazine and/ or the cannabinoid; and at least one terpene and/or enhancer configured for enhancing cannabinoid receptors’ binding and/or molecular docking and to enhance their binding and/or molecular docking to specific receptors of the targeted mammal.

The term Respiratory symptoms refers hereinafter to common symptoms of lung or heart conditions, emotions, or injury.

The term Coronaviruses refers hereinafter to a group of related RNA viruses that cause diseases in mammals and birds. In humans, these viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (which is also caused by other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARS, MERS, and COVID-19 (see hereinafter).

Known coronaviruses to infect humans, are: HCoV-229E, HCoV-OC43 HCoV-NL63, HCoV- HKU1, MERS-CoV, the original SARS-CoV (or SARS-CoV-1), and SARS-CoV-2.

These viruses are associated with a range of respiratory symptoms, including high-morbidity outcomes. For example, Human coronavirus OC43 (HCoV-OC43) is a member of the species Betacoronavirus 1 which infects humans and cattle. It is an enveloped, positive-sense, single- stranded RNA virus which enters its host cell by binding to the N-acetyl-9-O-acetylneuraminic acid receptor. Human coronavirus 229E (HCoV-229E) is a species of coronavirus which infects humans and bats. It is an enveloped, positive-sense, single-stranded RNA virus which enters its host cell by binding to the APN receptor. Both virus strains (Human coronavirus OC43 and Human coronavirus 229E ) are responsible for the common cold.

The term Middle East Respiratory Syndrome (MERS) refers hereinafter to an illness caused by a coronavirus called Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Most MERS patients developed severe respiratory illness with symptoms of fever, cough and shortness of breath. About 3 or 4 out of every 10 patients reported with MERS have died.

The term Severe Acute Respiratory Syndrome (SARS) refers hereinafter to a viral respiratory disease of zoonotic origin caused by severe acute respiratory syndrome coronavirus (SARS- CoV or SARS-CoV-1), the first-identified strain of the SARS coronavirus species severe acute respiratory syndrome-related coronavirus (SARSr-CoV). The syndrome caused the 2002-2004 SARS outbreak.

SARS was a relatively rare disease; at the end of the epidemic in June 2003, No cases of SARS- CoV have been reported worldwide since 2004

In 2019, the related virus strain severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) was discovered. This new strain causes COVID-19, a disease which brought about the COVID-19 pandemic.

The novel composition /cocktail provides :Prophylaxis; increasing efficacy ; reducing dosing; and dose sparing

The term COVID-19, short for "coronavirus disease 2019 " is the official name given by the World Health Organization to the disease caused by this newly identified coronavirus.

The term pyrazine refers hereinafter to a heterocyclic aromatic organic compound with the chemical formula C4H4N₂. (Fig. 2).

Pyrazine is less basic than pyridine, pyridazine and pyrimidine.

Pyrazine and a variety of alkylpyrazines are flavor and aroma compounds found in baked and roasted goods. Alkylpyrazines are chemical compounds based on pyrazine with different substitution patterns. Some alkylpyrazines are naturally occurring highly aromatic substances which often have a very low odor threshold and contribute to the taste and aroma of various foods including cocoa, baked goods, coffee and wines. Alkylpyrazines comprise inter alia :2- Methylpyrazine; 2,3-Dimethylpyrazin; 2,5-Dimethylpyrazine; 2,6-Dimethylpyrazine; and 2,3,5,6-Tetramethylpyrazine.

Tetramethylpyrazine (also known as ligustrazine) is reported to scavenge superoxide anion and decrease nitric oxide production in human polymorphonuclear leukocytes.

The term pyrazinamide (PZA) refers hereinafter to a nicotinamide analogue (Fig. 2), was first chemically synthesized in 1936 but its antituberculosis was not recognized till 1952. PZA is a critical frontline TB drug that plays a unique role in shortening the treatment period from 9-12 months to 6 months). The inclusion of PZA with isoniazid (INH) and rifampin (RIF) forms the basis for the current short course chemotherapy based on the work by McDermott and colleagues in a mouse model of TB infection (McCune RM, Jr, McDermott W, Tompsett R. The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug. J Exp Med. 1956;104:763 802). The terms nicotinamide (NAM) or niacinamide, relates to a form of vitamin B3 found in food and used as a dietary supplement and medication. It is an amide of nicotinic acid (Fig.

2). It is a water soluble vitamin.

The terms Avigan or Favipiravir relate to, is an antiviral medication used to treat influenza in Japan.. It is also being studied to treat a number of other viral infections including COVID-19.] Favipiravir is a pyrazinecarboxamide derivative. (Fig. 2).

The term cannabinoid refers hereinafter to a class of diverse chemical compounds which are ligands for cannabinoid receptors. Cannabinoids were primarily discovered in marijuana (cannabis flower) and hashish (compressed cannabis resin) from the plant of Cannabis Sativa. Cannabinoids, comprise, but not limited, to the following compounds d9- THC- Tetra- hydro-cannabinoids; THC total (THC+THCA); d8- THC neutral,- Tetra-hydro-cannabinoids; THCV etrahydrocannabivarin; THCA- d9- Tetra-hydro-cannabinolic acid; THCA; THCV/THC-C3 - Tetra-hydro-cannabivarin ;CBD - Cannabidiol and CBDA - Cannabidiolic acid; CBDV - Cannabidivarin ;CBG - Cannabigerol and CBGA - Cannabigerolic acid; CBN - Cannabinol; CBNA - Cannabidiolic acid, CBC; Cannabichromene ; and CBCA Cannabichromenic acid.

As used herein after, the term terpenes and/or enhancers, refers hereinafter to a large and diverse class of organic compounds, produced by a variety of plants. Terpenes are derived biosynthetically from units of isoprene, which has the molecular formula CsHx The basic molecular formula of terpenes are multiples of that, (CsHx)n where n is the number of linked isoprene units. Terpenes are fragrant oils that give cannabis its aromatic diversity.

Terpens and Alkaloids Mono-terpens ; Sesqui- terpens; Friedelin and Epifreidelin; carvone and dihydricarvone; Cannabistivine and Anhydrocannabistivin; Sterole; , Choline, Anandamide, capsaicin, LPI (Lysophosphatidylinositol), Resiniferatoxin (RTX), and also enhancers for other cannabinoid receptors as CB1, CB2, TRPV1 and TRPV2.

Terpenes as enhancers The cannabis plant consists of a wide variety of chemicals and compounds. About 140 of these belong to a large class of aromatic organic hydrocarbons known as terpenes

Terpenoids are known for their medicinal properties including anti-inflammatory and anticancer activities [21,22,23], as well as being considered as promoters and instigators of therapeutic phytocannabinoid activity. Although comprising only a few percent of the total secondary metabolites in cannabis flowers, the effect of terpenoids may be of great significance (Vega, R.J.S.; Xolalpa, N.C.; Castro, A.J.A.; Rέ bz Gonzdlez, C.; Rέ bz Ramos, J; Rέ bz Gutwrrez, S. Terpenes from Natural Products with Potential Anti-Inflammatory Activity. In Terpenes and Terpenoids; Perveen, S., Al-Taweel, A., Eds.; IntechOpen: London, UK, 2018; pp. 59 85).

Terpenes in Cannabis :The following are non- limiting examples of terpenes found in cannabis plants: a. Myrcene: Myrcene specifically b-myrcene, is a monoterpene and the most common terpene produced by cannabis; b. Pinene: Pinene is a bicyclic monoterpenoid; c. b-caryophyllene, Caryophyllene: Beta-caryophyllene is a sesquiterpene. Caryophyllene is the only terpene known to interact with the endocannabinoid system (CB2). Studies show b-caryophyllene holds promise in cancer treatment plans. Research shows shows that b-caryophyllene selectively binds to the CB2 receptor and that it is a functional CB2 agonist. Further, b-caryophyllene was identified as a functional non-psychoactive CB2 receptor ligand in foodstuff and as a macrocyclic anti-inflammatory cannabinoid in cannabis;

Linalool-Linalool is a non-cyclic monoterpenoid. As shown by the Ma et al study, (Ma, Jianqun, et al. "Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-KB activation." International immunopharmacology 29.2 (2015): 708- 713) , linalool may significantly reduce lung inflammation caused by cigarette smoke by blocking the carcinogenesis induced by benz[a]anthracene, a component of the tar generated by the combustion of tobacco. This finding indicates limonene may be helpful in reducing the harm caused by inhaling cannabis smoke. Linalool boosts the immune system as it directly activates immune cells through specific receptors and/or pathways. The Sabogal-Guaqueta et al study( Sabogal-Gudqueta AM, Osorio E, Cardona-Gomez GP. Linalool reverses neuropathological and behavioral impairments in old triple transgenic Alzheimer's mice. Neuropharmacology. 2016 Mar;102: 111- 120..) suggests linalool may reverse the histopathological (the microscopic examination of biological tissues to observe the appearance of diseased cells and tissues in very fine detail) hallmarks of Alzheimer’s Disease and could restore cognitive and emotional functions via an anti-inflammatory effect. d. Camphene: Camphene, a plant-derived monoterpene, e. Terpineol: a-Terpineol, terpinen-4-ol, and 4-terpineol are three closely related monoterpenoids. Terpineol, specifically a-terpineol, is known to have calming, relaxing effects. It also exhibits antibiotic, AChe inhibitor and antioxidant antimalarial properties; f. Phellandrene; g. Carene: Delta-3 -carene is a bicyclic monoterpene; h. Humulene: Humulene is a sesquiterpene also known as a-humulene and a- caryophyllene; an isomer of b-caryophyllene. Humulene is found in hops, cannabis sativa strains, and Vietnamese coriander, among other naturally occurring substances. Humulene is what gives beer its distinct ‘hoppy’ aroma. Humulene is considered to be anti-tumor, anti -bacterial, anti-inflammatory, and anorectic (suppresses appetite). It has commonly been blended with b-caryophyllene and used as a major remedy for inflammation. Humulene has been used for generations in Chinese medicine. It aids in weight loss by acting as an appetite suppressant. i. Pulegone: Pulegone, a monocyclic monoterpenoid, is a minor component of cannabis j. Sabinene: Sabinene is a bicyclic monoterpene

Phenolic Compounds: O-glycoside; Cannaflavin A; Cantalanin B; and Canabisin D, Friedelin and Epifreidelin.

Respiratory Symptoms: The medical terms for respiratory symptoms include dyspnea (difficulty breathing), tachypnea (rapid breathing), hypopnea (shallow breathing), hyperpnea (deep breathing), and apnea (absence of breathing). Breathing problems may occur in conditions affecting the lungs alone or may be seen in association with more generalized conditions, such as dehydration or infections.

Chronic obstructive pulmonary disease (COPD, includes emphysema and chronic bronchitis) and asthma are common causes of respiratory symptoms. Other common causes include infections, such as pneumonia or acute bronchitis. Inflammation causes respiratory symptoms, as seen in pleuritis or chronic bronchitis. Depending on the cause, respiratory symptoms may originate from one or both lungs and may be accompanied by rapid heart rate (tachycardia), low blood pressure (hypotension), or other cardiovascular signs and symptoms.

Respiratory conditions can also stem of :Asthma, Anaphylaxis, Chest trauma, Choking on a foreign object in airway, Epiglottitis, Myocardial infarction (heart attack), Pneumothorax (collapsed lung), Pulmonary embolism (blockage of a pulmonary artery due to blood clot), Chronic obstructive pulmonary disease, or COPD, lung cancer or Acute respiratory distress syndrome (ARDS).

Heart conditions can lead to respiratory symptoms, especially in severe cases, such as congestive cardiac failure. Anxiety and panic attacks are common causes of respiratory symptoms and include rapid breathing that may result in hyperventilation and fainting. Airway obstruction causes respiratory symptoms that may include rapid shallow breathing. Lung injury from chest trauma can also lead to respiratory symptoms.

Respiratory symptoms may accompany other symptoms that vary depending on the underlying disease, disorder or condition. Symptoms that frequently affect the respiratory tract may also involve other body systems.

Cardiovascular symptoms that may occur along with respiratory symptoms Respiratory symptoms may accompany symptoms related to the cardiovascular system including: Absence of heart beat (asystole); angina (chest pain due to decreased blood supply to heart muscle), chest pain or pressure, irregular heartbeats (arrhythmia), low heart rate (bradycardia), or rapid heart rate (tachycardia).

In some cases, respiratory symptoms can be life threatening. The potential complications of respiratory symptoms can be : heart failure, myocardial infarction (heart attack), organ failure or dysfunction, respiratory failure and respiratory arrest, spread of cancer, spread of infection, or stroke.

Coronavirus Infection: Coronavirus is one of the major pathogens that primarily targets the human respiratory system. Previous outbreaks of coronaviruses (CoVs) include the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome (MERS)- CoV which have been previously characterized as agents that are a great public health threat.

Severe acute respiratory syndrome-related coronavirus (SARSr-CoV or SARS-CoV) is a species of coronavirus which infects humans, bats and certain other mammals. It is an enveloped positive-sense single- stranded RNA virus that enters its host cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.

Two strains of the virus have caused outbreaks of severe respiratory diseases in humans: severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), which caused the 2002-2004 outbreak of severe acute respiratory syndrome (SARS), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is causing the current pandemic of COVID-19. There are hundreds of other strains of SARS-CoV, all of which are only known to infect non-human species.

Severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first identified strain of the SARS coronavirus species severe acute respiratory syndrome related coronavirus (SARSr-CoV). The syndrome caused the 2002-2004 SARS outbreak.

SARS was a relatively rare disease; at the end of the epidemic in June 2003, the incidence was 8,422 cases with a case fatality rate (CFR) of 11%. No cases of SARS-CoV-1 have been reported worldwide since 2004. As of 2020, SARS-CoV-1 is considered eradicated in humans, but as the virus also infects animals, it is possible that it will re-emerge in the future.

In December 2019, another strain of SARS-CoV was identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This new strain causes coronavirus disease 2019 (COVID-19), a disease which brought about the COVID-19 pandemic.

Symptoms of CO ID -19 The most common symptoms at onset of COVID-19 illness are fever, cough, and fatigue, while other symptoms include sputum production, headache, haemoptysis, diarrhoea, dyspnoea, and lymphopenia. Clinical features revealed by a chest CT scan presented as pneumonia, however, there were abnormal features such as RNAaemia, acute respiratory distress syndrome, acute cardiac injury, and incidence of grand-glass opacities that led to death In some cases, the multiple peripheral ground-glass opacities were observed in subpleural regions of both lungs that likely induced both systemic and localized immune response that led to increased inflammation. Regrettably, treatment of some cases with interferon inhalation showed no clinical effect and instead appeared to worsen the condition by progressing pulmonary opacities.

It is important to note that there are similarities in the symptoms between COVID-19 and earlier betacoronavirus such as fever, dry cough, dyspnea, and bilateral ground-glass opacities on chest CT scans. However, COVID-19 showed some unique clinical features that include the targeting of the lower airway as evident by upper respiratory tract symptoms like rhinorrhoea, sneezing, and sore throat. In addition, based on results from chest radiographs upon admission, some of the cases show an infiltrate in the upper lobe of the lung that is associated with increasing dyspnea with hypoxemia. (Fig. 1. ; taken from: Rothan HA, Byrareddy SN The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak [published online ahead of print, 2020 Feb 26] . J Autoimmun. 2020;109:102433. )

Pathogenesis The severe symptoms of COVID-19 are associated with an increasing numbers and rate of fatalities. Patients infected with COVID-19 showed higher leukocyte numbers, abnormal respiratory findings, and increased levels of plasma pro-inflammatory cytokines. Significantly high blood levels of cytokines and chemokines were noted in patients with COVID-19 infection that included ILl-b, IL1RA, IL7, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, PTNGg, IP 10, MCP1, MIRIa, MIRIb, PDGFB, TNFa, and VEGFA. Some of the severe cases that were admitted to the intensive care unit showed high levels of pro-inflammatory cytokines including IL2, IL7, ILIO, GCSF, IPIO, MCP1, MIPla, and TNFa that are reasoned to promote disease severity.

Cannabinoids- introduction: Cannabis sativa: This plant contains more than 80 phyto- cannabinoids. The main active constituent of marijuana is the psychoactive D9- tetrahydrocannabinol (A9-THC), which acts at cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors as a partial agonist. Other important natural cannabinoids present in marijuana are the non-psychoactive cannabidiol (CBD), A9-tetrahydro-cannabivarin (A9-THCV) and cannabichromene (CBC). Among them CBD has attracted the greatest attention thus far. It was shown to antagonize the effects of CB1/CB2 receptor agonists, to counteract the psychotropic and other negative effects of A9-THC and several data suggest that it behaves as an inverse agonist of CB1 and CB2 receptors.

In total, more than hundred cannabinoids in some eleven subclasses have been characterized in cannabis and are concentrated in the glandular trichomes of the female inflorescences and other cannabinoids classes include cannabigerols (CBG), cannabichromenes (CBC), and cannabinols (CBN). The cannabinoids occur primarily in acid form, with neutral cannabinoids formed during drying, storage, and decarboxylation during smoking. A9-THC, the main psychoactive cannabinoid, can be over 20% by weight in specially bred cannabis strains. CBD, known for its anti-inflammatory activity and antagonism of A9-THC-induced anxiety, can range from below 0.5% up to 6.5% by weight.

Pharmacologically, the principal psychoactive constituent is A9-tetrahydrocannabinol (THC). The amount of THC in conjunction with selected additional cannabinoid compounds (cannabidiol/CBD, cannabinol/CBN), determines the strength or potency of the cannabis product. While A9-tetrahydrocannabinol is responsible for psychoactive properties of cannabis some of the other components modulate its activity. Besides A⁹-THC, there are also non psychoactive cannabinoids with several medicinal functions, such as cannabidiol (CBD), cannabichromene (CBC), and cannabigerol (CBG), along with other non-cannabinoid constituents belonging to diverse classes of natural products. Today, more than 560 constituents have been identified in cannabis ( see Wilcox, M, et al. "Improving Sample Preparation Methods For cannabis-infused Edible and Topical Products. " Planta Medica 82.05 (2016): PA30 ).

Cannabinoid Receptors: The endocannabinoid signaling system emerged as a potential therapeutic target over the past years. In focus are the A9-THC mimicking hydrophobic polyunsaturated fatty acid derivatives, anandamide and 2-AG, that bind and functionally activate one or both cannabinoid receptor subtypes (CB1 and CB2), as well as other receptors. Endocannabinoids are synthesized on demand in response to increased intracellular calcium concentrations or stimulated by metabotropic glutamate receptors located on postsynaptic neuro

The cannabinoid (CB) receptors CB1 and CB2 are both members of the superfamily of metabotropic G-protein-coupled receptors (GPCRs), and have been cloned and identified in the human, rat, and mouse myocardium. The cannabinoid receptors are present in high abundance throughout the body where they, and their ligands, are involved in many important physiological functions and interactions with other neurotransmitters.

CB1 receptors are abundant metabotropic G-protein-coupled receptors found predominantly in neurons of the brain at regions associated with higher cognitive functions, movement control, motor and sensory functions of the autonomic nervous system, and neurotransmission modulation. In addition, CB1 receptors also function in the peripheral nervous system: in vascular and cardiac tissue, adipocytes, liver, GI tract and uterus to regulate basic physiological mechanisms such as energy balance and reproduction. The CB1 receptor also has influence on memory and learning behavior, plays a role in addiction processes, and mediation of the psychoactive effect of Tetrahydrocannabinol (THC). Signal transduction happens through the interaction with G proteins to inhibit adenylyl cyclase, activate mitogen-activated protein kinases, inhibit voltage-gated Ca2+ channels, and activate K+ currents; as well as to influence nitric oxide signaling. CB1 agonists include: D-9-THC, endogenous anandamide, 2-AG, 2- Arachidonoyl dopamine; and highly potent HU210, CP55940 and CP55244. Antagonists include: rimonabant, and structurally similar antagonists like AM241, taranabant, ACHSR, and AM41 13.53 CB1 receptors can be co-expressed with CB2 receptors.

CB2 receptors were first identified on macrophages and are also expressed on mast cells, B cells, some blood cells, and in the peripheral nervous system like the tonsils and thymus, and mediate cannabinoid-induced immune modulation. Like CB1 receptors, CB2 receptors belong to class A serpentine receptors that are coupled to G proteins, and modulate pathways of adenylyl cyclase, mitogen-activated protein kinases, extracellular signal-regulated kinases 1/2 (ERK1/2), some Ca2+ and K+ ion channels, and nuclear factors of activated T-cells and B- cells.522-AG is considered a primary agonist of CB2 receptors. Exogenous cannabinoids like THC and cannabinol and synthetic cannabinoids including WIN-55212-2 and CP55940 have also been described to bind to CB2.54

Ionotropic Cannabinoid Receptors (TRPV1): The transient receptor potential cation channel subfamily V, member 1 (TRPV1) is an ionotropic non-selective cation channel that is predominantly expressed in peripheral sensory neurons and widespread in the cardiovascular system. TRPV1 ion channels have important functions as cellular sensors, and are involved in nociception, taste perception, thermosensation, mechano- and osmolarity sensing, and regulation of signal transmission. TRPV1 is activated by tetrahydrocannabinol, cannabinol, cannabigerol and some propyl homologs of THC and cannabigerol. Cannabichromene (CBC), cannabidiol, and cannabinol are strong TRPA1 agonists and desensitizers, and THCV (from a botanical extract) is a potent regulator of TRPA1.62

(See Alfulaij, Naghum et al. “Cannabinoids, the Heart of the Matter. ” Journal of the American Heart Association vol. 7,14 e009099. 13 Jul. 2018).

TRPV2 Cannabinoid Receptors The transient receptor potential V2 (TRPV2) protein, also known as vanilloid receptor-like 1 (VRL-1), is a member of the TRP superfamily of nonselective, ligand-gated cation channels, many of which have been shown to serve as detectors and transducers of thermal sensory stimuli. Moreover TRPV2 has a potential role of TRPV2 in pain sensation. Compared with TRPV1, TRPV2 has a wider distribution pattern, including brain, skin, spleen, lung, stomach, intestines, bladder, prostate, and peripheral blood. Medicinal cannabis and therapeutic effect: Cannabinoids refer to cannabinoids that are obtained from the plant Cannabis sativa (phytocannabinoids) or synthesized analogues. The most studied phytocannabinoids include D-9-tetrahydrocannabinol (D-9-THC), cannabinol, and cannabidiol. These compounds, as well as native mixtures from marijuana, are the subject of intense interest due to their therapeutic potential. Medicinal cannabis is available as cookies or cakes, as sublingual drops, as a vaporized mist, or for smoking.

There is also is a large body of evidence from in vivo and in vitro models showing that cannabinoids and their receptors influence the immune system, viral pathogenesis, and viral replication as well as pronounced activity of the cannabinoid system in cardiovascular disease states. For example: Modulation of the ECS, CB1, and TRPV1 antagonism, as well as CB2 agonism, have proven to modulate disease state and severity in cardiovascular diseases; CB1 antagonism ;which has an anti-inflammatory effect and reduces smooth muscle cell proliferation, as well as CB2 agonism which results in decreased expression of adhesion molecules, reduced inflammatory response and reduced plaque size in atherosclerosis; or TRPV1 antagonism which protects the heart from heart failure-associated remodeling, especially given the plethora of available TRPV1 antagonists tested in Phase II clinical trials for pain, and other indications.

CBD: Cannabidiol (CBD) is one of the main cannabinoids found in the cannabis plant that, unlike A9-THC, is devoid of psychotropic effects and addictive potential. Long neglected, CBD is currently gaining traction as a therapeutic vector for a vast range of pathological conditions. Recently, Epidiolex®, a CBD-only drug, has been approved by Food and Drug Administration (FDA) to treat seizures in children with intractable forms of epilepsy. Since then, researchers have begun to search for more therapeutic applications for CBD.

CBD, for example ,has been suggested cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases; as it has been shown that Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury (see Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injuryA. Ribeiro, V. I. et al, , Journal of Immunopharmacology and Immunotoxicology Volume 37, Pages 35-41,2015. )

In view of the above, the current invention discloses a novel composition for the treatment of respiratory symptoms. The composition comprises a synergic combination of at least one pyrazine or pyrazine derivative, and at least one cannabinoid, in a specific enhancing formulation. The enhancing formulation comprises acidic or basic solutions configured to increase the effectiveness of the pyrazine and/ or the cannabinoid; and at least one terpene configured for enhancing cannabinoid receptors’ binding and/or molecular docking of the targeted mammal. . [Non limiting examples are Myrcene for enhancing CB1 receptors or Resiniferatoxin (RTX) for enhancing TRPVl & TRPV2]

Nicotinamide ribose:

A major event during acute viral infection with Covid-SARS-2, is a rapid decrease or loss of the major metabolite nicotinamide adenine dinucleotide (NAD +). [ Mueller , Amber L et al. "Why does COVID-19 disproportionately affect older people?" Aging vol. 12.10 (2020): 9959- 9981 , Published online 2020 May 29 , after priority date of filing of the provisional patent application of the current invention)] .

It is also known that in the elderly, and patients suffering from chronic diseases such as diabetes, obesity and vascular disease there is a decrease in NAD compared to younger people. This lower level may be a contributing factor in making the disease more severe in these patients, with significantly higher mortality. [Breton, Marie, et al. "Blood NAD levels are reduced in very old patients hospitalized for heart failure. " Experimental Gerontology 139 (2020): 111051; published on 1 October 2020; after priority date of filing of the provisional patent application of the current invention) ; Fang, Evandro F., et al. "NAD + in aging: molecular mechanisms and translational implications." Trends in molecular medicine 23.10 (2017): 899-9161

Mode of Action : The current invention discloses a unique composition /cocktail which optimizes DNA repair to block replication of the virus by providing the innate immunity system with sufficient energy. The mode of action is based on the recent COVID-19 and NAD+ Depletion hypothesis that when the body is infected by COVID-19 there is an immediate depletion of NAD+ from the body. Normally, poly-ADP ribose polymerase-1 (P ARP-1), a DNA base repair enzyme, activated by DNA breaks and contributes for maintenance of genome stability. Upon activation, PARP-1 rapidly uses the substrate NAD+ to transfer poly ADP- ribose (PAR) to itself, nuclear acceptor proteins and damaged DNA. Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death. Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. In vitro, SARS-CoV-1 is associated with increased ROS production. In vivo, severe lung injury and proinflammatory host response are dependent on activation of the oxidative stress machinery in monkeys infected by SARS-CoV-1. Increased intracellular ROS results in oxidative DNA damage. Single-strand DNA breaks are normally repaired by base excision repair involving the poly-ADP ribose polymerase (PARP). PARP also works as an anti-viral agent through the ADP-ribosylation of the viral genome and inhibition of viral transcripts translation. During aging, NAD+ levels decline. This decline, exacerbated by COVID-19, might trigger cytokine storms in COVID-19 patients. Thus, maintaining NAD+ levels may therefore alleviate COVID-19 symptoms, a possibility supported by recent data showing that SARS-CoV-2 proteins hyperactivate poly-ADP-ribose polymerases PARP9, -10, -12, and-14 and deplete cellular NAD+ and the ability of NAD precursors to lower inflammation in human subjects.

In view of these data, raising NAD levels by supplying an external source such as vitamin B3 may alter some of the detrimental effects of declining NAD levels, improving innate immunity. , Thus influencing the course of the disease and reducing its severity in patients with a relative deficiency of NAD. nicotinamide Ribose and nicotinic acid are variants of vitamin B3 and are routinely used to treat various medical conditions of hyperlipidemia, as well as as a dietary supplement. The vitamin can be obtained orally and the ability of oral administration of the vitamin, raising the level of NAD in the blood and cells has been demonstrated in a number of animal and human works.

CBD: One of the most well-known cannabinoids - it has anti-inflammatory effects, this effect, prominent in several publications in the respiratory system. Because pneumonia is such a key component in severe COVID19 disease, the possibility of influencing the course of the disease by administering CBD early in the disease may moderate the course, reducing the exacerbation of respiratory failure and the need for artificial respi rati on ./ Ri be iro, A., et al. "Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. "Immunopharmacology and immunotoxicology 37.1 (2015): 35-41 flrancieli Vuolo, et al "Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma", Mediators of Inflammation, vol. 2015, Article ID 538670, ]

A third component in the composition is the use of enhancers such as Caryophyllene and ATP which are known to increase the effect of the active ingredients on their unique receptors: Caryophyllene is a selective agonist for cannabis CB2 receptors and hence CBD. Whereas ATP activates the P2X7 receptor and thus affects the cells of the immune system. ATP also helps raise NAD levels at the cellular level. This help is critical for shortening the accumulation time of an adequate level of NAD in cells.

EXAMPLE 1

One embodiment of the current invention is a novel inhalation combination therapy for the treatment of Covid-19, or for patients suffering from Tuberculosis or other respiratory disorders. Specifically, for treating local lung inflammation and cardiac malfunctions. The inhalation combination offers local lung treatment of Pyrazinamide (PZA) and CBD, in acidic micro-environment, using inhaler or vaporizer. This inhalation combination therapy for the treatment of Covid-19 patients is prepared for optimal effectiveness of cannabinoids ( CBD for example) and for optimizing the conversion of PZA to POA (Pyrazinoic acid) by PZase. The acidic micro-environment offers enhanced absorption and effectiveness.

The specific inhalation combination comprises: a. Pyrazinamide b. Cannabidiol -CBD , as API 99.9%. c. Saline + Glycerin d. Acid, for example L-ascorbic acid , to ensure low pH level when inhaled at pH~5.5.

Pyrazinimide ( PZA ):PZA is antimicrobial pro-drug, commonly used for active tuberculosis (TB). PZA is a prodrug that is converted to the active form pyrazinoic acid (POA) by PZase/nicotinamidase encoded by the pncA gene in M. tuberculosis (see Fig. 3)

Activity of PZA is strongly related to the pH of the micro-environment of the bacilli, with activity increasing with acidity (see Zhang, Ying et al. “Mechanisms of Pyrazinamide Action and Resistance. ” Microbiology spectrum vol. 2,4 (2013): 1-12. )

In detail, the -minimum inhibitory concentration (MIC) of PZA changes by several orders of magnitude over a range of pH values that may be encountered in various in vivo compartments. The MICs of both PZA and POA against Mycobacterium tuberculosis are profoundly pH dependent, changing by several orders of magnitude over the range of pH values that may be encountered in vivo. For example, the PZA MIC is 1,000 pg/ml at a pH of 6.8, 50 pg/ml at a pH of 5.5, and theoretically as low as 5 pg/ml at a pH of 4.5, which M. tuberculosis may encounter in the phagolysosomes of activated macrophages (5-7). Thus, just as its activity in vivo is assumed to vary according to drug exposure at the site of infection, it also should vary significantly according to the pH at the site of infection (see, Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB/FeJ Mice Is Best Explained by Neutral pH of Caseum Jean-Philippe Lanoix, et al, Nuermberger Antimicrobial Agents and Chemotherapy Jan 2016, 60 (2) 735-743;

Thus, there is a need for acidic environment in order to effectiveness of pyrazinamide. Additionally, some cannabinoid system receptors activated by Low pH levels. For example, TRPV1 was shown to react to low pH (typical for inflamed tissues), as well as , (see Fabisiak, A., & Fichna, J. (2017). Cannabinoids as gastrointestinal anti-inflammatory drugs. Neurogastroenterology & Motility, 29(3), el3038. in the peripheral nervous system, where TRPV1 is activated by heat, low pH and the red chilli pepper substance capsaicin. (see Hu, F., et al (2008). TRPV1 mediates cell death in rat synovial fibroblasts through calcium entry- dependent ROS production and mitochondrial depolarization. Biochemical and biophysical research communications, 369(4), 989-993.) Recently, Pyrazinimide (PZA) has been suggested, by in silico analysis of FDA approved drugs, as a possible treatment against COVID-19 , by structural similarities between the COVID-19 and the PA structure (see Mahmoud Kandeel and MohammedAl-Nazawi , Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease , Life Science sVolume 251, 15 June 2020, 117627, published after priority date of filing of the provisional patent application of the current invention).

The medical treatment of the tuberculosis (TB) is very prolonged treatment.

The standard "short" treatment for TB is six months and include isoniazid (along with pyridoxal phosphate to obviate peripheral neuropathy caused by isoniazid), rifampicin (also known as rifampin in the United States), pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered to be free of living bacteria after six months. For latent tuberculosis, the standard treatment is six to nine months of daily isoniazid alone or three months of weekly (12 doses total) of isoniazid/rifapentine combination.

The current anti-TB therapies are fraught with problems, predominantly because of the long term treatment and the increasing occurrence of medication resistance types of M. tuberculosis organism, which is most probably due to treatment non-adherence and lost to follow up. The most dangerous thing of drug resistant is formation of Multi drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB). According to WHO 2012 global TB report about 3.7% of new TB patients in the world infected with MDR-TB strains. Of 3.7%, 9% is XDR- TB strain.

Despite implementation of internationally recommended strategy (DOTS) in almost all parts of WHO regions and many national and international efforts exerted against TB prevention and control, still the patients are failing to complete their treatment to declare cure or complete the treatment. Current WHO report shows considerable TB cases are failed after several treatments, many are relapsing after completion of the treatment, many are inter to retreatment after completion of treatment and many cases are developing MDR-TB among retreatment cases (20%) throughout the world. For this, most probability treatment non-adherence and lost to follow up are the main responsible.

In view of the above, the goal of this treatment of current invention is to shorten the time for treating tuberculosis .

EXAMPLE 3 Another embodiment of the current invention is a novel synergistic composition, comprising Pyrazine +CBD+ enhancers . In this embodiment the composition comprises: a pyrazine ( Nicotinamide) CBD, and a receptor enhancer.

The disclosed composition is administered as a sublingual / buccal formulation or as a tablet, encapsulated tablet , a capsule, a pill, lyophilized, powder, emulsion, granulated powder, liquid, a solution, a patch, nebulizer, inhaler, nasal spray, aerosol and any combination thereof.

The daily dosage sublingual/ buccal formulation provides protection (prophylaxis), innate immunity and prevent infection or replication of viral infections such as . Specifically the sublingual/ buccal formulation provides the following: a. boosting NAD* through the nicotinamide pathways, may restore antiviral PARP functions to support innate immunity to CoVs,;and b. NAD+ maintaining levels may therefore alleviate COVID-19 symptoms, and could increase survival in the elderly, not simply by inhibiting the virus, but by restoring patients’ ability to clear the infection.

The addition of CBD to sublingual/ buccal formulation, additionally provides a. improving lung function and inflammation; b. reducing of cytokines level in the lungs; and c. protection in cardiac injury.

EXAMPLE 4

Open- label clinical trial in Covid-19 patients

Treatment : Sublingual administration of drops of the following formulation : a. NAD+ , Nicotinamide; b. CBD; and c. Enhancers.

The enhancers are : d. Adenosine triphosphate (ATP); and e. Caryophyllene

The detailed formulation comprises:

The trial included N=6 COVID-19- diagnosed patients with the following symptoms: None of these were administrated with other medications for COVID-19. .

¹ Scoring was done by two questions: a. Mark ( 1-10, 10 is the highest score ) how much the invention formulation assisted you in recovering of the COVID-19 disease; and b. Mark(l-1010 is the highest score) how much the invention formulation assisted you in alleviating the related symptoms of the COVID-19 disease

² High fever- body temperature of above 37.5 degrees C.

Conclusions: The results clearly show that the treatment with the composition of the current invention alleviated the symptoms related to Covid -19 disease. There is also a trend of dose related efficacy, as moderate to high dose ( 25 drops or 40 drops twice a day) alleviated high fever in 2-4 days, while for patient treated with low dose (1 drop per day) , high body temperature was reduced to normal levels only after 8 days of treatment. This trend is shown in a very limited patients of this open label trial.

EXAMPLE 5:

A synopsis of a clinical trial with hospitalizes patients is presented:

Patients: Hospitalized patients with confirmed COVID-19 are included in this study if they fulfill two primary criteria: i) age above 18 years; ii) PCR documented SARS-CoV-2 carriage in nasopharyngeal sample at admission whatever their clinical status.

Breastfeeding and pregnant patients are excluded based on their declaration and pregnancy test results when required.

Procedure: Patients are seen at baseline for enrolment, initial data collection and treatment at day-0, and again for daily follow-up during 14 days. Each day, patients will receive a standardized clinical examination and when possible, a nasopharyngeal sample are collected. All clinical data will be collected using standardized questionnaires. All patients in will be administered the novel composition by inhalation. Patients who refuse the treatment or had an exclusion criterion, will be served as controls

Clinical classification: Patients are grouped into three categories: asymptomatic, upper respiratory tract infection (URTI) when presenting with rhinitis, pharyngitis, or isolated low- grade fever and myalgia, and lower respiratory tract infections (LRTI) when presenting with symptoms of pneumonia or bronchitis.

PCR assay: SARS-CoV-2 RNA is assessed by real-time reverse transcription-PCR of liquid samples collected from the nasopharyngeal swab of all patients.

Outcome: The primary endpoint is virological clearance at day-6 post-inclusion. Secondary outcomes were virological clearance overtime during the study period, clinical follow-up (body temperature, respiratory rate, long of stay at hospital and mortality), and occurrence of side- effects.

Statistics: Statistical differences are evaluated by Pearson's chi-square or Fisher's exact tests as categorical variables, as appropriate. Means of quantitative data were compared using Student's t-test.

Claims

CLAIMS:

1. A composition for the treatment of respiratory symptoms in a mammalian subject, wherein said composition comprising a combination of at least one pyrazine, at least one cannabinoid, in a specific enhancing formulation.

2. A composition for the treatment of respiratory symptoms in a mammalian subject, wherein said composition further comprising a pH controlling agent.

3. The composition of claim 1, wherein said enhancing formulation is configured to increase the effectiveness of said at least one pyrazine and/ or said at least one cannabinoid; and to enhance their binding and/or molecular docking to specific protein receptors of the said mammal.

4. The composition of claim 1, wherein said respiratory symptoms are selected from a group consisting of dyspnea, tachypnea, hypopnea, hyperpnea, apnea, pneumonia , acute bronchitis, chronic obstructive pulmonary disease, (COPD), acute respiratory distress syndrome (ARDS), emphysema, chronic bronchitis, pleuritis, COVID-19, SARS , MERS and any combination thereof.

5. The composition of claim 1, wherein said respiratory symptoms are selected from a group consisting of cardiovascular symptoms accompanying respiratory symptoms.

6. The cardiovascular symptoms of claim 4, said symptoms are selected from a group consisting of asystole, angina, arrhythmia, bradycardia, tachycardia and any combination thereof.

7. The composition of claim 1, wherein said mammal is human or animal.

8. The composition of claim 1, wherein said respiratory symptoms are caused by COVID- 19 infection.

9. The composition of claim 1, wherein said pyrazine is pyrazinamide.

10. The composition of claim 1, wherein said pyrazine is nicotinamide.

11. The composition of claim 1, wherein said cannabinoid is selected from a group consisting of Tetra-hydro-cannabinoids (d9- THC), Tetra-hydro-cannabinoids (d8- THC), Tetra-hydro-cannabinolic acid (THCA- d9), Tetra-hydro-cannabivarin (THCV/THC-C3), Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabigerolic acid (CBGA), Cannabinol (CBN), Cannabidiolic acid (CBNA), Cannabichromene (CBC), Cannabichromenic acid (CBCA), and any combination thereof.

12. The composition of claim 1, wherein said specific enhancing formulation comprises of two groups: a. cannabinoid system receptors enhancers/ligands; b. pH regulator for enhancing activity said pyrazine and/ or said cannabinoid.

13. The composition of claim 1, wherein said cannabinoid system receptors enhancers/ligands comprises terpenes .

14. The composition of claim 2, wherein said pH controlling agent is selected from a group consisting of acid, base, buffer and any combination thereof.

15. The composition of claim 1, wherein said composition is configured to be administrable in a manner selected from a group consisting of a tablet, a capsule, a pill, lyophilized, powder, emulsion, granulated powder, liquid, a solution, a patch, nebulizer, inhaler, nasal spray, aerosol and any combination thereof.

16. The composition of claim 1, wherein said composition is configured to be administrable in a manner selected from a group consisting of intravenous, buccal, sublingual, depository, inhalation and orally.

17. The composition of claim 1, wherein said composition is configured to be administrable in a manner selected from a group consisting of fast release, slow release, sustained release, controlled release and any combination thereof.

18. The composition of claim 1, wherein said composition additionally comprising ingredients selected from a group consisting solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers/reducers, surfactants, chelating agents, adjuvants and any combination thereof.

19. The composition of claim 1, additionally comprising at least one additional compound selected from a group consisting of binders, excipients, stabilizers, anti-adherents, disintegrants, sorbents and preservatives.

20. A method for treating of respiratory symptoms in a mammalian subject, comprising administrating a composition comprising a combination of at least one pyrazine, at least one cannabinoid, in a specific enhancing formulation