Eriodictyol Compositions and Methods

Abstract

Compositions and methods for the treatment or prevention of neurovascular inflammation and injury. The compositions comprise a pharma- ceutically acceptable amount of eriodictyol and / or its salts, cocrystals, analogs, or any pharma- ceutically acceptable form, including physically and / or chemically modified forms.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 316,685, filed March 4, 2022, entitled "Eriodictyol Compositions and Methods," the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates generally to compositions and methods for treating neurovascular inflammation and injury in a subject, as well as conditions, diseases, and disorders resulting from or associated with neurovascular inflammation and injury. In particular, the present disclosure relates to compositions comprising a pharmaceutically acceptable amount of eriodictyol and / or any pharmaceutically acceptable form thereof, including salts, cocrystals, analogs, or physically modified forms thereof, and combination treatments with eriodictyol. [Background technology]

[0003] Many chronic diseases involve the breakdown of the protective tissue-blood barrier. Notable, but not exhaustive, examples include disruption of the skin-blood barrier leading to atopic dermatitis (eczema) and psoriasis, disruption of the gut-blood barrier leading to irritable bowel syndrome (IBS) and gluten enteropathy (celiac sprue), food allergy / intolerance, disruption of the bladder-blood barrier leading to interstitial cystitis / bladder pain syndrome (IC / BPS), disruption of the lung-blood barrier leading to asthma, and disruption of the blood-brain barrier (BBB) ​​leading to allergies, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), long COVID syndrome, multiple sclerosis (MS) interstitial cystitis, mast cell activation syndrome, mastocytosis, migraine, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), perennial rhinitis, and traumatic brain injury (TBI).

[0004] In all these conditions, diseases, and disorders, the breakdown of the protective barrier is accompanied by increased vascular permeability leading to neurovascular inflammation and injury, and extravasation of circulating leukocytes, an associated neurovascular inflammatory response, disruption of neuronal connections, and sensitization of sensory nerves that contribute to chronic neuropathic pain. These pathogenic processes involve interactions between different cell types, including, but not limited to, endothelial cells, lymphocytes, mast cells, microglial cells, platelets, and nerves.

[0005] The integrity of protective barrier and subsequent immune response regulation are crucial in the prevention or treatment of the above-mentioned conditions, diseases and disorders.Currently available drugs aim to minimize the symptoms resulting from such barrier destruction and associated neurovascular inflammation and damage, rather than addressing the causes thereof.Therefore, compositions and methods of treatment are desired to reduce neurovascular damage and improve patient outcomes.

[0006] The accompanying drawings, which are included to provide a further understanding of the embodiments of the present disclosure, are incorporated in and constitute a part of this specification, illustrate the embodiments of the present disclosure, and together with the "detailed description" serve to explain the principles of the embodiments discussed herein. No more detailed structural details of the disclosure than may be required for a basic understanding of the embodiments discussed herein and the various ways in which they may be practiced. According to common practice, the various features of the drawings discussed below are not necessarily drawn to scale. Dimensions of various features and elements of the drawings may be expanded or reduced to more clearly show the embodiments of the present disclosure. [Brief description of the drawings]

[0007] [Figure 1] 1 is a graph of plaque reduction data obtained by treating cells infected with Chikungunya virus with eriodictyol or nobiletin (hexamethoxyluteolin), according to an exemplary embodiment of the present disclosure. [Diagram 2]1 is a graph of IL-1β release by microglia pretreated with either eriodictyol or nobiletin (hexamethoxyluteolin), according to an exemplary embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present disclosure provides compositions and methods for treating or preventing neurovascular inflammation and injury, as well as conditions, diseases, and disorders resulting from or associated with neurovascular inflammation and injury in a subject. The compositions disclosed herein include eriodictyol. Eriodictyol is a flavonone compound found in several plants, including yerba santa (Eriodictyon californicum). Eriodictyol, which may also be referred to as eriodictiol in at least some cases, has the following chemical structure, shown in Structure I below, and is a compound characterized as (2S)-3',4',5,7-tetrahydroxyflavan-4-one or (2S)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-2,3-dihydro-4H-1-benzopyran-4-one: [ka]

[0009] Eriodictyol can be used at any purity level, including purified active pharmaceutical ingredient (API) grade. Eriodictyol can be sourced, for example, from plant biomass, including standardized extracts of Eriodictyon californicum or Citrus limon (lemon).

[0010] According to at least one aspect of the present disclosure, a composition for treating or preventing neurovascular inflammation and injury in a subject is provided. The composition may comprise a pharmaceutically acceptable amount of eriodictyol and / or any pharmaceutically acceptable salt, cocrystal, analog, or physically modified form thereof. Alternatively, the composition may comprise a pharmaceutically acceptable amount of a compound according to structure I and any pharmaceutically acceptable salt, cocrystal, analog, or physically modified form thereof. The composition may also comprise one or more pharmaceutically acceptable excipients. In some cases, the one or more excipients may comprise at least one modified starch, including but not limited to cyclodextrin, and lipids, such as phospholipid phosphatidylcholine.

[0011] Eriodictyol can be in any form, including standardized extracts of Eriodictyon californicum or Citrus limon. In some cases, eriodictyol is in microcrystalline form. In some cases, the composition can be formulated to include exosomes containing eriodictyol, and the exosomes are engineered for targeted drug delivery. In other cases, the composition can be formulated to include liposomes containing eriodictyol, and the liposomes are engineered for targeted eriodictyol delivery. In other cases, eriodictyol can be complexed, reacted, linked, bound, and / or chelated with additional compounds, including, but not limited to, amino acids and their derivatives, and / or minerals, such as, but not limited to, zinc, calcium, magnesium, sodium, iron, manganese, and / or potassium.

[0012] In some cases, the composition of the present disclosure may comprise one or more exosome carriers, and one or more exosome carriers comprise eriodictyol and function to provide targeted eriodictyol delivery.In other cases, the composition may comprise one or more liposome carriers, and one or more liposome carriers comprise eriodictyol and function to provide targeted eriodictyol delivery.The composition of the present disclosure can also be formulated as a modified starch cavity-based system.

[0013] According to at least some aspects of the present disclosure, the composition of the present disclosure may include one or more additional active pharmaceutical ingredients. In some cases, the composition may include an active pharmaceutical ingredient selected from the group consisting of apigenin, fisetin, luteolin and quercetin, or their methylated metabolites, tetramethoxyluteolin, hexamethoxyluteolin (nobiletin), and any combination thereof. The composition may also include an active pharmaceutical ingredient selected from the group consisting of α-lipoic acid, berberine sulfate, berberine hydrochloride, L-threonine, prostaglandin precursors (e.g., arachidonic acid, di-homo-γ-linolenic acid, and eicosapentaenoic acid, and others), vitamin E, zinc, and any combination thereof. In some cases, the composition may further include an active pharmaceutical ingredient selected from the group consisting of antiallergic drugs, anti-inflammatory drugs, antiviral drugs, cytoprotective drugs, and any combination thereof. The composition may also comprise an active pharmaceutical ingredient selected from the group consisting of antiallergic and antihistamine drugs, including but not limited to benralizumab, camostat mesylate or analogs thereof, chloroquine or analogs thereof, e.g., azelastine, cromolyn sodium, famotidine, ketotifen, rupatadine, biologics, e.g., dupilumab, mepolizumab, omalizumab, flamipiriravir or analogs thereof, antiviral drugs, e.g., interferon-gamma, ivermectin, ligelizumab, oseltamivir or analogs thereof, pemirolast or analogs thereof, remdesivir or analogs thereof, reslizumab, rifampicin or analogs thereof, and serine protease inhibitors, including but not limited to ravugebrio and paxlobid, and any combination thereof. In addition, the compositions of the present disclosure may include an active pharmaceutical ingredient selected from the group consisting of additional zinc ionophore(s), additional flavonoids (including but not limited to methoxylated forms and derivatives thereof), and any combination thereof. Further, the compositions may include an active pharmaceutical ingredient selected from the group consisting of antiallergic agents, anti-inflammatory agents, antiviral agents, cytoprotective agents, and any combination thereof.

[0014] In at least some cases, compositions of the present disclosure comprising eriodictyol and at least one additional active pharmaceutical ingredient exhibit significant synergistic effects in improving patient outcomes compared to eriodictyol or the active pharmaceutical ingredient administered independently.

[0015] According to one aspect of the present disclosure, a method for treating or preventing neurovascular inflammation and damage in a subject is provided. The method may include administering a pharmacologic effective amount of one of the eriodictyol compositions of the present disclosure to a subject in need of such treatment or prevention. The neurovascular inflammation and damage in a subject may be due to a physiological response to a trigger selected from the group consisting of an allergic trigger, an environmental trigger, an inflammatory trigger, a pathogenic trigger, a stress trigger, and any combination thereof. In some cases, the neurovascular inflammation and damage in a subject may result in multiple organ failure. In some cases, the neurovascular inflammation and damage in a subject may be localized to an organ selected from the group consisting of the brain, the intestine, the heart, the lungs, the skin, and any combination thereof.

[0016] In some cases, a subject treated according to the methods and compositions disclosed herein may have been diagnosed with a disease of the brain selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, vasculitis, mast cell activation syndrome, migraine, myalgic encephalomyelitis / chronic fatigue syndrome, long COVID syndrome, traumatic brain injury, and any combination thereof.

[0017] The method of the present disclosure may include administering an eriodictyol composition to a subject via an administration route selected from the group consisting of intranasal, inhalation, oral, sublingual, transdermal, nasogastric or gastric tube routes, and any combination thereof. In at least some cases, about 1 mg to about 5000 mg of eriodictyol can be administered to the subject per day. In some cases, administering to the subject may include administering the composition such that about 0.0125 mg to about 62.5 mg of eriodictyol per kg of body weight per day is administered to the subject.

[0018] According to at least one embodiment of the present disclosure, a method for treating or preventing a condition, disease, or disorder in a subject is provided. The method may include administering a pharmacologic effective amount of one of the eriodictyol compositions of the present disclosure to a subject in need of treatment or prevention. The disease or disorder may be selected from the group consisting of allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), Long COVID syndrome, multiple sclerosis (MS), interstitial cystitis, mast cell activation syndrome, mastocytosis, migraine, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), perennial rhinitis, traumatic brain injury (TBI), and any combination thereof.

[0019] According to at least one embodiment of the present disclosure, a method is provided for treating or preventing a COVID-19 (novel coronavirus disease)-related sequelae in a subject. The method may include administering a pharmacologic effective amount of one of the eriodictyol compositions of the present disclosure to a subject in need of such treatment or prevention. The COVID-19-related sequelae may be selected from the group consisting of pulmonary edema, fibrosis and inflammation, inflammation around cerebrovascular tissue, cardiac inflammation including myocarditis, pericarditis, long COVID syndrome, and any combination thereof.

[0020] According to at least one embodiment of the present disclosure, a method for treating or preventing a neuroinflammatory and / or cardiac inflammatory condition associated with a COVID vaccine in a subject is provided. The method may include administering to a subject in need of such treatment or prevention a pharmacologic effective amount of one of the eriodictyol compositions of the present disclosure. The neuroinflammatory and / or cardiac inflammatory condition associated with a COVID vaccine may be selected from the group consisting of microvascular changes, platelet aggregation, myocarditis, pericarditis, thrombosis, neuroinflammatory damage, stroke, and any combination thereof.

[0021] According to at least one embodiment of the present disclosure, a combination therapy is provided for treating or preventing endothelial damage in a subject.The combination therapy can include administering to a subject requiring such treatment or prevention a composition comprising a pharma-ceutically acceptable amount of eriodictyol and / or any pharma-ceutically acceptable form thereof, including salts, cocrystals, analogs, or physically modified forms thereof, and an active pharmaceutical ingredient selected from the group consisting of apigenin, fisetin, luteolin and quercetin, or their methylated metabolites, tetramethoxyluteolin, hexamethoxyluteolin (nobiletin), α-lipoic acid, berberine sulfate, berberine hydrochloride, L-threonine, prostaglandin precursors (such as arachidonic acid, di-homo-γ-linolenic acid, and eicosapentaenoic acid), vitamin E, zinc, and any combination thereof.

[0022] In at least some cases, the combination therapy shows a significant synergistic effect in improving patient outcomes compared to administration of eriodictyol or active pharmaceutical ingredients administered alone. In some cases, the subject is diagnosed with a brain disease selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, autism spectrum disorder (ASD), Long COVID syndrome, mast cell activation syndrome, migraine, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), traumatic brain injury, and any combination thereof. In other cases, the subject is diagnosed with a COVID-19-related sequela selected from the group consisting of pulmonary edema, fibrosis and inflammation, inflammation around cerebrovascular vessels, cardiac inflammation including myocarditis, pericarditis, Long COVID syndrome, and any combination thereof. In still other cases, the subject has been diagnosed with or has a disorder selected from allergies, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), encephalitis, Long COVID syndrome, multiple sclerosis (MS), interstitial cystitis, mast cell activation syndrome, mastocytosis, migraine, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), rhinitis, traumatic brain injury (TBI), and any combination thereof. EXAMPLES

[0023] The examples presented below illustrate selected aspects of the compositions and methods of the present disclosure.

[0024] Example 1 - Treatment of RNA virus-infected plaques with eriodictyol To demonstrate the effect of eriodictyol treatment on RNA virus-infected plaques, human microglial cells infected with Chikungunya virus were treated with eriodictyol or nobiletin (hexamethoxyluteolin). Human microglial cell cultures were used because microglia are innate immune system cells in the brain and their activation is involved in all neuroinflammatory and neurogenic diseases. Chikungunya was selected as a suitable RNA virus surrogate for coronavirus. Data obtained from treatment of viral plaques with eriodictyol or nobiletin are shown in Figure 1. As shown in Figure 1, treatment of cells with eriodictyol significantly reduced plaques in a dose-dependent manner. Furthermore, eriodictyol was found to be a slightly more potent inhibitor than nobiletin at 100 micromolar concentrations.

[0025] Example 2 - Pretreatment of human SV40 microglial cultures with eriodictyol Cultured human SV40 microglial cells were pretreated with eriodictyol (Erio) or nobiletin (Nobi) for 2 hours to measure the extent to which eriodictyol and nobiletin inhibited the secretion of the proinflammatory cytokine interleukin-1β (IL-1β) and subsequently stimulated with bacterial lipopolysaccharide (LPS). Data obtained from the experiment are shown in Figure 2. As shown in Figure 2, eriodictyol, as well as nobiletin, were found to be more potent inhibitors of IL-1β secretion compared to luteolin (Lut) and methoxyluteolin (Methlut) at 50 micromolar concentrations.

[0026] Example 3 - Treatment of Long Covid Syndrome with Eriodictyol A 33-year-old Caucasian female subject diagnosed with Long COVID syndrome was administered 60 milligrams (mg) of eriodictyol per day (30 mg / vegetable capsule, two capsules per day) for three months. The subject reported a greater than 80% reduction in Long COVID symptoms, including an 80% reduction in fatigue, brain fog, difficulty concentrating, difficulty remembering, difficulty finding the right words, and difficulty multitasking.

[0027] Disclosure Statement Statement 1: A composition for treating or preventing neurovascular inflammation and injury in a subject, comprising a pharma- ceutically acceptable amount of eriodictyol and / or any pharma- ceutically acceptable form thereof, including salts, cocrystals, analogs, or physically modified forms thereof.

[0028] Statement 2: A composition for treating or preventing endothelial damage in a subject, comprising a pharma- ceutically acceptable amount of a compound according to structure I, and any pharma- ceutically acceptable form thereof, including salts, co-crystals, analogs, or physically modified forms thereof: [ka]

[0029] Statement 3: The composition of statement 1 or statement 2, further comprising one or more pharma- ceutically acceptable excipients.

[0030] Statement 4: The composition of statement 3, wherein the one or more excipients comprise at least one modified starch.

[0031] Statement 5: The composition of statements 3 and 4, wherein at least one modified starch is a cyclodextrin.

[0032] Statement 6: The composition of any one of statements 1 to 5, wherein the eriodictyol is a standardized extract of Eriodictyon californicum or Citrus limon.

[0033] Statement 7: The composition of any one of statements 1-6, wherein the eriodictyol is in microcrystalline form.

[0034] Statement 8: The composition of any one of statements 1-7, formulated to contain exosomes containing eriodictyol, said exosomes being engineered for targeted drug delivery.

[0035] Statement 9: A composition according to any one of statements 1 to 7, formulated to contain liposomes containing eriodictyol, said liposomes being engineered for targeted eriodictyol delivery.

[0036] Statement 10: A composition described in any one of statements 1-7, comprising one or more exosome carriers, said one or more exosome carriers comprising eriodictyol and functioning to provide targeted eriodictyol delivery.

[0037] Statement 11: A composition described in any one of statements 1-7, comprising one or more liposomal carriers, said one or more liposomal carriers comprising eriodictyol and functioning to provide targeted eriodictyol delivery.

[0038] Statement 12: The composition of any one of statements 1 to 11 formulated as a modified starch cavity based system.

[0039] Statement 13: The composition of any one of statements 1-12, further comprising an active pharmaceutical ingredient selected from the group consisting of apigenin, fisetin, luteolin and quercetin, or methylated metabolites thereof, tetramethoxyluteolin, hexamethoxyluteolin (nobiletin), and any combination thereof.

[0040] Statement 14: The composition of any one of statements 1-13, further comprising an active pharmaceutical ingredient selected from the group consisting of α-lipoic acid, berberine sulfate, berberine hydrochloride, L-threonine, prostaglandin precursors (e.g., arachidonic acid, di-homo-γ-linolenic acid, and eicosapentaenoic acid, and others), vitamin E, zinc, and any combination thereof.

[0041] Statement 15: The composition of any one of statements 1-14, further comprising an active pharmaceutical ingredient selected from the group consisting of antiallergic agents, anti-inflammatory agents, antiviral agents, cytoprotective agents, and any combination thereof.

[0042] Statement 16: The composition of any one of statements 1-15, further comprising an active pharmaceutical ingredient selected from the group consisting of antiallergics and antihistamines, including but not limited to benralizumab, camostat mesylate or analogs thereof, chloroquine or analogs thereof, azelastine, cromolyn sodium, famotidine, ketotifen, rupatadine; antioxidants, including but not limited to curcumin, oleorpein, hydroxytyrosol, resveratrol, sulforaphane; biologics, such as dupilumab, mepolizumab, omalizumab, flamipiriravir or analogs thereof; antivirals, such as interferon-gamma, ivermectin, ligelizumab, oseltamivir or analogs thereof, pemirolast or analogs thereof, remdesivir or analogs thereof, reslizumab, rifampicin or analogs thereof, and serine protease inhibitors, including but not limited to ravegebrio and paxlobid, and any combination thereof.

[0043] Statement 17: The composition of any one of statements 1-16, further comprising an active pharmaceutical ingredient selected from the group consisting of additional zinc ionophore(s), additional flavonoids, including but not limited to, methoxylated forms and derivatives thereof, and any combination thereof.

[0044] Statement 18: The composition of any one of statements 1-14, further comprising an active pharmaceutical ingredient selected from the group consisting of antiallergic agents, anti-inflammatory agents, antiviral agents, cytoprotective agents, and any combination thereof.

[0045] Statement 19: The composition of any one of statements 13 to 18, wherein the composition comprising eriodictyol and at least one further active pharmaceutical ingredient exhibits a significant synergistic effect in improving patient outcomes.

[0046] Statement 20: A method for treating or preventing neurovascular inflammation and damage in a subject, the method comprising administering to a subject in need of said treatment or prevention a pharma- ceutical effective amount of a composition described in any one of statements 1-19.

[0047] Statement 21: The method of statement 20, wherein the subject's neurovascular inflammation and damage is due to a physiological response to a trigger selected from the group consisting of an allergic trigger, an environmental trigger, an inflammatory trigger, a pathogenic trigger, a stress trigger, and any combination thereof.

[0048] Statement 22: The method of statement 20 or statement 21, wherein neurovascular inflammation and injury in a subject leads to multiple organ failure.

[0049] Statement 23: The method of any one of statements 20 to 22, wherein the subject's neurovascular inflammation and damage is localized to an organ selected from the group consisting of the brain, intestine, heart, lungs, skin, and any combination thereof.

[0050] Statement 24: The method of any one of statements 20-23, wherein the subject has been diagnosed with a brain disorder selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, autism spectrum disorder (ASD), encephalitis, Long COVID syndrome, mast cell activation syndrome, migraine, multiple sclerosis (MS), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), traumatic brain injury, and any combination thereof.

[0051] Statement 25: The method of any one of statements 20-24, wherein administering to the subject comprises administering via a route of administration selected from the group consisting of intranasal, inhalation, oral, sublingual, transdermal, nasogastric or gastric routes, and any combination thereof.

[0052] Statement 26: The method of any one of statements 20-25, wherein administering to the subject comprises administering the composition such that about 1 mg to about 5000 mg of eriodictyol is administered to the subject per day.

[0053] Statement 27: The method of any one of statements 20-25, wherein administering to the subject comprises administering the composition such that about 0.0125 mg to about 62.5 mg of eriodictyol per kg of body weight per day is administered to the subject.

[0054] Statement 28: A method of treating or preventing a disease or disorder in a subject, comprising administering to a subject in need of said treatment or prevention a pharma- tically effective amount of a composition of any one of statements 1-19, wherein the condition, disease or disorder is selected from the group consisting of allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), Long COVID syndrome, encephalitis, multiple sclerosis (MS), interstitial cystitis, mast cell activation syndrome, mastocytosis, migraine, myalgic encephalomyelitis / chronic fatigue syndrome (MS / CFS), rhinitis, traumatic brain injury (TBI), and any combination thereof.

[0055] Statement 29: The method of any one of statements 28, wherein administering to the subject comprises administering via a route of administration selected from the group consisting of intranasal, inhalation, oral, sublingual, transdermal, nasogastric or gastric routes, and any combination thereof.

[0056] Statement 30: The method of statement 28 or statement 29, wherein administering to the subject comprises administering the composition such that about 1 mg to about 5000 mg of eriodictyol is administered to the subject per day.

[0057] Statement 31: The method of any one of statements 28-30, wherein administering to the subject comprises administering the composition such that about 0.0125 mg to about 62.5 mg of eriodictyol per kg of body weight per day is administered to the subject.

[0058] Statement 32: A method of treating or preventing COVID-19 associated sequelae in a subject, the method comprising administering to a subject in need of said treatment or prevention a pharma- ceutical effective amount of a composition described in any one of statements 1-19.

[0059] Statement 33: The method of any one of statements 32, wherein the COVID-19 associated sequelae are selected from the group consisting of pulmonary edema, fibrosis and inflammation, inflammation around cerebrovascular disease, cardiac inflammation including myocarditis, pericarditis, Long COVID syndrome, and any combination thereof.

[0060] Statement 34: The method of statement 32 or statement 33, wherein administering to the subject comprises administering via a route of administration selected from the group consisting of intranasal, inhalation, oral, sublingual, transdermal, nasogastric or gastric routes, and any combination thereof.

[0061] Statement 35: The method of any one of statements 32-34, wherein administering to the subject comprises administering the composition such that about 1 mg to about 5000 mg of eriodictyol is administered to the subject per day.

[0062] Statement 36: The method of any one of statements 32-35, wherein administering to the subject comprises administering the composition such that about 0.0125 mg to about 62.5 mg of eriodictyol per kg of body weight per day is administered to the subject.

[0063] Statement 37: A method of treating or preventing a neuroinflammatory and / or cardiac inflammatory condition associated with a COVID vaccine in a subject, the method comprising administering to a subject in need of said treatment or prevention a pharma- tically effective amount of a composition described in any one of statements 1-19.

[0064] Statement 38: The method of statement 37, wherein the neuroinflammatory and / or cardiac inflammatory condition associated with a COVID vaccine is selected from the group consisting of microvascular changes, platelet aggregation, myocarditis, pericarditis, thrombosis, neuroinflammatory injury, stroke, and any combination thereof.

[0065] Statement 39: The method of statement 37 or statement 38, wherein administering to the subject comprises administering via a route of administration selected from the group consisting of intranasal, inhalation, oral, sublingual, transdermal, nasogastric or gastric routes, and any combination thereof.

[0066] Statement 40: The method of any one of statements 37-39, wherein administering to the subject comprises administering the composition such that about 1 mg to about 5000 mg of eriodictyol is administered to the subject per day.

[0067] Statement 41: The method of any one of statements 37-40, wherein administering to the subject comprises administering the composition such that about 0.0125 mg to about 62.5 mg of eriodictyol per kg of body weight per day is administered to the subject.

[0068] Statement 42: A combination therapy for treating or preventing endothelial damage in a subject, comprising administering to a subject in need of said treatment or prevention a composition comprising a pharma- ceutically acceptable amount of eriodictyol and / or any pharma- ceutically acceptable form thereof, including salts, cocrystals, analogs, or physically modified forms thereof, and an active pharmaceutical ingredient selected from the group consisting of apigenin, fisetin, luteolin and quercetin or methylated metabolites thereof, tetramethoxyluteolin, α-lipoic acid, berberine sulfate, berberine hydrochloride, L-threonine, prostaglandin precursors (such as arachidonic acid, di-homo-γ-linolenic acid, and eicosapentaenoic acid), vitamin E, zinc, and any combination thereof.

[0069] Statement 43: The combination therapy of statement 42, wherein the endothelial damage in the subject is due to a physiological response to a trigger selected from the group consisting of an allergic trigger, an environmental trigger, an inflammatory trigger, a pathogenic trigger, a stress trigger, and any combination thereof.

[0070] Statement 44: The combination therapy of statement 41 or statement 42, wherein endothelial injury in the subject results in multiple organ failure.

[0071] Statement 45: The combination therapy of any one of statements 41-44, wherein the subject's endothelial injury is confined to an organ selected from the group consisting of the brain, the heart, the lungs, the skin, and any combination thereof.

[0072] Statement 46: The combination therapy of any one of statements 41-45, wherein the subject has been diagnosed with a disease or disorder of the brain selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, vasculitis, autism spectrum disorder (ASD), mast cell activation syndrome, migraine, myalgic encephalomyelitis / chronic fatigue syndrome, Long COVID syndrome, traumatic brain injury, and any combination thereof.

[0073] Statement 47: The combination therapy of any one of statements 41-46, wherein administering to the subject comprises administering via a route of administration selected from the group consisting of intranasal, inhalation, oral, sublingual, transdermal, nasogastric or gastric routes, and any combination thereof.

[0074] Statement 48: The combination therapy of any one of statements 41-47, wherein administering to the subject comprises administering the composition such that about 1 mg to about 5000 mg of eriodictyol is administered to the subject per day.

[0075] Statement 49: The combination therapy of any one of statements 41-47, wherein administering to the subject comprises administering the composition such that about 0.0125 mg to about 62.5 mg of eriodictyol per kg of body weight per day is administered to the subject.

[0076] Statement 50: A combination therapy according to any one of statements 41-49, which combination therapy exhibits significant synergistic effects in improving patient outcomes compared to administration of eriodictyol alone or to the active pharmaceutical ingredients administered alone.

[0077] Statement 51: The combination therapy of any one of statements 41-50, wherein the subject has been diagnosed with a COVID-19 associated sequelae selected from the group consisting of pulmonary edema, fibrosis and inflammation, inflammation around cerebrovascular tissue, cardiac inflammation including myocarditis, pericarditis, Long COVID syndrome, and any combination thereof.

[0078] Statement 52: The combination therapy of any one of statements 41-50, wherein the subject has been diagnosed with a condition, disease, or disorder selected from allergies, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), Long COVID syndrome, multiple sclerosis (MS), interstitial cystitis, mast cell activation syndrome, mastocytosis, migraine, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), perennial rhinitis, traumatic brain injury (TBI), and any combination thereof.

Claims

1. 1. A composition for treating or preventing neurovascular inflammation and injury in a subject, comprising: The composition comprises a pharma- ceutically acceptable amount of eriodictyol and / or its salts, cocrystals, analogs, or any pharma- ceutically acceptable form, including physically modified forms.

2. The composition of claim 1 further comprising a cyclodextrin.

3. 2. The composition of claim 1, comprising one or more exosome carriers, wherein the one or more exosome carriers comprise eriodictyol and function to provide targeted eriodictyol delivery.

4. 10. The composition of claim 1, further comprising an active pharmaceutical ingredient selected from the group consisting of apigenin, fisetin, luteolin and quercetin, or methylated metabolites thereof, tetramethoxyluteolin, hexamethoxyluteolin (nobiletin), and any combination thereof.

5. 10. The composition of claim 1, further comprising an active pharmaceutical ingredient selected from the group consisting of α-lipoic acid, berberine sulfate, berberine hydrochloride, L-threonine, arachidonic acid, di-homo-γ-linolenic acid, eicosapentaenoic acid, vitamin E, zinc, and any combination thereof.

6. 10. The composition of claim 1, further comprising an active pharmaceutical ingredient selected from the group consisting of antiallergy and antihistamine drugs, including but not limited to benralizumab, camostat mesylate or analogs thereof, chloroquine or analogs thereof, azelastine, cromolyn sodium, famotidine, ketotifen, rupatadine; antioxidants, including but not limited to curcumin, oleorpein, hydroxytyrosol, resveratrol, sulforaphane; biologics, such as dupilumab, mepolizumab, omalizumab, furamipiriravir or analogs thereof; antivirals, such as interferon-gamma, ivermectin, ligelizumab, oseltamivir or analogs thereof, pemirolast or analogs thereof, remdesivir or analogs thereof, reslizumab, rifampicin or analogs thereof, and serine protease inhibitors, including but not limited to ravegubrio and paxlobid, and any combination thereof.

7. 10. The composition of claim 1, further comprising an active pharmaceutical ingredient selected from the group consisting of additional zinc ionophore(s), additional flavonoids (including but not limited to methoxylated forms and derivatives thereof), and any combination thereof.

8. 10. The composition of claim 1, further comprising an active pharmaceutical ingredient selected from the group consisting of anti-allergy agents, anti-inflammatory agents, anti-viral agents, cytoprotective agents, and any combination thereof.

9. The composition according to any one of claims 13 to 18, wherein the composition comprising eriodictyol and at least one further active pharmaceutical ingredient exhibits a significant synergistic effect in improving patient outcomes.

10. 1. A method for treating or preventing neurovascular inflammation and injury in a subject, comprising: The method comprises administering to a subject in need of said treatment or prevention a pharma- ceutical effective amount of the composition of claim 1.

11. 11. The method of claim 10, wherein the subject's neurovascular inflammation and damage is due to a physiological response to a trigger selected from the group consisting of an allergic trigger, an environmental trigger, an inflammatory trigger, a pathogenic trigger, a stress trigger, and any combination thereof.

12. 11. The method of claim 10, wherein the neurovascular inflammation and injury in the subject leads to multiple organ failure.

13. 11. The method of claim 10, wherein the subject's neurovascular inflammation and damage is localized to an organ selected from the group consisting of the brain, gut, heart, lungs, skin, and any combination thereof.

14. 11. The method of claim 10, wherein the subject has been diagnosed with a brain disorder selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, autism spectrum disorder (ASD), encephalitis, long COVID syndrome, mast cell activation syndrome, migraine, multiple sclerosis (MS), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), traumatic brain injury, and any combination thereof.

15. 11. The method of claim 10, wherein administering to a subject comprises administering the composition such that about 0.0125 mg to about 62.5 mg of eriodictyol per kg of body weight per day is administered to the subject.

16. 1. A method of treating or preventing a disease or disorder in a subject, comprising:

20. The method of claim 1, comprising administering to a subject in need of said treatment or prevention a pharmacologic effective amount of the composition of claim 1, wherein the condition, disease or disorder is selected from the group consisting of allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), Long COVID syndrome, encephalitis, multiple sclerosis (MS), interstitial cystitis, mast cell activation syndrome, mastocytosis, migraine, myalgic encephalomyelitis / chronic fatigue syndrome (MS / CFS), rhinitis, traumatic brain injury (TBI), and any combination thereof.

17. 17. The method of claim 16, wherein the condition, disease or disorder is Long COVID Syndrome.

18. 1. A method of treating or preventing a COVID-19 associated sequelae in a subject, comprising: The method comprises administering to a subject in need of said treatment or prevention a pharma- ceutical effective amount of the composition of claim 1.

19. 19. The method of claim 18, wherein the COVID-19 associated sequelae are selected from the group consisting of pulmonary edema, fibrosis and inflammation, inflammation around cerebrovascular vessels, cardiac inflammation including myocarditis, pericarditis, long COVID syndrome, and any combination thereof.

20. 1. A combination therapy for treating or preventing endothelial injury in a subject, comprising: To a subject in need of the treatment or prevention, a pharma- ceutically acceptable amount of eriodictyol, or any pharma- ceutically acceptable form thereof, including a salt, cocrystal, analog, or physically modified form; an active pharmaceutical ingredient selected from the group consisting of hexamethoxyluteolin (nobiletin), apigenin, fisetin, luteolin and quercetin or their methylated metabolites, tetramethoxyluteolin, α-lipoic acid, berberine sulfate, berberine hydrochloride, L-threonine, prostaglandin precursors (e.g., arachidonic acid, di-homo-γ-linolenic acid, and eicosapentaenoic acid, and others), vitamin E, zinc, and any combination thereof; The combination therapy comprises administering a composition comprising:

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