Erydictyol compositions and methods

Abstract

Compositions and methods for treating or preventing neurovascular inflammation and injury in a subject. The compositions comprise a pharmaceutically acceptable amount of eriodictyol and / or any pharmaceutically acceptable form thereof, including salts, co-crystals, analogues, or physically and / or chemically modified forms.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 316,685, filed on March 4, 2022, entitled “Eriodictyol Compositions and Methods,” the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure generally relates to compositions and methods for treating neurovascular inflammation and injury in a subject, as well as conditions, diseases, and disorders caused by or associated with neurovascular inflammation and injury. Specifically, 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), and to combination therapies with eriodictyol. Background Art

[0004] Most chronic diseases involve disruption of the protective tissue-blood barrier. Notable, but non-exhaustive, examples include disruption of the skin-blood barrier, which leads to atopic dermatitis (eczema) and psoriasis; disruption of the gut-blood barrier, which leads to irritable bowel syndrome (IBS) and gluten enteropathy (celiac disease); food allergies / food intolerances; disruption of the bladder-blood barrier, which leads to interstitial cystitis / bladder pain syndrome (IC / BPS); disruption of the lung-blood barrier, which leads to asthma; and disruption of the blood-brain barrier (BBB), which leads to allergies, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), long-term COVID-19 syndrome, multiple sclerosis (MS), interstitial cystitis, mast cell activation syndrome, mastocytosis, migraines, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), perennial rhinitis, and traumatic brain injury (TBI).

[0005] In all of these conditions, diseases, and disorders, the breakdown of the protective barrier is involved in neurovascular inflammation and damage and increased vascular permeability, leading to extravasation of circulating leukocytes, associated neurovascular inflammatory responses, disruption of neuronal connectivity, 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, microglia, platelets, and neurons.

[0006] Modulating the integrity of the protective barrier and the subsequent immune response is crucial for preventing or treating the aforementioned conditions, diseases, and disorders. Existing medications aim to minimize the symptoms caused by this barrier disruption and the associated neurovascular inflammation and damage, rather than addressing the underlying causes. Therefore, compositions and treatments for mitigating neurovascular damage and improving patient outcomes are desirable. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The inclusion of the accompanying drawings is provided to assist in further understanding the embodiments of the present disclosure, and the accompanying drawings are incorporated into and constitute a part of this specification to illustrate the embodiments of the present disclosure and, together with the detailed description, to explain the principles of the embodiments discussed herein. We have not attempted to show the structural details of the present disclosure in a more detailed manner than is necessary for a basic understanding of the embodiments discussed herein and their various practices. As a matter of convention, the various features of the drawings discussed below are not necessarily drawn to scale. The sizes of the various features and elements in the drawings may be enlarged or reduced to more clearly show the embodiments of the present disclosure.

[0008] Figure 1 is a graphical representation of plaque reduction data obtained from treating Chikungunya virus-infected cells with eriodictyol or nobiletin (hexamethoxyluteolin), according to exemplary embodiments of the present disclosure.

[0009] Figure 2 is a graphical representation of IL-1β release resulting from pre-treatment of microglia with eriodictyol or nobiletin (hexamethoxyluteolin), according to an exemplary embodiment of the present disclosure. DETAILED DESCRIPTION

[0010] The present disclosure provides compositions and methods for treating neurovascular inflammation and injury in a subject, as well as illnesses, diseases and conditions caused by or associated with neurovascular inflammation and injury, or their prevention. The compositions disclosed herein include eriodictyol. Eriodictyol is a flavonoid compound found in a variety of plants including eriodictyon (Eriodictyon californicum). In at least some cases, eriodictyol (also sometimes referred to as eriodictiol) is a compound with the chemical structure shown in the following structure I, which is 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:

[0011]

[0012] Eriodictyol can be used in various degrees of purity, including purified active pharmaceutical ingredient (API) grade.Eriodictyol can be derived from plant biomass sources, including, for example, standardized extracts of North American sage or Citrus limon.

[0013] 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. Said composition may include a pharmaceutically acceptable amount of eriodictyol and / or any pharmaceutically acceptable salt, co-crystal, analog or physical modification thereof. Alternatively, said composition may include a pharmaceutically acceptable amount of a compound according to structure I, and any pharmaceutically acceptable salt, co-crystal, analog or physical modification thereof. Said composition may also include one or more pharmaceutically acceptable excipients. In some cases, one or more excipients may include at least one modified starch (including but not limited to cyclodextrin) and a lipid (such as phospholipid phosphatidylcholine).

[0014] The eriodictyol may be in any form, including standardized extracts of North American eriodictyol or lemon. In some cases, the eriodictyol is in microcrystalline form. In some cases, the composition may be formulated to include exosomes comprising eriodictyol, wherein the exosomes are engineered for targeted drug delivery. In other cases, the composition may be formulated to include liposomes comprising eriodictyol, wherein the liposomes are engineered for targeted eriodictyol delivery. Additionally, in other cases, eriodictyol may be complexed, reacted, combined, conjugated, and / or chelated with other compounds, including but not limited to amino acids and derivatives thereof and / or minerals (such as, but not limited to, zinc, calcium, magnesium, sodium, iron, manganese, and / or potassium).

[0015] In some cases, the compositions disclosed herein may comprise one or more exosome carriers comprising eriodictyol and operable to provide targeted eriodictyol delivery. In other cases, the compositions disclosed herein may comprise one or more liposome carriers comprising eriodictyol and operable to provide targeted eriodictyol delivery. The compositions disclosed herein may also be formulated as modified starch cavity-based systems.

[0016] According to at least some aspects of the present disclosure, the composition disclosed by the present invention can include one or more additional active pharmaceutical ingredients. In some cases, said composition can include the active pharmaceutical ingredient selected from the group consisting of the following: apigenin, fisetin, luteolin and quercetin or their methylated metabolites, tetramethoxy luteolin, hexamethoxy luteolin (nobiletin) and any combination thereof. Said composition can also include the active pharmaceutical ingredient selected from the group consisting of the following: alpha-lipoic acid, berberine sulfate, berberine hydrochloride, L-threonine, prostaglandin precursors (for example, arachidonic acid, dihomo-gamma-linolenic acid and eicosapentaenoic acid, etc.), vitamin E, zinc and any combination thereof. In some cases, said composition can also include the active pharmaceutical ingredient selected from the group consisting of the following: antiallergic drugs, anti-inflammatory drugs, antiviral drugs, cytoprotective drugs and any combination thereof. The composition may further comprise an active pharmaceutical ingredient selected from the group consisting of benralizumab, camostat mesylase or its analogs, chloroquine or its analogs, for example, antiallergics and antihistamines, including but not limited to nitrogen azelastine, sodium cromoglycate, famotidine, ketotifen, rupatadine, biologics such as dupilumab, mepolizumab, omalizumab, flamipiriravil or its analogs, antivirals such as interferon-γ, ivermectin, ligelizumab, oseltamivir or its analogs, pemirolast or its analogs, remdesivir or its analogs, reslizumab, rifampicin or its analogs, and serine protease inhibitors, including but not limited to lavgevrio and paxlovid, and any combination thereof. In addition, the composition disclosed herein may comprise an active pharmaceutical ingredient selected from the group consisting of: an additional zinc ionophore, an additional flavonoid (including but not limited to their methoxylated forms and derivatives), and any combination thereof. In addition, the composition may comprise an active pharmaceutical ingredient selected from the group consisting of: an antiallergic drug, an anti-inflammatory drug, an antiviral drug, a cytoprotective drug, and any combination thereof.

[0017] In at least some cases, the disclosed compositions comprising eriodictyol and at least one additional active pharmaceutical ingredient exhibit a measurable synergistic effect in improving patient outcomes compared to eriodictyol or the active pharmaceutical ingredient administered alone.

[0018] According to one aspect of the present disclosure, a method for treating or preventing neurovascular inflammation and injury in a subject is provided. The method may include administering a pharmaceutically effective amount of one of the eriodictyol compositions disclosed herein to a subject in need. The neurovascular inflammation and injury in the subject may be caused by a physiological response to a triggering factor selected from the group consisting of: an allergic triggering factor, an environmental triggering factor, an inflammatory triggering factor, a pathogenic triggering factor, a stress triggering factor, and any combination thereof. In some cases, the neurovascular inflammation and injury in the subject may lead to multiple organ failure. In some cases, the neurovascular inflammation and injury in the subject may be localized to an organ selected from the group consisting of: the brain, intestines, heart, lungs, skin, and any combination thereof.

[0019] In some cases, a subject treated according to the methods and compositions disclosed herein may be diagnosed with a brain disorder selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, vasculitis, mast cell activation syndrome, migraine, myalgic encephalomyelitis / chronic fatigue syndrome, prolonged COVID-19 syndrome, traumatic brain injury, and any combination thereof.

[0020] The methods disclosed herein may include administering an eriodictyol composition to a subject via a route of administration selected from the group consisting of: an intranasal route, an inhalation route, an oral route, a sublingual route, a transdermal route, a nasogastric tube route, or a gastric tube route, and any combination thereof. In at least some cases, the subject may be administered about 1 mg to about 5000 mg of eriodictyol daily. In some cases, administering to a subject may include administering the composition so that the subject is administered about 0.0125 mg / kg body weight to about 62.5 mg / kg body weight of eriodictyol daily.

[0021] According to at least one aspect of the present disclosure, a method for treating or preventing an illness, disease or condition of a subject is provided. The method may include administering a pharmaceutically effective amount of the eriodictyol composition disclosed herein to a subject in need thereof. The disease or condition 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-term new crown 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.

[0022] According to at least one aspect of the present disclosure, a method for treating or preventing COVID-19 related sequelae in a subject is provided. The method may include administering a pharmaceutically effective amount of one of the eriodictyol compositions disclosed herein to a subject in need. COVID-19 related sequelae may be selected from the group consisting of: pulmonary edema, fibrosis and inflammation, inflammation around cerebral blood vessels, cardiac inflammation (including myocarditis, pericarditis), long-term new crown syndrome, and any combination thereof.

[0023] According to at least one aspect of the present disclosure, a method for treating or preventing COVID-19 vaccine-related neuroinflammatory symptoms and / or cardiitis symptoms in a subject is provided. The method may comprise administering a pharmaceutically effective amount of one of the eriodictyol compositions disclosed herein to a subject in need thereof. COVID-19 vaccine-related neuroinflammatory symptoms and / or cardiitis symptoms may be selected from the group consisting of: microvascular changes, platelet aggregation, myocarditis, pericarditis, thrombosis, neuritis, stroke, and any combination thereof.

[0024] According to at least one aspect of the present disclosure, a combination therapy for treating or preventing endothelial injury in a subject is provided. The combination therapy may include administering a composition to a subject in need thereof, the composition comprising: a pharmaceutically acceptable amount of eriodictyol and / or any pharmaceutically acceptable form thereof, including a salt, cocrystal, analog, or physically modified form; 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 (e.g., arachidonic acid, dihomo-γ-linolenic acid, and eicosapentaenoic acid, etc.), vitamin E, zinc, and any combination thereof.

[0025] In at least some cases, the combination therapy shows a measurable synergistic effect in improving patient outcomes compared to eriodictyol or the active pharmaceutical ingredient 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-term new crown 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 sequelae selected from the group consisting of pulmonary edema, fibrosis and inflammation, cerebral perivascular inflammation, cardiac inflammation (including myocarditis, pericarditis), long-term new crown syndrome, and any combination thereof. In still other cases, the subject is diagnosed with a disease, or has a condition, selected from the group consisting of: allergies, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), encephalitis, long-term COVID-19 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.

[0026] Example

[0027] The examples provided below illustrate selected aspects of the compositions and methods disclosed herein.

[0028] Example 1 - Treatment of RNA virus infected plaques using eriodictyol

[0029] Chikungunya virus-infected human microglia were treated with eriodictyol or nobiletin (hexamethoxyluteolin) to demonstrate the effects of eriodictyol treatment on RNA virus-infected plaques. Human microglial cell cultures were used because microglia are cells of the brain's innate immune system, and microglial activation is implicated in a wide range of neuroinflammatory and neurodegenerative diseases. Chikungunya virus was chosen as a suitable RNA virus surrogate for coronavirus. Figure 1 Data obtained from virus plaques treated with eriodictyol or nobiletin are shown. Figure 1 As shown, the result of treating cells with eriodictyol was a significant reduction in plaques in a dose-dependent manner. In addition, it was found that at a concentration of 100 micromolar, eriodictyol had a slightly stronger inhibitory potency than nobiletin.

[0030] Example 2 - Pretreatment of human SV40 microglial cell cultures with eriodictyol

[0031] Cultured human SV40 microglia were pretreated with eriodictyol (Erio) or nobiletin (Nobi) for two hours to determine the extent to which eriodictyol and nobiletin inhibit the secretion of the proinflammatory cytokine interleukin-1β (IL-1β) and subsequent stimulation with bacterial lipopolysaccharide (LPS) production. Figure 2 The data obtained from the experiment are shown in Figure 2. Figure 2 As shown, it was found that at a concentration of 50 micromolar, eriodictyol and nobiletin inhibited IL-1β secretion more potently than luteolin (Lut) and methoxyluteolin (Methlut).

[0032] Example 3 - Treatment of long-term COVID-19 syndrome with eriodictyol

[0033] A 33-year-old Caucasian female subject diagnosed with long-term COVID-19 syndrome was given 60 milligrams (mg) of eriodictyol (30 mg / vegetarian capsule; 2 capsules per day) daily for three months. The subject reported a greater than 80% reduction in long-term COVID-19 symptoms, including an 80% reduction in fatigue, brain fog, difficulty concentrating, difficulty remembering, finding the right words, and difficulty multitasking.

[0034] Public Content Statement :

[0035] Statement 1: A composition for treating or preventing neurovascular inflammation and damage in a subject, the composition comprising: a pharmaceutically acceptable amount of eriodictyol and / or any pharmaceutically acceptable form thereof, including salts, co-crystals, analogs, or physically modified forms.

[0036] Statement 2: A composition for treating or preventing endothelial injury in a subject, comprising: a pharmaceutically acceptable amount of a compound according to Structure I, and any pharmaceutically acceptable form thereof, including salts, co-crystals, analogs, or physically modified forms:

[0037]

[0038] Statement 3: The composition according to statement 1 or statement 2, further comprising one or more pharmaceutically acceptable excipients.

[0039] Statement 4: The composition of statement 3, wherein the one or more excipients comprises at least one modified starch.

[0040] Statement 5: The composition of statement 3 and statement 4, wherein the at least one modified starch is a cyclodextrin.

[0041] Statement 6: The composition of any one of statements 1 to 5, wherein the eriodictyol is a standardized extract of North American eriodictyol or lemon.

[0042] Statement 7: A composition according to any one of statements 1 to 6, wherein the eriodictyol is in microcrystalline form.

[0043] Statement 8: The composition of any one of statements 1 to 7, which is formulated to include exosomes comprising said eriodictyol, wherein said exosomes are engineered for targeted drug delivery.

[0044] Statement 9: The composition of any one of statements 1 to 7, formulated to include liposomes comprising said eriodictyol, wherein said liposomes are engineered for targeted eriodictyol delivery.

[0045] Statement 10: The composition of any one of statements 1 to 7, comprising one or more exosome carriers comprising eriodictyol and operable to provide targeted eriodictyol delivery.

[0046] Statement 11: The composition of any one of statements 1 to 7, comprising one or more liposome carriers comprising eriodictyol and operable to provide targeted eriodictyol delivery.

[0047] Statement 12: The composition of any one of statements 1 to 11, formulated as a modified starch cavity-based system.

[0048] Statement 13: The composition according to any one of statements 1 to 12, further comprising 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.

[0049] Statement 14: The composition of any one of statements 1 to 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, dihomo-γ-linolenic acid, and eicosapentaenoic acid, etc.), vitamin E, zinc, and any combination thereof.

[0050] Statement 15: The composition of any one of statements 1 to 14, further comprising an active pharmaceutical ingredient selected from the group consisting of anti-allergic drugs, anti-inflammatory drugs, antiviral drugs, cell protection drugs, and any combination thereof.

[0051] Statement 16: The composition according to any one of statements 1 to 15, further comprising an active pharmaceutical ingredient selected from the group consisting of benralizumab, camostat mesylate or an analog thereof, chloroquine or an analog thereof, antiallergic drugs and antihistamines, including but not limited to nitrogen statin, sodium cromoglycate, famotidine, ketotifen, rupatadine; antioxidants, including but not limited to curcumin, oleuropein, hydroxytyrosol, resveratrol, sulforaphane; biologics, such as dupilumab, mepolizumab, omalizumab, flamipiravir or its analogs; antiviral drugs, such as interferon-γ, ivermectin, liglizumab, oseltamivir or its analogs, pemirolast or its analogs, remdesivir or its analogs, reslizumab, rifampicin or its analogs, and serine protease inhibitors, including but not limited to ragviroc and belaviravir and any combination thereof.

[0052] Statement 17: The composition of any one of statements 1 to 16, further comprising an active pharmaceutical ingredient selected from the group consisting of an additional zinc ionophore, an additional flavonoid including but not limited to their methoxylated forms and derivatives, and any combination thereof.

[0053] Statement 18: The composition of any one of statements 1 to 14, further comprising an active pharmaceutical ingredient selected from the group consisting of anti-allergic drugs, anti-inflammatory drugs, antiviral drugs, cell protection drugs, and any combination thereof.

[0054] Statement 19: The composition of any one of Statements 13 to 18, wherein the composition comprising eriodictyol and at least one additional active pharmaceutical ingredient exhibits a measurable synergistic effect in improving patient outcomes.

[0055] Statement 20: A method of treating or preventing neurovascular inflammation and damage in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition of any one of Statements 1 to 19.

[0056] Statement 21: The method of statement 20, wherein the neurovascular inflammation and damage in the subject is caused by 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.

[0057] Statement 22: The method of statement 20 or statement 21, wherein the neurovascular inflammation and damage in the subject results in multiple organ failure.

[0058] Statement 23: The method of any one of statements 20 to 22, wherein the neurovascular inflammation and damage in the subject is localized to an organ selected from the group consisting of: brain, intestine, heart, lung, skin, and any combination thereof.

[0059] Statement 24: The method of any one of statements 20 to 23, wherein the subject is 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-term COVID-19 syndrome, mast cell activation syndrome, migraine, multiple sclerosis (MS), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), traumatic brain injury, and any combination thereof.

[0060] Statement 25: The method of any one of statements 20 to 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 tube, and any combination thereof.

[0061] Statement 26: The method of any one of statements 20 to 25, wherein administering to the subject comprises administering the composition such that from about 1 mg to about 5000 mg of eriodictyol is administered to the subject per day.

[0062] Statement 27: The method of any one of statements 20 to 25, wherein administering to the subject comprises administering the composition such that from about 0.0125 mg / kg body weight to about 62.5 mg / kg body weight of eriodictyol is administered to the subject daily.

[0063] Statement 28: A method for treating or preventing a disease or condition in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition according to any one of Statements 1 to 19, wherein the condition, the disease or the condition is selected from the group consisting of: allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), long-term COVID-19 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.

[0064] Statement 29: The method of any one of statement 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 tube, and any combination thereof.

[0065] Statement 30. The method of statement 28 or statement 29, wherein administering to the subject comprises administering the composition such that from about 1 mg to about 5000 mg of eriodictyol is administered to the subject daily.

[0066] Statement 31. The method of any one of statements 28 to 30, wherein administering to the subject comprises administering the composition such that from about 0.0125 mg / kg body weight to about 62.5 mg / kg body weight of eriodictyol is administered to the subject daily.

[0067] Statement 32: A method for treating or preventing COVID-19-related sequelae in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition according to any one of Statements 1 to 19.

[0068] Statement 33: The method of any one of Statement 32, wherein the COVID-19 related sequelae is selected from the group consisting of: pulmonary edema, fibrosis and inflammation, cerebral perivascular inflammation, cardiac inflammation including myocarditis, pericarditis, long-term COVID syndrome, and any combination thereof.

[0069] 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 tube, and any combination thereof.

[0070] Statement 35: The method of any one of statements 32 to 34, wherein administering to the subject comprises administering the composition such that from about 1 mg to about 5000 mg of eriodictyol is administered to the subject per day.

[0071] Statement 36: The method of any one of statements 32 to 35, wherein administering to the subject comprises administering the composition such that from about 0.0125 mg / kg body weight to about 62.5 mg / kg body weight of eriodictyol is administered to the subject daily.

[0072] Statement 37: A method for treating or preventing COVID-19 vaccine-related neuroinflammatory symptoms and / or cardiitis symptoms in a subject, the method comprising administering a pharmaceutically effective amount of a composition according to any one of Statements 1 to 19 to the subject in need.

[0073] Statement 38: The method according to Statement 37, wherein the COVID-19 vaccine-related neuroinflammatory symptoms and / or cardiinflammatory symptoms are selected from the group consisting of: microvascular changes, platelet aggregation, myocarditis, pericarditis, thrombosis, neuroinflammatory damage, stroke and any combination thereof.

[0074] 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 tube, and any combination thereof.

[0075] Statement 40: The method of any one of statements 37 to 39, wherein administering to the subject comprises administering the composition such that from about 1 mg to about 5000 mg of eriodictyol is administered to the subject per day.

[0076] Statement 41. The method of any one of statements 37 to 40, wherein administering to the subject comprises administering the composition such that from about 0.0125 mg / kg body weight to about 62.5 mg / kg body weight of eriodictyol is administered to the subject daily.

[0077] Statement 42: A combination therapy for treating or preventing endothelial injury in a subject, the combination therapy comprising: administering to the subject in need thereof a composition comprising: a pharmaceutically acceptable amount of eriodictyol and / or any pharmaceutically acceptable form thereof, including salts, cocrystals, analogs or physically modified forms; and an active pharmaceutical ingredient selected from the group consisting of: 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, dihomo-γ-linolenic acid and eicosapentaenoic acid, etc.), vitamin E, zinc and any combination thereof.

[0078] Statement 43: The combination therapy of statement 42 wherein the endothelial injury 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.

[0079] Statement 44: The combination therapy of statement 41 or statement 42, wherein the endothelial injury in the subject results in multiple organ failure.

[0080] Statement 45: The combination therapy of any one of statements 41 to 44, wherein the endothelial injury in the subject is localized to an organ selected from the group consisting of: brain, heart, lung, skin, and any combination thereof.

[0081] Statement 46: The combination therapy of any one of Statements 41 to 45, wherein the subject is diagnosed with a brain disease or brain disorder 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-term COVID-19 syndrome, traumatic brain injury, and any combination thereof.

[0082] Statement 47: The combination therapy of any one of statements 41 to 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 tube, and any combination thereof.

[0083] Statement 48. The combination therapy of any one of statements 41 to 47, wherein administering to the subject comprises administering the composition such that from about 1 mg to about 5000 mg of eriodictyol is administered to the subject daily.

[0084] Statement 49: The combination therapy of any one of Statements 41 to 47, wherein administering to the subject comprises administering the composition such that from about 0.0125 mg / kg body weight to about 62.5 mg / kg body weight of eriodictyol is administered to the subject daily.

[0085] Statement 50: The combination therapy of any one of Statements 41 to 49, wherein the combination therapy exhibits a measurable synergistic effect in improving patient outcomes compared to eriodictyol or the active pharmaceutical ingredient administered alone.

[0086] Statement 51: A combination according to any one of statements 41 to 50 therapy , wherein the subject is diagnosed with COVID-19 related sequelae selected from the group consisting of: pulmonary edema, fibrosis and inflammation, cerebral perivascular inflammation, cardiac inflammation including myocarditis, pericarditis, long-term COVID syndrome and any combination thereof.

[0087] Statement 52: The combination therapy of any one of statements 41 to 50, wherein the subject is diagnosed with a condition, disease or disorder selected from the group consisting of: allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), long-term 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. A composition for treating or preventing neurovascular inflammation and injury in a subject, the composition comprising: A pharmaceutically acceptable amount of eriodictyol and / or any pharmaceutically acceptable form thereof, including salts, co-crystals, analogs or physically modified forms.

2. The composition according to claim 1, further comprising cyclodextrin.

3. The composition of claim 1, comprising one or more exosome carriers comprising eriodictyol and operable to provide targeted eriodictyol delivery.

4. The composition according to claim 1, further comprising 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.

5. The composition according to 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, dihomo-γ-linolenic acid, eicosapentaenoic acid, vitamin E, zinc, and any combination thereof.

6. The composition according to claim 1, further comprising an active pharmaceutical ingredient selected from the group consisting of benralizumab, camostat mesylate or its analogs, chloroquine or its analogs, antiallergic drugs and antihistamines, including but not limited to nitrogen Sting, sodium cromoglycate, famotidine, ketotifen, rupatadine; antioxidants, including but not limited to curcumin, oleuropein, hydroxytyrosol, resveratrol, sulforaphane; biologics, such as dupilumab, mepolizumab, omalizumab, flamipilavir or their analogs; antiviral drugs, such as interferon-γ, ivermectin, ligelimumab, oseltamivir or its analogs, pemirolast or its analogs, remdesivir or its analogs, reslizumab, rifampicin or its analogs, and serine protease inhibitors, including but not limited to ragviroc and belavir and any combination thereof.

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

8. The composition according to claim 1, further comprising an active pharmaceutical ingredient selected from the group consisting of anti-allergic drugs, anti-inflammatory drugs, anti-viral drugs, cell protection drugs, and any combination thereof.

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

10. A method for treating or preventing neurovascular inflammation and damage in a subject, the method comprising: Administering a pharmaceutically effective amount of the composition according to claim 1 to the subject in need thereof.

11. The method of claim 10, wherein the neurovascular inflammation and damage in the subject is caused by 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. The method of claim 10, wherein the neurovascular inflammation and damage in the subject results in multiple organ failure.

13. The method of claim 10, wherein the neurovascular inflammation and damage in a subject is localized to an organ selected from the group consisting of: brain, intestine, heart, lung, skin, and any combination thereof.

14. The method of claim 10, wherein the subject is 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-term 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. The method of claim 10, wherein administering to the subject comprises administering the composition such that from about 0.0125 mg / kg body weight to about 62.5 mg / kg body weight of eriodictyol is administered to the subject per day.

16. A method of treating or preventing a disease or condition in a subject, the method comprising: A pharmaceutically effective amount of the composition according to claim 1 is administered to the subject in need thereof, wherein the disorder, the disease or the condition is selected from the group consisting of: allergy, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), vasculitis, asthma, atopic dermatitis, autism spectrum disorder (ASD), long-term new crown 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. The method of claim 16, wherein the disorder, the disease or the condition is long-term COVID-19 syndrome.

18. A method for treating or preventing COVID-19 related sequelae in a subject, the method comprising: Administering a pharmaceutically effective amount of the composition according to claim 1 to the subject in need thereof.

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

20. A combination therapy for treating or preventing endothelial injury in a subject, the combination therapy comprising: administering to the subject in need thereof a composition comprising: a pharmaceutically acceptable amount of eriodictyol or any pharmaceutically acceptable form thereof, including salts, co-crystals, analogs or physically modified forms; as well as 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, dihomo-γ-linolenic acid and eicosapentaenoic acid, etc.), vitamin E, zinc and any combination thereof.

Images