TECHNICAL FIELD

[0001] The various embodiments herein relate to compositions and methods for treating COVID-19 infections and associated symptoms.

BACKGROUND

[0002] Disclosed herein are compositions and methods for treating damage caused by oxidative stress on cellular systems. More specifically, the present invention relates to the treatment of conditions associated with oxidative stress and inflammatory cell activation, particularly conditions impacting respiration, such as viral infections. Such exuberant inflammation can result in multiple tissue and organ damage including, but not limited to vasculitis, renal and cardiac damage as well as damage to the central nervous system.

[0003] Neurodegenerative diseases are associated with oxidative stress and the accumulation of cellular damages associated with overproduction of such cellular messengers as Reactive Oxygen Species (ROS). Less widely understood is the impact of elevated ROS on pulmonary function, and the potential to cause the damage associated with conditions such as Idiopathic Pulmonary Fibrosis (IPF) as well as fibrosis associated with certain infections, including viral infections of the lungs.

[0004] Considerable data implicates oxidative damage in viral pathogenesis. In a human cohort infected with influenza, markers of oxidative stress are persistently elevated even after recovery. Indeed, those with the most persistent symptoms also showed the greatest changes in oxidative stress markers. At present, it has been found that there are numerous host-cell factors that can directly or indirectly affect viral infection. Pro-/anti- oxidant balance is important to maintain normal functioning of the host. Oxidative stress caused by viral infection and replication breaks the redox balance, leading to significant changes of host defense systems.

[0005] Studies have shown that oxidative stress produced by macrophages infiltrated into the virus-infected organs is implicated in the development of severe virus-associated complications. Selected anti-oxidants, such as N-acetyl-L-cysteine, glutathione, resveratrol, and ascorbic acid inhibit the proliferation of influenza virus and scavenge reactive oxygen species and free radicals.

[0006] New and emerging respiratory viruses such as severe acute respiratory syndrome (SARS) viruses pose a considerable threat to human life. In 2003, a coronavirus (CoV) was identified as a novel respiratory pathogen responsible for a global outbreak of SARS. First emerging in 2002 in China, the outbreak resulted in almost 10,000 infections and nearly 800 deaths. In 2012, the Middle East respiratory syndrome (MERS) CoV (hCoV- EMC) was identified as a novel virus associated with an epidemic of respiratory illness in Saudi Arabia. Presently, COVID-19, caused by the severe acute respiratory syndrome coronavirus 2, hereinafter SARS-CoV-2 coronavirus, is responsible for almost 36 million infections in the US and over 600,000 deaths. Globally, SARS-CoV-2 infections account for over 200 million COVID-19 infections and close to 4.2 million deaths.

[0007] These coronaviruses comprise enveloped, single- and positive-stranded RNA viruses. The RNA genome encodes a nonstructural replicase polyprotein and several structural proteins, including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. It is believed that the S1 subunit of SARS-CoV S protein plays substantial roles in viral infection and pathogenesis, i.e., it recognizes and binds to host receptors, and the binding brings about subsequent conformational changes in the S2 subunit of the S protein to facilitate fusion between the viral envelope and the host cell membrane. Among all structural proteins of SARS-CoV, S protein is the main antigenic component responsible for inducing host immune responses, neutralizing antibodies, and possibly providing protective immunity against viral infection.

[0008] SARS is mainly a respiratory disease, the clinical features on initial presentation are very similar to influenza infection or atypical pneumonia. The most common features at onset of illness include fever, chills, myalgia, malaise, nonproductive cough, headache, and dyspnea. Less common symptoms include sputum production, sore throat, rhinorrhea, nausea, vomiting, and diarrhea. During the initial clinical phase of up to 10 days, the increasing viral load is associated with clinical features of mainly systemic symptoms, including, most notably, fever and myalgia, which generally improve within days among patients having a short mild to intermediate clinical course. In some patients, despite the falling viral load during the second through the third week, immunopathological damage may ensue with persistent or recurrent fever, oxygen desaturation, and radiologic progression of pneumonia. For those in whom ARDS (up to 20%) later ensues, pulmonary function begins to show progressive worsening in the second week of illness, including the progression of radiographic opacities or bilateral fibrotic lung changes. It has been observed that disease severity can be intensified by slower and prolonged recovery with complications of pulmonary fibrosis occurring in the third week in some patients.

[0009] Infections caused by new and emerging viruses such as SARS-CoV-2 pose a substantial and global impact on health. Many such viral infections with significant lung involvement are both complex and poorly understood. There remains a need to better understand these lung conditions and their multitude of aberrant molecular pathways involved in the cycle of pulmonary alveolar damage, inflammation, healing and fibrosis. Additionally, it would be a boon to the treatment of viral respiratory conditions caused or exacerbated by ROS to identify potential targets for therapeutic intervention.

[0010] It should be noted that this Background is not intended to be an aid in determining the scope of the claimed subject matter nor be viewed as limiting the claimed subject matter to implementations that solve any or all of the disadvantages or problems presented above. The discussion of any technology, documents, or references in this Background section should not be interpreted as an admission that the material described is prior art to any of the subject matter claimed herein.

SUMMARY

[0011] In one implementation, a method of treating one or more symptoms associated with COVID-19 is provided. The method may include identifying an individual in need thereof; and administering an effective amount of a first therapeutic agent comprising a SOD mimetic having the formula:

[0012] The SOD mimetic can be administered in any number of routes. For example, the SOD mimetic can be administered subcutaneously.

[0013] The symptoms may include fever, chills, muscle pain, headache, sore throat, loss of taste or smell, fatigue, sputum production, diarrhea, and/or malaise.

Additionally, one or more symptoms may include acute respiratory distress syndrome (ARDS), hypoxia, dyspnea, pneumonia, shock, sepsis, respiratory failure, multiorgan dysfunction, arrhythmia, myocardial infarction, or stroke.

[0014] The SOD mimetic may be administered at a dose of between about 1 to 15 mg/kg body weight. Advantageously, the SOD mimetic is administered at a dosage of about 5 mg/kg body weight.

[0015] The SOD mimetic may be administered alone or it may be administered with an effective dose of a second therapeutic agent. The second therapeutic agent may be an anti-viral agent such as remdesivir, molnupiravir, or other SARS anti-viral. The anti-viral agent may be an anti-influenza drug such as amantadine, zanamivir (Relenza®), balozavir marboxil (Xofluza®) and oseltamivir (Tamiflu®). The antiviral agent may also be or may alternatively be favipiravir (Avifavir), nitazoxanide, ivermectin, lopinar/ritonavir, GM-CSF inhibitors Humanigen’s plonmarlimab and l-MAB’s TJM2, which block cytokine storm, merimepodib, niclosamide, rintatolimod, beta-D-N4-hydroxycytidine, bemcentinib, umifenovir, plitidepsin, VIR-2073 (ALN-COV; Vir Biotecnology Inc. and Alnylam Pharmaceuticals, Inc.), EIDD-2801 (Merck, Ridgeback Bio), Emetine hydrochloride (Acer Therapeutics), or combinations thereof.

[0016] Also contemplated is the co-administration of the SOD mimetic with an antiinflammatory drug. Exemplary anti-inflammatory drugs can include anakinra (Kineret®) and IL-6 blocker Tocilizumab or JAK/STAT inhibitors or Dexamethasone.

[0017] In another aspect, a method of treating one or more symptoms associated with COVID-19, is provided: The method may include identifying an individual in need thereof; and administering to an effective amount of a first therapeutic agent. The first therapeutic agent is advantageously a SOD mimetic having the formula:

[0018] The SOD mimetic may be administered subcutaneously.

[0019] In another aspect, the one or more symptoms may include fever, chills, muscle pain, headache, sore throat, loss of taste or smell, fatigue, sputum production, diarrhea , and/or malaise. Optionally, the conditions can include acute respiratory distress syndrome (ARDS), hypoxia, dyspnea, pneumonia, shock, sepsis, respiratory failure, multiorgan dysfunction, arrhythmia, myocardial infarction, and stroke.

[0020] The SOD mimetic may be administered at a dose of between about 1 to 15 mg/kg body weight. Optionally, the SOD mimetic can be administered with an effective dose of a second therapeutic agent such as an anti-viral agent. Exemplary anti-viral agents can include an anti-influenza drug such as amantadine, zanamivir (Relenza) and oseltamivir (Tamiflu). The anti-viral may include remdesivir, favipiravir (Avifavir), nitazoxanide, ivermectin, lopinar/ritonavir, merimepodib, niclosamide, rintatolimod, beta-D-N4- hydroxycytidine, bemcentinib, umifenovir, plitidepsin, VIR-2073 (ALN-COV; Vir Biotechnology Inc. and Alnylam Pharmaceuticals, Inc.), EIDD-2801 (Merck, Ridgeback Bio), Emetine hydrochloride (Acer Therapeutics), or combinations thereof.

[0021] Also disclosed herein is a composition for the treatment of COVID-19. The composition includes a first therapeutic SOD mimetic agent having the formula:

[0022]

[0023] The composition may further include a second therapeutic agent. The second therapeutic agent may be an antiviral agent such as amantadine, zanamivir (Relenza) and oseltamivir (Tamiflu), remdesivir, favipiravir (Avifavir), nitazoxanide, ivermectin, lopinar/ritonavir, merimepodib, niclosamide, rintatolimod, beta-D-N4-hydroxyctidine, bemcentinib, umifenovir, plitidepsin, VIR-2073 (ALN-COV; Vir Biotecnology Inc. and Alnylam Pharmaceuticals, Inc.), EIDD-2801 (Merck, Ridgeback Bio), Emetine hydrochloride (Acer Therapeutics), and combinations thereof

[0024] The second therapeutic may be a second metalloporphyrin compound having a formula as follows:

[0025]

[0026] It is understood that various configurations of the subject technology will become apparent to those skilled in the art from the disclosure, wherein various configurations of the subject technology are shown and described by way of illustration. As will be realized, the subject technology is capable of other and different configurations and its several details are capable of modification in various other respects, all without departing from the scope of the subject technology. Accordingly, the summary, drawings and detailed description are to be regarded as illustrative in nature and not as restrictive.

DETAILED DESCRIPTION

[0027] The following description and examples illustrate some exemplary implementations, embodiments, and arrangements of the disclosed invention in detail. Those of skill in the art will recognize that there are numerous variations and modifications of this invention that are encompassed by its scope. Accordingly, the description of a certain example embodiment should not be deemed to limit the scope of the present invention.

[0028] Implementations of the technology described herein are directed generally to compositions and methods for treating reactive oxygen species-mediated damage with a superoxide dismutase (SOD) mimetic. During a viral infection, multiple substances that cause dramatic secondary changes in the infected tissues are released, resulting in inflammation. Inflammation is characterized by vasodilation of the local blood vessels, creating excess local blood flow, increased permeability of the capillaries with leakage of large quantities of fluid into the interstitial spaces, and other effects, soon after the onset of inflammation, neutrophils, macrophages, and other cells invade the inflamed area. These cells set about to rid the tissue of infectious or toxic agents. One method these cells use to defend the body from harmful foreign substances includes the production and release of reactive oxygen species.

[0029] A variety of reactive oxygen species are produced in the monovalent pathway of oxygen reduction. These ROS are enzymatically produced by phagocytes such as monocytes and polymorphonuclear neutrophils (PMNs) and frequently released in a respiratory burst. Hydrogen peroxide and other ROS play an important role in a host's immunological defenses. Nevertheless, ROS produced in excessive amounts or at inappropriate times or locations, act to damage a host's cells and tissues, and thus can be detrimental to the host.

[0030] The effects of ROS production are many faceted. ROS are known to cause apoptosis in NK cells. ROS are also known to cause anergy and apoptosis in T-cells. The mechanisms by which ROS cause these effects are not fully understood. Nevertheless, some commentators believe that ROS cause cell death by disrupting cellular membranes and by changing the pH of cellular pathways critical for cell survival.

[0031] Additionally, phagocytes that undergo a respiratory burst, and produce and release large quantities of ROS also produce and release secondary cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1 ). An example of secondary cytokine mediated cell damage is found in the Shwartzman Reaction, where neutrophil mediated cell damage is thought to be activated by TNF and IL-1. Imamura S, et al., “Involvement of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-8, and interleukin-1 receptor antagonist in acute lung injury caused by local Shwartzman reaction” Pathol Int. 47(1 ): 16-24 (1997). This cytokine release augments the cell damage inflicted by a variety of sources as these potent chemical compounds are disseminated throughout the body. Although released as a defensive measure by the cells of the immune system, the ROS-mediated cell damage and the secondary cytokines cause a rapid deterioration of the patient, resulting often in death.

[0032] As reactive oxygen species play a central role in inflammatory responses and viral replication, antioxidants that exert antiviral and anti-inflammatory effects offer the potential to be an effective treatment of the “cytokine storm” induced by severe viral infections. It is one of the surprising discoveries of the present invention that compounds that reduce or inhibit the amount of ROS and secondary cytokines produced or released by sources within a subject can facilitate the treatment and recovery of individuals suffering from acute respiratory illness. Disclosed herein is an ROS-induced cytokine production by infected host cells and infiltrating activated neutrophils, macrophages and monocytes.

[0033] Activated macrophages are heavily reliant on glycolysis for the production of energy used in inflammation. Modulating cellular redox status with a SOD mimetic would alter the energy balance, pushing macrophages to a more pro-resolving/less inflammatory phenotype, reducing the virally-induced observed cytokine storm.

[0034] Evidence for the central role for generation of ROS as being involved in this cytokine storm event continues to accrue. Disclosed herein is a superoxide dismutase (SOD) mimetic compounds which are capable of decreasing oxidative stress, pulmonary inflammation, and inhibit pulmonary fibrosis. These compounds are particularly well suited to treat conditions associated with oxidative stress, including pulmonary injury associated with viral infection, because this SOD mimetic can augment antioxidant defenses and thus serve as a therapy for various infections and conditions caused or exacerbated by oxidative stress, oxygen radicals, and resulting fibrotic response.

[0035] While ROS generation is an intrinsic component of aerobic energy production, mitochondrial and soluble SOD helps prevent excess generation of superoxide and subsequently reactive oxygen, nitrogen, and lipid species. The generation of ROS and subsequent altered cellular components is an addressable drug target via the use of the SOD mimetics disclosed herein.

[0036] An important balance of defensive enzymes against oxidants maintains normal cell and organ function. Superoxide dismutases (SODs) are a family of metalloenzymes that catalyze the intra- and extracellular conversion of superoxide ( O ₂ - ) into H ₂ O ₂ plus O ₂ , and represent the first line of defense against the detrimental effects of superoxide radicals. Mammals produce three distinct SODs. One is a dimeric copper- and zinc-containing enzyme (CuZn SOD) found in the cytosol of all cells. A second is a tetrameric manganese- containing SOD (Mn SOD) found within mitochondria, and the third is a tetrameric, glycosylated, copper- and zinc-containing enzyme (EC-SOD) found in the extracellular fluids and bound to the extracellular matrix. Several other important antioxidant enzymes are known to exist within cells, including catalase and glutathione peroxidase. While extracellular fluids and the extracellular matrix contain only small amounts of these enzymes, other extracellular antioxidants are also known to be present, including radical scavengers and inhibitors of lipid peroxidation, such as ascorbic acid, uric acid, and a- tocopherol (Halliwell et al., Arch. Biochem. Biophys. 280:1 (1990)).

[0037] The present invention relates generally to low molecular weight porphyrin compounds suitable for use in modulating intra- and extracellular processes in which superoxide radicals, or other oxidants such as hydrogen peroxide or peroxynitrite, are a participant. The compounds and methods of the invention find application in various physiologic and pathologic processes in which oxidative stress plays a role. In particular, the pharmaceutical compositions comprising a SOD mimetic is particularly well suited for treating Covid-19 infections and injuries to the lungs associated thereto. As used herein, a SOD mimetic refers to a class of substituted porphyrin compounds, including manganese containing porphyrins such as the porphyrins described in US Publication No. 2016/0333019A, the contents of which are hereby incorporated by reference in their entirety. Mimetics of scavengers of reactive oxygen species appropriate for use in the present methods include methine (i.e., meso) substituted porphines, or pharmaceutically acceptable salts thereof (e.g., chloride or bromide salts), including both metal-free and metal-bound porphines. In the case of metal-bound porphines, manganic derivatives of methine (meso) substituted porphines are preferred, however, metals other than manganese such as iron (II or III), copper (I or II), cobalt (II or III), or nickel (I or II), can also be used. It will be appreciated that the metal selected can have various valence states, for example, manganese II, III or V can be used. Zinc (II) can also be used even though it does not undergo a valence change and therefore will not directly scavenge superoxide. The choice of the metal can affect selectivity of the oxygen species that is scavenged. Iron- bound porphines, for example, can be used to scavenge NO. In a particularly preferred embodiment, the SOD mimetic as a molecular weight of 1033.2 g/mol and includes the molecular formula C ₄₈ H ₅₆ Cl ₅ MnN ₁₂ . [0038] The SOD mimetic can be manganese (3+);5,10,15,20-tetrakis(1 ,3- diethylimidazol-1 ium-2-yl)porphyrin-22,24-diide;pentachloride and has a formula as set forth as follows:

(I)

[0039] Briefly, and more generally, the substituted porphyrin compound can have the following formula: R ¹ is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0040] In another aspect, the substituted porphyrin compound has the formula:

In Formula III, R ¹ is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl and n is 2 or 3.

[0041] In still another aspect, a plurality of substituted porphyrin compounds are provided, wherein the plurality of compounds include the following formula: [0042] Synthesis of the SOD mimetic having a plurality of substituted porphyrin can be accomplished according to the methods set forth in U.S. Patent Publication No. 2016/033019A, previously incorporated by reference in its entirety.

[0043] In another aspect, the SOD mimetic has a formula as follows:

[0044] Or a pharmaceutically acceptable salt thereof wherein: R ₁ and R ₃ are the same and are:

[0046] R ₂ and R ₄ are the same and are:

[0047] Y is halogen or —CO ₂ X, each X is the same or different and is an alkyl and each R ₅ is the same or different (preferably the same) and is H or alkyl. [0048] Preferably, R ₁ and R ₃ are the same and are: [0049] R ₂ and R ₄ are the same and are: [0050] Y is —F or —CO ₂ X each X is the same or different and is an alkyl (preferably, C _{1 -4} alkyl, e.g., methyl or ethyl) and each R ₅ is the same or different (preferably the same) and is H or alkyl (preferably, Ci- 4 alkyl, e.g., — CH ₃ or — CH ₂ CH ₃ ).

[0051] Most preferably, R ₁ , R ₂ , R ₃ and R ₄ are the same and are or and each X is the same or different and is C _1-4 alkyl, advantageously, methyl or ethyl, particularly, methyl.

[0052] In addition to the methine (meso) substituents described above, one or more of the pyrrole rings of the porphyrin can be substituted at any or all beta carbons, i.e.: 2, 3, 7, 8, 12, 13, 17 or 18. Such substituents can be hydrogen or an electron withdrawing group, for example, each can, independently, be a NO ₂ group, a halogen (e.g., Cl, Br or F), a nitrile group, a vinyl group, or a formyl group. Such substituents alter the redox potential of the porphyrin and thus enhance its ability to scavenge oxygen radicals. For example, there can be 1 , 2, 3, 4, 5, 6, 7, or 8 halogen (e.g., Br) substituents (preferably, 1 -4), the remaining pyrrole substituents advantageously being hydrogen. When the pyrrole substituent is formyl, it is preferred that there not be more than 2 (on non-adjacent carbons), more preferably, 1 , the remaining pyrrole substituents preferably being hydrogen. When the pyrole substituent is NO2, it is preferred that there not be more than 4 (on non-adjacent carbons), more preferably, 1 or 2, the remaining substituent being hydrogen.

[0053] Where isomers are possible, all such isomers of the herein described mimetics are within the scope of the invention.

[0054] The mimetics of the present invention are suitable for use in a variety of methods. The compounds of Formulas l-VII, particularly the metal bound forms (advantageously, the manganese bound forms), are characterized by the ability to inhibit lipid peroxidation and regulate nitric oxide (NO). NO is an intercellular signal and, as such, NO must traverse the extracellular matrix to exert its effects. NO however, is highly sensitive to inactivation mediated by O ₂ - present in the extracellular spaces. The methine (meso) substituted porphyrins of the invention can increase bioavailability of NO by preventing its degradation by O ₂ -.

[0055] The present invention relates, in a further specific embodiment, to a method of inhibiting production of superoxide radicals associated with infection by a coronavirus, especially SARS-CoV-2. In this embodiment, the mimetics of the invention (particularly, metal bound forms thereof) inhibit oxidases, such as xanthine oxidase, responsible for production of superoxide radicals attendant to COVID-19 infections.

[0056] The mimetics of the invention (particularly, metal bound forms thereof) can also be used as catalytic scavengers of reactive oxygen species. Use of the SOD mimetics to treat COVID-19 infection and its associated symptoms is specifically contemplated. These symptoms include some of the milder symptoms such as fever, chills, muscle pain, headache, sore throat, loss of taste or smell, fatigue, sputum production, diarrhea, and malaise to more serious acute conditions including, but not limited to, acute respiratory distress syndrome (ARDS), hypoxia, dyspnea, pneumonia, shock, sepsis, respiratory failure, multiorgan dysfunction, arrhythmia, myocardial infarction, and stroke. The mimetics can also be useful in treatment of persistent symptoms of COVID long-haulers (i.e. Individuals presenting with COVID-19 syndrome) such as brain fog, fatigue, headaches, body aches, loss of tase and smell, difficulty sleeping, dizziness and shortness of breath, for example.

[0057] SOD mimetic compositions as described herein are powerful antioxidants effective in reducing oxidative stress following injury. The SOD mimetic compositions are particularly well suited for use in the treatment of lung injury attendant to coronavirus infection. The term “treatment” refers to therapeutic treatment as well as prophylactic or preventative measures to cure or halt or at least retard disease progress. Those in need of treatment include those already afflicted with a condition resulting from infection with a coronavirus such as SARS-CoV, as well as those in which infection with the virus is to be prevented. Subjects partially or totally recovered from infection with SARS-CoV might also be in need of treatment. Prevention encompasses inhibiting or reducing the spread of viral infection or inhibiting or reducing the onset, development or progression of one or more of the symptoms associated with infection with the disease. [0058] As used herein, coronaviruses include, but are not limited to, avian infectious bronchitis virus, avian infectious laryngotracheitis virus, enteric coronavirus, equine coronavirus, coronavirus Group 1 species such as human coronavirus 229E or human coronavirus NL63, coronavirus Group 2 species such as human coronavirus OC43 or chicken enteric coronavirus, coronavirus Group 3 species, human enteric coronavirus 4408, and SARS-CoV. In a preferred embodiment, the coronavirus is SARS-CoV-2 and variants thereof. The compositions can be administered to a mammal to treat, prevent or ameliorate one or more symptoms associated with a coronavirus infection.

[0059] As will be appreciated by a skilled artisan, the SOD mimetic can be administered to a mammal in any conventional manner to treat, prevent, or ameliorate one or more symptoms associated with a coronavirus infection. The SOD mimetic can be formulated with an appropriate carrier, excipient or diluent. Typically, pharmaceutical compositions must be sterile and stable under the conditions of manufacture and storage. The compositions of the present invention can be in powder form for reconstitution in the appropriate pharmaceutically acceptable excipient before or at the time of delivery. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Compositions described herein can be formulated individually or in combination with a second therapeutic agent. Compositions can be formulated for oral administration and administered as a prophylactic or as a therapeutic or therapeutics after diagnosis. In addition to oral administration, the SOD mimetic can be formulated as a transdermal or intradermal patch using conventional techniques commonly performed by skilled artisans.

[0060] Alternatively, the compositions of the present invention can be in solution and the appropriate pharmaceutically acceptable excipient can be added and/or mixed before or at the time of delivery to provide a unit dosage injectable form. Preferably, the pharmaceutically acceptable excipient used in the present invention is suitable to high drug concentration, can maintain proper fluidity and, if necessary, can delay absorption.

[0061] The choice of the optimal route of administration of the pharmaceutical compositions will be influenced by several factors including the physico-chemical properties of the active molecules within the compositions, the urgency of the clinical situation and the relationship of the plasma concentrations of the active molecules to the desired therapeutic effect. For instance, if necessary, the compositions of the invention can be prepared with carriers that will protect them against rapid release, such as a controlled release formulation, including implants, transdermal patches, microneedle patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can inter alia be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Furthermore, it may be necessary to coat the compositions with, or co-administer the compositions with, a material or compound that prevents the inactivation of the binding molecules in the compositions. For example, the binding molecules of the compositions may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.

[0062] The routes of administration can be subcutaneous, oral, via inhalation or nebulization for pulmonary applications, or parenteral administration as will be appreciated by a skilled person. The preferred administration route is via subcutaneous injection.

[0063] Oral dosage forms can be formulated in several formulations and may contain pharmaceutically acceptable excipients including, but not limited to, inert diluents, granulating and disintegrating agents, binding agents, lubricating agents, preservatives, coloring, flavoring or sweetening agents, vegetable oils, mineral oils, wetting agents, and thickening agents.

[0064] The pharmaceutical compositions of the present invention can also be formulated for parenteral administration. Formulations for parenteral administration can be inter alia in the form of aqueous or non-aqueous isotonic sterile non-toxic injection or infusion solutions or suspensions. The solutions or suspensions may comprise agents that are non-toxic to recipients at the dosages and concentrations employed. Such agents are well known to the skilled artisan and include 1 ,3-butanediol, Ringer's solution, Hank's solution, isotonic sodium chloride solution, oils or fatty acids, local anesthetic agents, preservatives, buffers, viscosity or solubility increasing agents, water-soluble antioxidants, oil-soluble antioxidants, and metal chelating agents.

[0065] In a further aspect, the pharmaceutical compositions of the invention can be used as a medicament. Thus, a method of treatment and/or prevention of a coronavirus infection using the pharmaceutical compositions of the invention is another part of the present invention. The SOD mimetics be used in the prophylaxis, treatment, or combination thereof, of one or more conditions resulting from a coronavirus. They are suitable for treatment of yet untreated patients suffering from a condition resulting from a coronavirus and patients who have been or are treated from a condition resulting from a coronavirus. They protect against further infection by a coronavirus and/or will retard the onset or progress of the symptoms associated with a coronavirus. They may even be used in the prophylaxis of conditions resulting from a coronavirus in, for instance, people exposed to the coronavirus such as hospital personnel taking care of suspected patients. Preferably, the compositions can be used in a method to prevent and/or treat a human coronavirus, such as SARS-CoV- 2, infection.

[0066] The above-mentioned compositions and pharmaceutical compositions may be employed in conjunction with other molecules useful in diagnosis, prophylaxis and/or treatment of a coronavirus infection. The pharmaceutical compositions of the invention can be co-administered with a vaccine against a coronavirus, such as SARS-CoV. Alternatively, the vaccine may also be administered before or after administration of the SOD mimetic of the invention. Administration of the SOD mimetic with a vaccine might be suitable for postexposure prophylaxis and might also decrease possible side effects of a live-attenuated vaccine in immunocompromised recipients.

[0067] A pharmaceutical composition comprising a SOD mimetic as disclosed herein can further comprise at least one other therapeutic, prophylactic and/or diagnostic agent. Preferably, the therapeutic and/or prophylactic agents are agents capable of preventing and/or treating an infection and/or a condition resulting from a coronavirus, such as SARS- CoV. Therapeutic and/or prophylactic agents can include, but are not limited to, an effective amount of an anti-viral agent such as remdesivir and/or HIV protease inhibitors such as lopinavir/ritonavir or other HIV protease inhibitors. Such agents can be binding molecules, small molecules, organic or inorganic compounds, enzymes, polynucleotide sequences, etc. In other aspects, the SOD mimetic can be combined with other anti-viral agents such as chloroquine or hydroxychloroquine and/or an antibiotic such as azithromycin for the treatment of COVID-19. In yet another aspect, the SOD mimetics can be co-administered with an effective amount of an anti-influenza drug selected from the group consisting of amantadine, neuraminidase inhibitors such as zanamivir (Relenza), baloxavir marvoxil (Xofluza®) and oseltamivir (Tamiflu), favipiravir (Avifavir), nitazoxanide, ivermectin, merimepodib, niclosamide, rintatolimod, beta-D-N4-hydroxycytidine, bemcentinib, umifenovir, plitidepsin, VIR-2073 (ALN-COV; Vir Biotechnology Inc. and Alnylam Pharmaceuticals, Inc.), EIDD-2801 (Merck, Ridgeback Bio), Emetine hydrochloride (Acer Therapeutics), or combinations thereof. In still another aspect, the SOD mimetic can be combined with an effective amount of one or more immunomodulators such as methylprednisolone to reduce the incidence of immunopathological lung injury. Pharmaceutical compositions comprising a SOD mimetic as described herein can be coadministered with interferon alfacon-1 plus corticosteroids to reduce disease-associated impaired oxygen saturation and reduce radiographic lung opacities.

[0068] In addition to the other therapeutic agents listed above, other well-known antiviral agents can be co-administered with the disclosed SOD mimetic. These anti-viral agents can include interferon-alpha, steroids and potential replicase inhibitors. Furthermore, patients infected with SARS-CoV can be treated concomitantly by transfusion of serum produced from blood donated by recovering/recovered COVID-19 patients who have produced antibodies after being exposed to the virus (i.e. convalescent plasma therapy). Agents capable of preventing and/or treating an infection with SARS-CoV or other coronavirus and/or a condition resulting from SARS-CoV or other coronavirus that are in the experimental phase might also be used as other therapeutic and/or prophylactic agents useful in the present invention.

[0069] The SOD mimetic can be formulated in the compositions and pharmaceutical compositions of the invention in a therapeutically or diagnostically effective amount. Dosage regimens can be adjusted to provide the optimum desired response (e.g., a therapeutic response). A suitable dosage range may, for instance, be 0.05-100 mg/kg body weight, preferably 0.1 -15 mg/kg body weight. In one aspect, the dosage is about 5 mg/kg body weight.

[0070] As suggested above, the SOD mimetic compounds disclosed herein can be administered alone or in combination with other therapeutic agents. When the disclosed SOD mimetic is combined with antiviral drugs, for example, the combination synergistically reduces the lethal effects of virus infections. In one embodiment, the SOD mimetic is administered first and then the other therapeutic agent. In another embodiment, the other therapeutic agent is administered first and then the SOD mimetic. In still another embodiment, the SOD mimetic and other therapeutic agent are co-formulated and/or administered substantially contemporaneously. The other therapeutic agents useful in diagnosis, prophylaxis and/or treatment can be administered in a similar dosage regimen as proposed for the SOD mimetics. If the other molecules are administered separately, they may be administered to a patient prior to (e.g., 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 7 days, 2 weeks, 4 weeks or 6 weeks before), concomitantly with, or subsequent to (e.g., 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 7 days, 2 weeks, 4 weeks or 6 weeks after) the administration of the SOD mimetic.

[0071] The pharmaceutical compositions of the invention can be tested in suitable animal model systems prior to use in humans. Such animal model systems include, but are not limited to, ferrets, mice, rats, chicken, cows, monkeys, pigs, dogs, rabbits, etc. It will be appreciated that compositions described herein are suitable for clinical use in humans as well as for veterinary indications.

[0072] In another aspect of the invention, kits comprising a pharmaceutical composition having a SOD mimetic as disclosed herein is provided. Optionally, components of the kits of the invention are packed in suitable containers and labeled for diagnosis, prophylaxis and/or treatment of the indicated conditions. The SOD mimetic in the (pharmaceutical) compositions may be packaged individually. The above-mentioned components may be stored in unit or multi-dose containers, for example, sealed ampules, vials, bottles, syringes, and test tubes, as an aqueous, preferably sterile, solution or as a lyophilized, preferably sterile, formulation for reconstitution. The containers may be formed from a variety of materials and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The kit may further comprise more containers comprising a pharmaceutically acceptable buffer. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, culture medium for one or more of the suitable hosts. Associated with the kits can be instructions customarily included in commercial packages of therapeutic, prophylactic or diagnostic products, that contain information about, for example, the indications, usage, dosage, manufacture, administration, contraindications and/or warnings concerning the use of such therapeutic, prophylactic or diagnostic products.

[0073] In another aspect, a method of treating an individual infected with a coronavirus is provided. The term “treatment” refers to therapeutic treatment as well as prophylactic or preventative measures to cure or halt or at least retard disease progress. Subjects partially or totally recovered from a coronavirus infection such as COVID-19 might also be in need of treatment, particularly subjects suffering from post-Covid syndrome Prevention encompasses inhibiting or reducing the spread of the virus or inhibiting or reducing the onset, development or progression of one or more of the symptoms associated with infection. In a preferred embodiment, the coronavirus is SARS-CoV-2. The method includes identifying an individual in need of treatment for a coronavirus infection with an effective amount of a SOD mimetic as described herein. Identification can be accomplished via testing of a patient sample. The sample may be a biological sample including, but not limited to, blood, serum, urine, tissue or other biological material from (potentially) infected subjects. The (potentially) infected subjects may be human subjects. Animals that are suspected as carriers of a coronavirus, such as SARS-CoV-2, may also be tested for the presence of the coronavirus. Preferred assay techniques, especially for large-scale clinical screening of patient sera and blood and blood-derived products, are ELISA and Western blot techniques. ELISA tests are particularly preferred and well known to persons skilled in the art.

[0074] Once identified, individuals are administered an effective dose of a pharmaceutical composition comprising a SOD mimetic as described herein. The SOD mimetic is administered orally, parenterally, or subcutaneously. In a preferred embodiment, it is administered subcutaneously. In a hospital setting, substantially continuous infusion is contemplated. Infusion can occur over a period of between about 24 hours and two weeks Infusion of suitable volumes delivering tolerable concentrations could be done every four, six, 24, 48, and/or 72 hours for periods of time ranging from acute to chronic (i.e. from days to weeks). Alternatively, the SOD mimetic can be administered orally, inhaled in a respiratory gas such as a nebulizer, or similar. The SOD mimetic may be administered prophylactically, upon initial diagnosis, and/or during the later stages of illness when the body mounts an immune response needing ROS. For CNS indications, the SOD mimetic or mimetics can be administered prior to developing Cytokine Release Syndrome (CRS). In instances where an individual is experiencing a cytokine storm with excess runaway inflammation, it is contemplated that the SOD mimetic will be administered in a hospital setting. In some embodiments, a patient can be given a SOD mimetic alone. In another embodiment, the patient can be given one or more conventional therapeutic and/or antiviral agents with the SOD mimetic.

[0075] In a further aspect, a composition comprising a combination of the disclosed SOD mimetics described above and an alternate second SOD mimetic compound is provided. The SOD mimetic and alternate second SOD mimetic compound can be formulated and administered together. Alternatively, the SOD mimetic and alternate second SOD mimetic compound can be administered substantially contemporaneously, the SOD mimetic first then the alternate second SOD mimetic compound, or the alternate second SOD mimetic compound first and then the first SOD mimetic as described above. The compounds can be formulated for parenteral or oral administration.

[0076] As used herein, the “alternate second SOD mimetic compound” refers to a relatively more highly soluble metalloporphyrin compound having a formula as follows:

[0077]

[0078] Features of this alternate compound (AEOL1114) are described in Li-Ping Liang et al., Toxicol Appl Pharmacol. 2017 July 01 ; 326: 34-42, and US Patent Publication No. 2013/0225545 A1 , the entire contents of which are hereby incorporated by reference. The combination therapy of the disclosed and preferred SOD mimetic and AEOL 1114 can be particularly useful for treating CNS conditions associated with or without covid infection. The combination therapy can also be useful in treating non-covid related CNS conditions, wherein the therapeutic agents mitigate oxidative stress associated with, for example, Alzheimer’s, Parkinson’s disease, ALS, PSP, and the like.

[0079] A composition and method for treating animal hosts of a virus associated with respiratory infections is likewise provided. In one embodiment, the animal is a bird or fowl such as chickens, ducks, pheasants, and turkeys. In another embodiment, the animal is porcine, equine, or bovine. In still another aspect, the animal can be feline or canine. The disclosed preferred SOD mimetic can be administered to combat infections in animal populations. The SOD mimetic can be administered prophylactically to reduce incidence of animal transmission and/or prevent infection. In one aspect, the SOD mimetic (with or without additional therapeutic agents as described above), can be formulated as a lyophilized substance added to animal feed prophylactically as a potent antioxidant.

[0080] As described herein, a suitable SOD mimetic includes NAS150 (formerly AEOL10150), a small molecule catalytic antioxidant SOD (superoxide dismutase) mimetic. Additional SOD mimetics include, without limitation, analogs of NAS150 such as NAS114 and NAS415 (formerly AEOL11114 and AEOL20415, respectively). These molecules reduce reactive oxygen species (ROS) and subsequently their oxidation of cellular proteins and lipids. In doing so, the potential downstream sequelae resulting from maladies associated with increased ROS can be mitigated.

[0081] SOD mimetics as described herein can mitigate “Long Haul” COVID-19 symptoms and may serve as a prophylactic in high-risk groups such as in frontline workers in healthcare and others who may have been exposed to someone who tested positive for SARS-CoV-2.

[0082] Administration routes can include manual subcutaneous injection as well as auto-injectors and/or microneedle patches.

Overview of COVID-19 Disease

[0083] COVID-19 is caused by the novel betacoronavirus formally designated as SARS- CoV-2. This zoonotic virus has a high rate of human-to-human respiratory transmission with the first set of cases of disease emerging out of Wuhan, China in late 2019. On March 11 , 2020 the World Health Organization (WHO) officially declared COVID-19 a pandemic as cases were spreading globally. In the USA alone, there have been approximately 30 million reported cases and more than 500,000 deaths. Based on current epidemiological trends the CDC issued a March 1 , 2021 ensemble forecast predicting the total number of deaths will be 540,000 - 564,000 by March 27, 2021 . Globally 116 million infections have been reported with 2.57 million dead.

[0084] Those infected with SARS-CoV-2 have been reported to show a spectrum of symptoms ranging from mild and asymptomatic to more generalized symptoms including fever, dyspnea, arthralgia, and fatigue with most cases resolving within a month. However, for others COVID-19 can progress to a life-threatening condition triggered by a hyperinflammatory immune response which can lead to local and systemic tissue damage, coagulopathies, and multi-organ failure culminating in death if left untreated (FIGURE 1 ). Finally, it is estimated that 10% of all those infected with SARS-CoV-2 progress to some form of a “Long Haul” COVID-19 syndrome characterized by a constellation of post-infection complications involving neurological, cardiological, and respiratory symptoms of differing degrees and lasting from a few weeks to several months after putative viral clearance (Greenhalgh, 2020).

[0085] For acute COVID-19 one of the most severe complications is when pneumonia progresses to Acute Respiratory Distress Syndrome (ARDS) resulting in patients being unable to breathe on their own. As a result, they may require mechanical ventilation support to ensure adequate levels of oxygen are circulating within their bodies. At a more granular level, patients exhibiting ARDS show extensive alveolar damage as demonstrated by the presence of infiltrated immune effectors (macrophages, mononuclear cells), hyaline membrane formation, and diffuse thickening of the alveolar wall (Xu, 2020). The longer- term outcomes of ARDS include the development of pulmonary fibrosis driven by chronic inflammation and the emergence of scar tissue (Gibson, 2020). In conjunction with ARDS, the development of diffuse thrombotic lesions and vascular coagulation and vascular enlargement have been observed in COVID-19 patients (Gibson, 2020). Together these complications portend to poor outcomes in terms of morbidity and mortality.

Acute COVID-19 is Driven By Cytokine Release Syndrome

[0086] A major theme inextricably linked to the deterioration of a COVID-19 patient’s condition and progression to ARDS, coagulopathies, vascular dysfunction, and multi-organ failure is the development of a systemic hyperinflammatory condition called Cytokine Release Syndrome (CRS) (Cecchini, 2020) and colloquially referred to as cytokine storm. CRS is caused when a controlled localized inflammatory response to a viral or bacterial infection becomes unregulated and spreads systemically. At local levels of infection, SARS- CoV-2 binds to Angiotensin-Converting Enzyme 2 (ACE2) receptors located on vascular endothelial cells in the lower respiratory tract to enable entry and intracellular viral propagation. Local infection events such as these will promote the release of pro- inflammatory cytokines from infected cells to trigger an initial immune response. In the case of SARS-CoV-2, macrophages and dendritic cells function to promote lymphocytosis and cytokine release however; the ensuing inflammatory response leads to lymphocyte destruction resulting in an overall lymphopenia as observed in patients who required ICU admission (Schulert, 2020) (Diao, 2020). At this stage cytokine production becomes dysregulated leading to extensive damage in healthy pulmonary tissue via disruption of the epithelial barrier which then systemically cascades and spreads to other tissues and organs including blood vessels, kidneys, heart, and brain. In concordance with this, high levels of pro-inflammatory cytokines and chemokines have been detected in the plasma of patients burdened with acute COVID-19. Inflammatory mediators such as IL-1 β , IL-2, IL-6, IL-7, IL- 8, IL-10, or IL-17, interferon (IFN)y, IFNy-inducible protein 10, monocyte chemoattractant protein 1 (MCP1 ), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein 1 a, and tumor necrosis factor-alpha (TNFa), among others have been detected (Huang, 2020) (Zhang W. Z., 2020) (Wu, 2020) (Wu D. Y., 2020) (Ruan, 2020) (Mehta, 2020). Finally, it has been postulated that activation of the NOD, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes can be driven by, and itself increase, ROS (Anais, 2015: Redox Regulation of NLRP3 Inflammasomes:

ROS as Trigger or Effector?). This strongly links ROS generation with inflammasome activation and CRS and further supports a role for ROS in driving the cascading hyperinflammatory response.

Reactive Oxygen Species Initiates and Sustains Cytokine Release Syndrome

[0087] While CRS is clearly involved in the later stages of acute disease, evidence from other viral respiratory infections such as severe influenza where CRS is involved suggest that oxidative stress caused by the overproduction of Reactive Oxygen Species (ROS) and concomitant imbalances in the cellular redox state may be responsible for the post-infection initiation and perpetuation of the hyperinflammatory state in COVID-19 (Cecchini, 2020) (Checconi, 2020). This suggests that maintaining control and balance of ROS production and elimination sits at the nexus of antiviral defense, immune response, and patient outcome. Therefore, modulation of upstream ROS levels and redox balance may be the optimal therapeutic area to target in COVID-19 in order to offset the development of both short term acute and possibly the longer-term sequelae observed in those infected with SARS-CoV-2.

[0088] To better elucidate the pathogenic role of ROS in COVID-19 CRS, one needs to understand how and where ROS are generated locally and systemically and how they influence the production of cytokines and modulate the immune response from two perspectives. The first is how ROS are involved in the local antiviral immune response to infection and the second is the systemic dysregulated immune response to the ensuing cellular damage caused and amplified by ROS that leads to more cytokine expression and ROS production creating an uncontrolled self-amplifying feedback loop.

[0089] At the local level, ROS and pro-inflammatory cytokine production in endothelial cells is directly stimulated by decreasing plasma membrane availability of Angiotensin- Converting Enzyme 2 (ACE2) to cleave circulating Angiotensin II (Ang II) due to ACE2 binding of SARS-CoV-2 spike protein (Beltran-Garcia, 2020). As a result, circulatory levels of un-cleaved Ang II rise and bind to Angiotensin Type 1 Receptor (AT1 R). The binding of Ang II to AT1 R activates NADPH oxidases (NOX) which leads to the production of ROS including superoxide anion ( O ₂ - ) and hydrogen peroxide (H ₂ O ₂ ). Due to NOX-mediated ROS production, nitric oxide (NO) levels are depleted which leads to vasoconstriction, inflammation, redox imbalance, and endothelial dysfunction (Beltran-Garcia, 2020). Of note, increased ROS production from NOX can elevate intracellular mitochondrial ROS production to further stimulate NOX activity which leads to a positive feedback loop of increasing oxidative stress and endothelial cell damage (Chernyak, 2020). Finally, AT1 R activation by Ang II activates the transcription factor NF-κB to upregulate the expression of pro-IL-18 , pro-IL-1 β cytokines, NLRP3, and thioredoxin interacting/inhibiting protein (TXNIP) to facilitate assembly of the inflammasome and pro-caspase-1 autocleavage to further exacerbate inflammation. Inflammasome formation in this context may be initiated early on by virion particles being recognized by Pattern Associated Molecular Patterns (PAMPs) and then later driven more by Damage Associated Molecular Patterns (DAMPs) as a result of ROS-mediated damage to endothelial cells as the disease progresses. Finally, SARS-CoV-2 promotes intracellular oxidative stress by downregulating global antioxidant enzyme expression through the suppression of the transcriptional regulator Nuclear factor erythroid 2-related factor 2 (Nrf2) (Olagnier, 2020). Enzymes under Nrf2 control include those that are responsible for ROS and xenobiotic detoxification and GSH synthesis (NADPH quinone oxoreductase-1 (NQO-1 ), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase-1 (GPx), glutathione-S-transferase (GST), glutamate cysteine ligase (GCL), glutathione reductase (GSR); heme and iron metabolism (heme oxygenase-1 (HO-1 )); proteins of the thioredoxin (TXN)-based system, and NADPH regeneration (glucose-6-phosphate dehydrogenase (G6PD)) (Checconi, 2020). Taken together, in the context of COVID-19 disease, SARS-CoV-2 converts the Renin- Angiotensin-Aldosterone System (RAAS) into a pro-oxidant and pro-inflammatory feedback loop at the local level in blood vessel endothelial cells by depleting ACE2 levels (FIGURE 2). Of note, while therapeutic blocking of AT1 R with Angiotensin Receptor Blockers (ARBs) such as Losartan and others may be promising in offsetting some of the initial production of ROS, one must keep in mind that SARS-CoV-2 also ensures a state of oxidative stress by negatively regulating Nrf2 to shut off all the key endogenous enzyme-based antioxidant systems. This maintains a permissive environment for viral replication and propagation leading to the production of pro-inflammatory cytokines and an inflammatory state as a result of PAMPs and DAMPs recognition.

[0090] As SARS-CoV-2 infection progresses more systemically with ever increasing levels of ROS and inflammation, hematological injury in the form of intravascular coagulopathy and hemolysis can occur. High levels of ROS can damage erythrocyte membranes which can trigger phagocytosis in macrophages and neutrophils and lead to ROS production (Oliveira, 2017). This process can lead to the liberation of heme and free Fe(lll) ions into the bloodstream creating extremely toxic and highly reactive hydroxyl radicals (♦OH) via Fenton and Haber-Weiss reactions which in turn increases local oxidative stress and damage to nearby cells leading to lipid peroxides and protein oxidation. Additionally, the interaction of hydroxyl radicals with soluble plasma fibrinogen in blood vessels create enzymatically-resistant dense matted deposits which cause thrombotic lesions (Pretorius, 2013) (Schaer, 2013). Organ system level ischemia begins to set in as more thrombotic lesions occlude blood vessels and circulating NO is depleted by the increased concentration of free heme (Oliveira, 2017) (Mantzarlis, 2017). In this systemic- level hypoxic environment, hypoxia also sets in and worsens within individual cells via mitochondrial impairment as manifested through reduced energy production and increased ROS generated by the mitochondrial electron transport chain (Mantzarlis, 2017) (Fink, 2002) (Ottolenghi, 2020) (Takeda, 1984) (Ademowo, 2017). One of these deleterious forms of intracellular ROS is hydrogen peroxide. Hydrogen peroxide will trigger the expression of pro-inflammatory cytokines such as TNF- α, IL-6, and IL-1 which will then activate macrophages, neutrophils, and nearby endothelial cells (via NOX) which produce more ROS including superoxide anion and hydrogen peroxide. Lastly, mitochondrial function is further impaired by the presence of NO and by the formation of peroxynitrite when NO interacts with superoxide anion (Ademowo, 2017). [0091] It is clear ROS and its subsequent effects on cytokine expression and tissue damage play a fundamental role in initiating and perpetuating COVID-19 CRS within intracellular and extracellular compartments both at local and systemic levels (FIGURE 3). These findings also suggest that pre-existing imbalances in cellular redox state prior to infection and exacerbated further after infection potentiate embarking on a path towards CRS. In concordance with this thesis, several of the comorbidities associated with COVID- 19 such as diabetes, hypertension, and obesity have underlying levels of chronic oxidative stress and inflammation and may explain part why those afflicted with these portend to worse outcomes.

[0092] At the local level, SARS-CoV-2 infection of airway epithelial cells leads to increased ROS production which can trigger cell death and activate macrophages. This in turn leads to production of pro-inflammatory cytokines and destruction of epithelial cell contacts. Pro-inflammatory cytokines are also produced by infected cells via the NF-κB pathway to activate the inflammasome in an ROS-dependent manner that leads to further production of pro-inflammatory cytokines. Of note, disruption of the epithelial barrier increases susceptibility to bacterial superinfections which can exacerbate the inflammatory response.

[0093] As the disease becomes more systemic, the inflammatory response spreads outside the alveoli to the blood stream where damaged erythrocytes release heme and free iron and activated infiltrating neutrophils and macrophages produce bursts of ROS (hydrogen peroxide and superoxide) leading to oxidative stress. In this environment, blood vessel epithelial cells are damaged when free iron interacts with ROS to produce extremely toxic hydroxyl radicals. This in turn leads to further release of pro-inflammatory cytokines via the NF-κB pathway and further infiltration of ROS-producing neutrophils and macrophages resulting in more oxidative damage and clot formation in addition to increased vascular permeability. Taken together this leads to CRS characterized by the self- perpetuating amplification loop where ROS leads to pro-inflammatory cytokine production and pro-inflammatory cytokine production leads to increasing levels of ROS. If unabated this scenario will lead to massive levels of tissue damage and death (Khomich, 2018) (Cecchini, 2020). Current Therapeutic Strategies and Clinical Landscape for COVID-19

[0094] Current therapeutic strategies to date appear to be primarily focused on treating the early stages of COVID-19 with an emphasis on targeting the virus or select immunological effectors that contribute to CRS. Clinical efforts and activities to date for these approaches include investments and utilization going towards antivirals and antibody/plasma-based therapies. While there is some therapeutic efficacy for the early stages of COVID-19, these approaches have showed little impact in late-stage infections. Once the virus has been cleared and/or a CRS is underway, these therapeutics are of minimal utility. Therefore, the need for therapeutics to treat and/or blunt the development of complications leading to late-stage COVID-19 is paramount.

[0095] Towards that end, there are thrusts exploring different immunomodulating therapeutic strategies in treating CRS in COVID-19 patients including neutralizing antibodies (tocilizumab, siltuximab) targeting pro-inflammatory cytokines such as IL-6 and its receptor, kinase inhibitors (baricitinib, fedratinib, ruxolitinib), corticosteroids (dexamethasone), pathway checkpoints (CD24Fc), interferons, and others. With respect to neutralizing antibodies, analyses of recent clinical trials showed improved survival outcomes with treatments targeting the IL-6 receptor such as tocilizumab (Gordon, 2021 ) (Khan, 2021 ). Of note, the Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway plays a pivotal role in driving expression of pro-inflammatory genes, and the impact of the kinase inhibitors on COVID-19 morbidity reflect a likely benefit of reducing oxidative stress directly. For the most part these are rational and potentially beneficial approaches as they target individual components involved in CRS; however, neither therapeutic strategy really addresses the fundamental component that starts and facilitates the perpetuation of CRS and that is ROS.

Therapeutic Approaches to Leverage Antioxidants for COVID-19

[0096] Efforts by many groups are underway to explore the potential of using antioxidant compounds to treat COVID-19 in the early stages of disease as a possible intervention to stop viral replication and in the later stages to mitigate the hyperinflammatory state. As an antiviral, classes of antioxidants such as thiol-based agents (N-acetyl-L-cysteine (NAC), GSH and analogues), polyphenols (resveratrol, curcumin, sulphorafane), and vitamins /oligoelements (ascorbic acid (Vitamin C), tocopherols (Vitamin E), Selenium) have demonstrated inhibitory effects towards replication across different viruses including influenza, Epstein Barr virus (EBV), West Nile virus (WNV), Zika (ZIKV), among others (Checconi, 2020). Some of these compounds such as NAC have shown synergy with antiviral compounds oseltamivir and ribavirin in protecting mice from lethal influenza infection (Ghezzi, 2004) (Garozzo, 2007). Taken together, these findings suggest that use of antioxidants as a primary or adjuvant therapy with existing antivirals may be therapeutically beneficial.

[0097] One therapeutic strategy being investigated is the reactivation of Nrf2 to restore redox homeostasis by activating the endogenous enzyme-based antioxidant systems to resolve inflammation. Some antioxidants that could activate Nrf2 include melatonin, resveratrol, sulforaphane, and Vitamin D (Song, 2009) (Ungvari, 2010) (Nakai, 2014) (Ahmadi, 2020). Additionally, Nrf2 agonists 4-octyl-taconate and dimethyl fumarate appear to limit host inflammatory responses with the latter being a clinically approved drug that could be repurposed for COVID-19 (Olagnier, 2020). In concordance with restoring enzymatic function, a collaborative group of researchers from the US and China acknowledge excessive ROS drives oxidative stress, promotes viral replication and induces a systemic hyperinflammatory state (Qin, 2020). They are pursuing a stabilized encapsulated catalase therapeutic which would drive SOD detoxification of superoxide anion and decrease oxidative damage. Last but not least, serious efforts are underway in investigating melatonin due to its potent anti-inflammatory properties which include its ability to block NF-κB and the NLRP3 inflammasome (Acuna-Castroviejo, 2020). Taken together, these efforts and findings support our hypothesis that therapeutically mitigating deleterious ROS production at different stages of COVID-19 could lead to improved patient outcomes.

Aberrant Neutrophil-Mediated ROS Production Drives Clinical Deterioration in Severe COVID-19

[0098] Since the beginning of the pandemic, increasing amounts of compelling evidence have shown that neutrophils are a driving force behind the severe form of COVID-19. Neutrophils are part of the innate arm of the immune system and serve as the first line of cell-mediated defense against microbes. Following infection, neutrophils will migrate to the site of infection where they normally phagocytose microbes and destroy them by fusing cytosolic granules that produce ROS and those containing defensins, antimicrobial peptides, and proteases. Of note, neutrophils will also migrate to sites of tissue damage in response to injury. In the context of COVID-19, normal neutrophil function is compromised, and their response is greatly exaggerated leading to severe levels of tissue damage, inflammation, and secondary ROS production in damaged tissues both at local and distal sites. This exaggerated neutrophil response directly influences mortality through ROS- mediated damage which drives CRS and ARDS and is responsible for the diffuse pulmonary damage and thrombotic events which are characteristics of this disease.

[0099] Clinical evidence to date has shown neutrophilia being a prominent pathological feature in patients with severe COVID-19. Patients presenting with severe disease show a dynamic change in their Neutrophil Lymphocyte Ratio (NLR) with increased numbers of neutrophils and decreased numbers of lymphocytes. Additionally, levels of D-dimer formation are markedly higher in patients with severe COVID-19 as compared to patients with mild/moderate disease supporting the thesis that neutrophils are playing a causal role in mediating tissue damage (Fu 2020; Liu J 2020 MedRxiv). In fact, the presence of neutrophilia in severe COVID-19 is associated with poor clinical outcome (Wang 2020 JAMA 323:1061 2019). Previous studies on histology samples from deceased COVID-19 patients have demonstrated massive neutrophil infiltration within damaged alveolar spaces and/or pulmonary vessels providing further evidence of their role in causing pulmonary damage (Fox et al 2020; Yao 2020)

[0100] The source of neutrophil-mediated damage comes from this cell type’s cytotoxic ability to generate massive amounts ROS and hypochlorous acid (HOCI). The potent ROS superoxide anion is primarily generated by NADPH oxidase 2 (NOX2) and HOCI is generated by myeloperoxidase (MPO). Both enzymes and their respective reactive intermediates are inextricably linked. If superoxide anion interacts with molecular water in lieu of its intended microbial target, hydrogen peroxide (H ₂ O ₂ ) is formed. The resulting H2O2 is then utilized as a substrate by MPO in combination with chloride anion (Cl) to generate HOCI. In concordance with COVID-19 neutrophilia, high levels of MPO have been measured in patient blood samples (Hazeldine 128, 141 ). The increased levels of MPO that precede clinical deterioration suggest that HOCI production synergizes with and exacerbates the oxidative stress and tissue damage already caused by NOX2-related ROS production which has been proposed in a “multiple hit hypothesis” model (Goud PT 2021 ). In this model, ROS production derived from superoxide anion and HOCI interactions with intracellular and extracellular components lead to several concomitant effects. These include 1 ) decreases in overall oxygen saturation by HOCI competing with oxygen at hemebinding sites; and 2) the generation and expansion of additional harmful oxidative reactions leading to hemoglobin-heme iron oxidation, heme destruction, and the release of free iron into the extracellular milieu which mediates tissue damage via the formation of hydroxyl radicals and reactive nitrogen species (RNS) including peroxynitrite (ONOO- ). The formation of RNS is of particular concern because it depletes levels of nitric oxide (NO) which can lead to generalized vasoconstriction and set up an environment ripe for thrombogenesis.

[0101] In addition to generating oxidative stress at sites of infection and injury, neutrophils can initiate and propagate inflammation and thrombosis through the formation of Neutrophil Extracellular Traps (NETs). NETs are an evolutionary conserved defense function where neutrophils release “traps” made up of webs of DNA containing chromatin and oxidative enzymes into the extracellular space to capture and destroy microbes. In patients with severe COVID-19 who were diagnosed with thrombosis, markedly elevated levels of NETs remnants were detected in their blood and correlated strongly to neutrophil activation markers and D-dimer formation (Zuo 2020). These NETs remnants included cell- free DNA (cfDNA), citrullinated Histone H3, and MPO-DNA complexes. Of note, aberrant NETs formation is strongly associated with the Acute Lung Injury (ALI), ARDs, and multiorgan failure observed in severe COVID-19 (Hazeldine 30, 161 -165). The mechanism by which NETs initiate and propagate inflammation and thrombosis in severe COVID-19 is best explained by the delivery of oxidative enzymes (MPO-DNA, NADPH-DNA complexes) to the extracellular space where they can expand deleterious ROS production to new areas to cause further tissue damage. This includes damage to erythrocytes and blood vessel endothelial cells. NETs-mediated damage to blood vessel endothelial cells can drive occlusions in arteries and veins (Zuo 12-15, Fuchs 2012 from Barnes).

[0102] High levels of NETs in the bloodstream can trigger occlusion of small vessels such as capillaries and can explain the systemic spread of microthrombi that leads to organ damage, multiorgan failure, and death in patients with severe COVID-19 (Cedervall 2015, Fuchs 2010, Laridan, Martinod and Wagner2014 in Barnes). A feedback loop exists where the pro-coagulant activity of thrombin leads to platelet activation and activated platelets trigger more NETs formation. Taken together, the role of neutrophil-mediated oxidative stress provides a rational explanation for the clinical deterioration and generalized inflammation, tissue injury, vasoconstriction, severe hypoxia, and systemic-wide thromboses observed in patients with severe COVID-19. This also provides a compelling therapeutic rationale to target neutrophil-derived ROS produced from uncontrolled respiratory bursts and aberrant NETs formations and by extension, the ROS produced from damaged and inflamed tissue.

[0103] A unique feature of neutrophil biology is their centralized position and general role in the body’s first line response to inflammation. Depending on the severity (e.g. dose, virulence, causticity, etc.) of the insult, if the tissue damage from ROS is not controlled, further damage can lead to downstream sequelae including ALI, ARDS, thrombosis, and even

[0104] After binding to the ACE2 receptor, SARS-CoV-2 will quickly replicate in the host cell and promote the release of progeny virus. This process in turn leads to the secretion of PAMPS and DAMPS which triggers a massive inflammatory response characterized by the infiltration of leukocytes to sites of infection and cellular damage.

[0105] In severe COVID-19, activated neutrophils can amplify their ROS-mediated damage with the release of MPO from azurophilic granules. The combination of superoxide and HOCI not only damages local tissue but can also lead to the generation of additional ROS locally and more systemically via NETs formation. This synergistic combination could be mitigated by reducing MPO activity indirectly by attenuating pulmonary neutrophil influx and/or directly inhibiting MPO activity through a catalytic depletion of the hydrogen peroxide substrate.

[0106] Many studies to date have reported highly elevated levels of pro-inflammatory cytokines in patients with severe COVID-19. Overwhelming production of these cytokines is associated with the development of ARDS, CRS, and rapid clinical deterioration. In patients with severe COVID-19, increased levels of IL-1 β, IL-6, IL-18, IL-12, TNF- α, and other chemokines have been described (Yang Lan 2021 Signal Pathways and Cytokine Storm). Several of these pro-inflammatory cytokines are under NF-κB signaling control. Previous studies have shown ROS are known to activate NF-κB signaling and can provide an explanation to how ROS mediates inflammation by directly activating pro-inflammatory cytokine production to recruit ROS-producing immune effectors (neutrophils, macrophages) and enabling their activation to produce ROS. In the context of severe COVID-19, aberrant ROS production from infiltrating neutrophils and damaged tissue can easily amplify and perpetuate the pro-inflammatory environment which further leads to more cytokine production and neutrophil infiltration/activation and further tissue damage.

[0107] In addition to the pro-inflammatory cytokines discussed above, neutrophilspecific cytokines are also expressed following pulmonary injury. In patients with severe COVID-19, high circulating levels of the neutrophil attractant IL-8 is associated with disease severity and poor prognosis (Del Valle DM Nature 2020; Li L 2020, Li H 2021 ). Additionally, levels of ICAM-1 , the cellular adhesion molecule responsible for stabilizing neutrophil adhesion prior to migration out of the circulation to sites of damage, are markedly elevated in patients with severe COVID-19 and may be contributory to endothelial dysfunction which increase thrombotic risk (2020 Nagashima S “Endothelial dysfunction...; 2020 Tong M “Elevated expression serum endothelial cell adhesion molecules in COVID-19 patients).

[0108] A consequence of the tissue injury in severe COVID-19 is the development of pulmonary edema. This is due to several sequential and concomitant factors including 1 ) SARS-CoV-2 destruction of alveolar epithelial cells, 2) the ensuing innate immune response characterized by neutrophil infiltration and destruction of alveolar endothelial cells, and 3) vascular permeability and leakage. Vascular leakage is due to the exfiltration of neutrophils and other leukocyte effectors out of pulmonary blood vessels to sites of injury and infection within alveoli as well as ROS-mediated damage to endothelial cells lining the lumen.

[0109] Oxidative stress occurs when endogenous antioxidant defense systems become overwhelmed by aberrant ROS production. Deleterious levels of ROS will damage various cellular components including lipids, proteins, and nucleic acids, which if left uncontrolled, can lead to alterations or loss of function, uncontrolled neutrophilia and oxidative stress plays a driving role in COVID-19 morbidity and mortality. This is due to uncontrolled ROS- production causing tissue damage which results in further amplifying the inflammatory response which leads to more tissue damage. If unabated, the resulting sequelae include hypoxia, thrombosis, and multiorgan failure.

Background on NAS150

[0110] Superoxide dismutase (SOD) mimetic NAS150, can be an effective treatment and adjuvant therapeutic for SARS-CoV-2 infection and COVID-19. NAS150 is a Mn- metalloporphyrin catalytic SOD mimetic with catalase activity that has demonstrated antioxidant and anti-inflammatory activities (Tse, 2004) (Zhang, 2018):

[0111] [0112] Molecular Structure of NAS150 NAS150 is a broad-spectrum metalloporphyrin superoxide dismutase (SOD) mimic with catalase activity specifically designed to neutralize reactive oxygen species (ROS) and reactive nitrogen species (RNS). [0113] NAS150 can reduce multiple ROS types including superoxide anion, hydrogen peroxide, peroxynitrite, and inhibit lipid peroxidation and downregulate inflammatory cytokines that are triggered by ROS. Unlike scavenger antioxidants which are consumed in detoxifying reactions or enzyme antioxidants that are predominantly restricted to discrete intracellular/extracellular loci, NAS150 can traverse lipid membranes to bring continuous broad spectrum catalytic antioxidant activity across intracellular and extracellular loci wherever deleterious ROS are being generated without imposing additional demands on endogenous reducing systems. In previous studies using models of radiation injury where high levels of ROS and ROS-triggered cytokines perpetuate acute and long-term damage (e.g., fibrosis), NAS150 was shown to be extremely effective in mitigating injury pathologies and other radiation exposure-related sequelae (Zhang, 2018). [0114] In the context of ROS-induced CRS in COVID-19, NAS150’s broad spectrum antioxidant capabilities in combination with its continuous catalytic activity is effective in downregulating deleterious ROS production within overstimulated infiltrating immune effectors such as activated macrophages and neutrophils as well as downregulating ROS produced by, in, and around damaged tissues; factors that perpetuate and amplify CRS both at local and systemic levels. The impact of NAS150 in the treatment of SARS-CoV-2 infections can be observed in the following manner: [0115] 1) reduction of ROS-induced intracellular damage and cytokine expression in endothelial cells, [0116] 2) Reduction of oxidative stress conditions that are conducive to inflammasome formation, [0117] 3) minimization of cellular damage to endothelial cells by reducing the activation and infiltration of overstimulated ROS-producing innate immune effectors (neutrophils, macrophages, monocytes),

[0118] 4) detoxification of deleterious ROS that are produced in extracellular compartments as a result of cellular damage,

[0119] 5) mitigation of the formation of fibrotic lesions caused by cellular damage and the activation of the compensatory repair mechanisms, and

[0120] 6) re-establishment of an equilibrium between deleterious ROS production and antioxidant levels that will alter the energy balance and lower the overall inflammatory state associated with severe COVID-19 and consequently reinstate immunological homeostasis.

[0121] The role of ROS in symptoms, hyperinflammation, and disease progression with COVID-19 infections is described. Covid 19, caused by SARS-CoV-2 betacoronavirus, presents with a range of symptoms from asymptomatic/mild to severe and lethal. Hyperinflammation leads to Acute Respiratory Distress (ARDS) and multi-organ failure for those that die or lung scarring and organ damage in survivors and increased risk of developing pulmonary (lung) fibrosis and other pathologies associated with “Long Haul” syndrome. Viral variants, anti-vaccine sentiment, continued disregard for public health guidance, possible short-term immunity, continuous outbreaks outside the US drives the need for therapeutics. Treatments to date focus primarily on mitigating virus (antivirals, convalescent plasma, antibodies for hospitalized patients or host hyperinflammatory response (dexamethasone, baracitinib, select cytokine/receptors inhibitors, supportive care). At least 10% of all infected with SARS-CoV-2 progress to “Long Haul” syndrome. The impact of severe Covid-19 cannot be understated. From headache, confusion, lack of coordination to organ impairment, severe Covid-19 can result in pneumonia, ARDs, reduced oxygen absorption, myocarditis, heart enlargement, increased troponins, diarrhea, impaired absorption, kidney impairment, vomiting, nausea, increased enzymes, increased albumin, endothelial dysfunction, and blood clots. CRS-induced damage from COVID-19 can be followed by dysregulated cellular repair mechanisms implicated in developing pulmonary fibrosis. ROS drives COVID-19 inflammation and can lead to tissue damage and death in acute cases and pulmonary fibrosis in chronic cases. [0122] Typically, Covid-19 progression includes infection and viral replication, host immune response (inflammation) and in some instances, hyperinflammation and cytokine storm, which in turn can result in multiorgan failure, death, and in some instances, long haul syndrome in survivors. ROS Initiates and sustains the cytokine storm in severe COVID-19. ROS produced during infection, replication, and viral release in alveolar endothelial cells, macrophages causing viral-mediated cell death . PAMPS/DAMPs recognition leads to pro- inflammatory cytokine/chemokine release and lymphocyte recruitment to the lungs. With hyper inflammation, excessive infiltration of ROS-producing lymphocytes to lungs results in tissue damage. Overproduction of pro-inflammatory cytokines and more infiltration of ROS- producing lymphocytes exacerbates organ damage. With multi-organ failure/death, the inflammatory response spreads to blood vessels and leads to tissue damage from ROS, cytokine release, ROS-producing lymphocytes, vascular permeability and blood clots.

[0123] Also described is the mitigating effect of NAS150 in inhibition of ROS-mediated damage and cell death, especially in connection with COVID-19 infection. NAS150 platform technology mitigates and prevents cell death and inflammation through action on oxidative stress and regulation of growth factors and chemokines, as well as impacting subsequent signaling pathways of reactive oxygen species production, apoptosis and fibrosis. NAS150 is a broad-spectrum superoxide dismutase and catalase mimetic that reduces oxidative stress by destroying multiple ROS types. Providing continuous detoxification inside and outside cells wherever ROS is produced, NAS150 has superior effectiveness as compared to endogenous and exogenous scavenger antioxidants (glutathione, vitamins, NAC, polyphenols). By reducing ROS, NAS150 reduces inflammation and the risk of developing fibrosis.

[0124] Indeed, NAS150 reverses multiple biomarkers of inflammation, oxidative stress, and immune response that ultimately drive DNA oxidation, fibrosis, and airway obstruction. NAS150 targeting activity includes superoxide dismutase mimetic, catalase mimetic, scavenger of per-oxy-nitrates, and scavenger of lipid peroxides. NAS150 modulates ROS at the nexus of pathways that drive inflammation and fibrosis. These pathways include oxidative stress, inflammatory response, fibrotic response, and synthesis and activation of cytokines, chemokines and growth factors. NAS150 reduces oxidative stress and down regulates production of cytokines, chemokines, and growth factors associated with inflammation and fibrosis.

[0125] NAS150 can be administered as a monotherapy or co-therapy. As a co-therapy, NAS150 can be administered with antivirals, anti-inflammatories, and anti-fibrotics. The antiviral can be remdesivir, bamlanivimab, or etesevimab. Anti-inflammatories can include dexamethasone, baracitinib, tocilizumab, or sarilumab, for example. Exemplary anti- fibrotics include, without limitation, pirfenidone and nintedanib.

[0126] Treatment of COVID-19 infections with the disclosed compounds is based in part on the discovery of the role of ROS on acute and chronic inflammation, which results in tissue damage. NAS150, alone or in combination with NAS1 14, which can cross the blood brain barrier, offers a promising therapy for mitigating the ROS, apoptosis, and inflammation. In addition to acute cases, NAS150 alone or in combination with other therapies, can treat long haul covid-19. Long Haul syndrome appears to be a multisystem disease with sequelae ranging beyond three weeks (acute) from onset of first symptoms to beyond 12 weeks (chronic). A constellation of symptoms make clinical management difficult and, as referenced above, can range in severity and presentations. With mild/moderate long haul, patients may suffer from persistent cough, fever, fatigue, dyspnea, chest pain, upset Gl, thromboembolic conditions, brain fog, tachycardia, headaches, skin rashes, and depression. In severe cases, lung fibrosis has been observed. Chronic oxidative stress elevates ROS levels which can activate pro-fibrotic TGF-beta1 signaling pathways and pro-fibrotic genes such as NOX4, alpha-SMA, COL I. NOX4 generates additional ROS and activates NF-KB and JNK kinases. The formation of scar tissue (fibroblast proliferation, ECM production, EMT) drives fibrosis. ROS is implicated in oxidizing DNA and inducing genetic damage. Forty percent of covid-19 patients develop ARDS with 25% developing lung disease six months after ARDS diagnosis. In milder cases, patients observe impaired gas transfer and reduced lung capacity. The duration of ARDS is correlated with increased incidence of pulmonary fibrosis. The administration of NAS150 results in the reduction/amelioration of many of these symptoms.

General Interpretive Principles for the Present Disclosure

[0127] Various aspects of the novel systems, compositions, and methods have been described herein. The teachings disclosure may, however, be embodied in many different forms and should not be construed as limited to any specific structure or function presented throughout this disclosure. Rather, these aspects are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. Based on the teachings herein one skilled in the art should appreciate that the scope of the disclosure is intended to cover any aspect of the novel systems and methods disclosed herein, whether implemented independently of or combined with any other aspect of the disclosure. For example, a system may be implemented, or a method may be practiced using any one or more of the aspects set forth herein. In addition, the scope of the disclosure is intended to cover such a composition or method which is practiced using other structure, functionality, or structure and functionality in addition to or other than the various aspects of the disclosure set forth herein. It should be understood that any aspect disclosed herein may be set forth in one or more elements of a claim. Although some benefits and advantages of the preferred aspects are mentioned, the scope of the disclosure is not intended to be limited to particular benefits, uses, or objectives. The detailed description and drawings, if any, are merely illustrative of the disclosure rather than limiting, the scope of the disclosure being defined by the appended claims and equivalents thereof.

[0128] With respect to the use of plural vs. singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity.

[0129] When describing an absolute value of a characteristic or property of a thing or act described herein, the terms “substantial,” “substantially,” “essentially,” “approximately,” and/or other terms or phrases of degree may be used without the specific recitation of a numerical range. When applied to a characteristic or property of a thing or act described herein, these terms refer to a range of the characteristic or property that is consistent with providing a desired function associated with that characteristic or property.

[0130] In those cases where a single numerical value is given for a characteristic or property, it is intended to be interpreted as at least covering deviations of that value within one significant digit of the numerical value given.

[0131] If a numerical value or range of numerical values is provided to define a characteristic or property of a thing or act described herein, whether or not the value or range is qualified with a term of degree, a specific method of measuring the characteristic or property may be defined herein as well. In the event no specific method of measuring the characteristic or property is defined herein, and there are different generally accepted methods of measurement for the characteristic or property, then the measurement method should be interpreted as the method of measurement that would most likely be adopted by one of ordinary skill in the art given the description and context of the characteristic or property. In the further event there is more than one method of measurement that is equally likely to be adopted by one of ordinary skill in the art to measure the characteristic or property, the value or range of values should be interpreted as being met regardless of which method of measurement is chosen.

[0132] It will be understood by those within the art that terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are intended as “open” terms unless specifically indicated otherwise (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.).

[0133] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should typically be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations).

[0134] In those instances where a convention analogous to “at least one of A, B, and C” is used, such a construction would include systems that have A alone, B alone, C alone, A and B together without C, A and C together without B, B and C together without A, as well as A, B, and C together. It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include A without B, B without A, as well as A and B together.” [0135] Various modifications to the implementations described in this disclosure can be readily apparent to those skilled in the art, and generic principles defined herein can be applied to other implementations without departing from the spirit or scope of this disclosure. Thus, the disclosure is not intended to be limited to the implementations shown herein but is to be accorded the widest scope consistent with the claims, the principles and the novel features disclosed herein. The word “exemplary” is used exclusively herein to mean “serving as an example, instance, or illustration.” Any implementation described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other implementations.

[0136] Certain features that are described in this specification in the context of separate implementations also can be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation also can be implemented in multiple implementations separately or in any suitable subcombination. Moreover, although features can be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination can be directed to a sub-combination or variation of a sub-combination.

[0137] The methods disclosed herein comprise one or more steps or actions for achieving the described method. The method steps and/or actions may be interchanged with one another without departing from the scope of the claims. In other words, unless a specific order of steps or actions is specified, the order and/or use of specific steps and/or actions may be modified without departing from the scope of the claims. Bibliography

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