TW202416945A - Combination therapies for treating inflammation - Google Patents

Abstract

The present disclosure relates to therapeutic agents and combinations thereof (e.g., pharmaceutical compositions) for the treatment of inflammation and an inflammatory disease or disorder in a subject, tissue or cell.

Description

Combination therapy for treating inflammation

There is a need for therapeutic agents that can be used to modulate inflammatory responses in cells or tissues and to treat inflammation and inflammatory diseases and disorders in individuals.

The present invention relates to therapeutic agents and combinations thereof (e.g., pharmaceutical compositions) for treating inflammation and inflammatory diseases and conditions in an individual, tissue, or cell. In one aspect, the present invention provides a method for treating inflammation or an inflammatory disease or condition (e.g., a skin condition) in an individual, comprising administering to the individual a combination of a flavonoid (e.g., quercetin) and a sesquiterpene lactone (e.g., parthenolide). In one embodiment, administering to the individual a combination of a flavonoid (e.g., quercetin) and a sesquiterpene lactone (e.g., parthenolide) produces a beneficial effect in the individual, for example, compared to administering the flavonoid and/or sesquiterpene lactone alone. For example, administration of a combination of flavonoids and sesquiterpene lactones to a cell or subject may result in one or more of the following: (i) a decrease in the level of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a) in the cell or subject; (ii) an increase in the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) in the cell or subject; (iii) a decrease in the level of allergy markers (e.g., IL-13, The invention relates to the invention to increase the level of IL-14, INF-g and serum IgE in cells or individuals; (iv) induce the expression of anti-inflammatory macrophages (e.g., M2 macrophages) in cells or individuals; (v) improve the health of the skin in cells or individuals; (vi) improve the symptoms of skin conditions (e.g., atopic dermatitis, psoriasis and skin allergies) in cells or individuals; and (vii) improve the symptoms of inflammation or inflammatory diseases or disorders in cells or individuals.

CLAIM OF PRIORITY This application claims priority to U.S. Provisional Application No. 63/396,940, filed on August 10, 2022, the contents of which are incorporated herein by reference in their entirety.

Compositions comprising (i) a flavonoid or a pharmaceutically acceptable salt thereof and (ii) a sesquiterpene lactone or a pharmaceutically acceptable salt thereof, as well as compositions and methods of use thereof are described herein. In one embodiment, administration of a combination of a flavonoid and a sesquiterpene lactone to an individual produces a beneficial effect in the individual, for example, compared to administration of a flavonoid and/or a sesquiterpene lactone alone. For example, a combination of a flavonoid and a sesquiterpene lactone can reduce the level of inflammatory cytokines in a cell or individual, or treat a skin condition in a cell or individual. Descriptions of exemplary embodiments of the invention are provided herein.

Definitions As used herein, the articles "a" and "an" refer to one or to more than one (eg, to at least one) of the grammatical object of the article.

"About" and "substantially" should generally mean an acceptable degree of error in the quantity measured, given the nature or precision of the measurement result. Exemplary degrees of error are within 20 percent (%) of a stated value or range of values, typically within 10%, and more typically within 5%.

As used herein, the term "acquire" or "acquiring" as used herein refers to obtaining a physical entity (e.g., a sample, such as a blood sample or a liver biopsy sample) or a value (e.g., a numerical value) by "directly obtaining" or "indirectly obtaining" the physical entity or value. "Directly obtaining" means performing a process (e.g., an analytical method) to obtain the physical entity or value. "Indirectly obtaining" means receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly obtains the physical entity or value). Directly obtaining a value includes performing a process involving a physical change of a sample or another substance, such as performing an analytical process involving a physical change of a substance (e.g., a sample), performing an analytical method, such as the methods described herein, such as by analysis of a sample of a cell titer or body fluid, such as by mass spectrometry (e.g., LC-MS) or PCR (e.g., RT-PCR).

As used herein, "co-administered," "co-administered," "co-provided," "combined," and "combination" in the context of administering flavonoids and sesquiterpene lactones refer to simultaneous administration, or administration of one therapy first and subsequent administration (e.g., immediately thereafter, within less than about 5, about 10, about 15, about 30, about 45, about 60 minutes, about 1, about 2, about 3, about 4, about 6, about 8, about 10, about 12, about 16, about 20, about 24, about 48, about 72, or more hours thereafter) of a second therapy. In some embodiments, the co-administered therapies are formulated in a single composition. In other embodiments, the co-administered therapies are formulated separately.

Many ranges are provided herein, such as ranges of amounts of a therapy administered daily. In some embodiments, the range includes both endpoints. In other embodiments, the range does not include one or both endpoints. For example, a range may not include a starting endpoint. Thus, in such embodiments, a range of 250 to 400 mg/day excluding the starting endpoint would cover amounts greater than 250 mg/day and less than or equal to 400 mg/day.

The term "comprising" is intended to mean "including". When a term is provided in the singular, it also encompasses aspects of the invention described by the plural form of the term. The term "and/or" used herein should be considered as a specific disclosure of each of a plurality of specified features or components with or without another feature or component. Thus, the term "and/or" as used herein in phrases such as "A and/or B" is intended to include "A and B", "A or B", "A" (alone) and "B" (alone). Similarly, the term "and/or" as used in phrases such as "A, B and/or C" is intended to cover each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

As referred to herein, a "course" or "treatment course" comprises one or more separate administrations of a therapeutic agent or combination of therapeutic agents (e.g., flavonoids and/or sesquiterpene lactones). A treatment course may comprise one or more cycles of a therapeutic agent. In some embodiments, a therapeutic agent is administered to a subject at least once, at least twice, at least three times, at least four times, or more during a treatment course. One or more treatment courses may be administered to a subject. In some embodiments, a rest period may be between treatment courses. For example, the length of the suspension period can be about 1, about 2, about 4, about 6, about 8, about 10, about 12, about 16, about 20, or about 24 hours; or about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days; or about 1, about 2, about 3, about 4, about 5, about 6, or about 7 weeks.

As used herein in the context of a cycle of administration of a therapeutic agent or combination of therapeutic agents, "cycle" refers to the period of time during which a therapeutic agent or combination of therapeutic agents is administered to a patient. For example, if a therapeutic agent is administered in a 4-week cycle, then cyclical administration (e.g., once a day or twice a day) is performed for 4 weeks. A therapeutic agent or combination of therapeutic agents may be administered for more than one cycle. In some embodiments, the first cycle and the second or subsequent cycles are identical in one or both of duration and cyclical administration. In embodiments, the first cycle and the second or subsequent cycles differ in one or both of duration and periodic administration. A rest period may be between cycles. The length of the rest period may be about 1, about 2, about 4, about 6, about 8, about 10, about 12, about 16, about 20, or about 24 hours; or about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days; or about 1, about 2, about 3, about 4, about 5, about 6, or about 7 weeks; or about 1, about 2, about 3, about 4 weeks or more.

As used herein, the term "efficacy" in the context of a therapeutic agent or combination of therapeutic agents refers to the ability of a therapeutic agent or combination of therapeutic agents to achieve a desired therapeutic outcome, such as (i) reducing the level of inflammatory cytokines (e.g., IL-6, IL-1b, and TNF-a) in a cell or subject; (ii) increasing the level of anti-inflammatory cytokines (e.g., IL-4 and IL-10) in a cell or subject; (iii) reducing the level of allergy markers (e.g., TNF-α) in a cell or subject. (e.g., IL-13, IL-14, INF-g, and serum IgE); (iv) inducing the expression of anti-inflammatory macrophages (e.g., M2 macrophages) in cells or individuals; (v) improving skin health in cells or individuals; (vi) improving symptoms of skin conditions (e.g., atopic dermatitis, psoriasis, and skin allergies) in cells or individuals; and (vii) improving symptoms of inflammation or inflammatory diseases or disorders in cells or individuals.

As used herein, the terms "increase" and "decrease" refer to a greater or lesser modulation of the amount of a particular measured function, expression or activity relative to a reference, respectively. For example, after administering the combination of flavonoids and sesquiterpene lactones described herein to cells, tissues or individuals, the amount of a marker measured as described herein (e.g., cell viability, interleukin levels) may be increased or decreased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98%, 2-fold, 3-fold, 5-fold, 10-fold or more relative to the amount of the marker before administration or relative to the effect of a negative control. Measurements can be made after administration, when administration has had the described effect (e.g., at least 12 hours, 24 hours, one week, one month, three months, or six months after initiation of treatment).

As used herein, the term "prevent" or "preventing" as used in the context of a disease or disorder described herein, such as inflammation or an inflammatory disease or disorder, refers to administering a combination of a flavonoid and a sesquiterpene lactone, such as administration of parthenolide and quercetin, to a subject such that the onset of at least one symptom of the disorder or disease is delayed compared to when the combination is not administered.

As used herein, the term "subject" is intended to include humans and non-human animals. Exemplary human subjects include human patients suffering from a disease or disorder (e.g., a disorder described herein, such as inflammation or an inflammatory disease or disorder) or healthy individuals. The term "non-human animal" includes all vertebrates, such as non-mammalian animals (e.g., chickens, amphibians, reptiles) and mammals, such as non-human primates, domestic and/or agriculturally useful animals, such as sheep, dogs, cats, cows, pigs, etc.

As used herein, an amount of a compound, conjugate or substance effective to treat a disease or condition (e.g., inflammation or an inflammatory disease or condition), a "therapeutically effective amount," an "effective amount," or an "effective course of treatment" refers to an amount of a compound or composition that, after administration to a subject in a single or multiple doses, is effective to treat the subject or to cure, relieve, ameliorate, or improve a subject suffering from inflammation or an inflammatory disease or condition as compared to what would be expected in the absence of such treatment.

As used herein, the term "treat" or "treating" as used in the context of a disease or condition described herein, such as inflammation or an inflammatory disease or condition, refers to the administration of a combination of flavonoids and sesquiterpene lactones, such as parthenolide and quercetin, to a subject such that at least one symptom of the condition or disease is cured, diagnosed, alleviated, reduced, altered, healed, improved, or improved. Treatment includes administration of an amount effective to alleviate, alleviate, alter, heal, improve, ameliorate, or affect the condition or disease or a symptom of the condition or disease. Treatment may inhibit deterioration or worsening of symptoms of the condition or disease. In some embodiments, treatment includes prevention. In some embodiments, treatment does not include prevention.

Therapeutic Agents Described herein are flavonoids administered in combination with sesquiterpene lactones to provide a therapeutic benefit to a cell or an individual, such as to treat inflammation or an inflammatory disease or disorder.

Flavonoids Flavonoids are a class of polyphenolic compounds that contain at least one heterocyclic ring containing a heteroatom, such as an oxygen atom. Flavonoids can be derived from plants, where they play a variety of functions. For example, flavonoids play a role in plant pigmentation, UV filtering, nitrogen fixation, and certain metabolic pathways. Depending on their structure, flavonoids can be further divided into subclasses such as anthocyanins, chalcone, flavonols, flavanones, and isoflavones.

In one embodiment, the flavonoid is a compound of formula (A): (A) or a pharmaceutically acceptable salt thereof, wherein each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently hydrogen or -OR ^A ; ^RA is hydrogen, C ₁ -C ₆ alkyl or cycloalkyl; and " " is a single key or a double key.

In one embodiment, the flavonoid is a compound of formula (Ai): (Ai) or a pharmaceutically acceptable salt thereof, wherein each of ^R1 and ^R2 is independently hydrogen or ^-ORA ; ^R3 is hydrogen or ^-ORA ; ^R4 is hydrogen or ^-ORA ; ^RA is hydrogen, _C1 - _C6 alkyl or cycloalkyl; and " " is a single key or a double key.

In one embodiment, R ¹ is -OR ^A . In one embodiment, R ¹ is -OH. In one embodiment, R ² is -hydrogen. In one embodiment, R ³ is -OR ^A . In one embodiment, R ^{3 is -OH. In one embodiment, R 4} is -OR ^A . In one embodiment, R ⁴ is -OH ^. In one embodiment, is a double key.

In one embodiment, the flavonoid is a compound of formula (A-ii): (A-ii) or a pharmaceutically acceptable salt thereof, wherein each of R ¹ and R ² is independently hydrogen or -OR ^A ; R ⁴ is hydrogen or -OR ^A ; and ^RA is hydrogen, C ₁ -C ₆ alkyl or cycloalkyl.

In an embodiment of formula (Ai), ^R1 is ^-ORA ; ^R2 is hydrogen; and ^R4 is ^-ORA . In an embodiment of formula (Ai), ^R1 is -OH; ^R2 is hydrogen; and ^R4 is -OH.

In one embodiment, the flavonoid is a compound of formula (A-iii): (A-iii) or a pharmaceutically acceptable salt thereof, wherein each of R ¹ is hydrogen or -OR ^A ; R ⁴ is hydrogen or -OR ^A ; and ^RA is hydrogen, C ₁ -C ₆ alkyl or cycloalkyl.

In embodiments of formula (A-iii), R ¹ is -OR ^A and R ⁴ is -OR ^A . In embodiments of formula (A-ii), R ¹ is -OH and R ⁴ is -OH.

In one embodiment, the flavonoid is a compound shown in Table 1. Table 1. Exemplary flavonoids Compound Structure Leaf flavonoids Quercetin Myricetin Taxifolin Fisetin Kaempferol Apigenin Tricetin Isohamnetin Eriodictyol Dihydromyricetin Chryseriol 7,3',4'-Trihydroxyflavone 4',7-Dihydroxyflavone Hesperitin Galangin Chrysin 7-O-Methylflavonoids Genkwanin Acacetin Retusin 7-Hydroxyflavone Apigenin 7,4'-dimethyl ether Pratol Ombuin Quercetin 3,3'-dimethyl ether Tectochrysin Tricin

In one embodiment, the flavonoid is flavonoids or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is quercetin or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is quercetin or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is flavonoids or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is taxifolin or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is flavonoids or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is flavonol or a pharmaceutically acceptable salt thereof.

In one embodiment, the flavonoid is apigenin or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is triticum truncatum or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is isorhamnetin or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is eriodictyol or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is dihydroerucyl flavonoid or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is geranyl flavonoid or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is geranyl flavonoid or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is 7,3',4'-trihydroxyflavone or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is 4',7-dihydroxyflavone or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is hesperidin or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is galangin or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is flavonoid or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is 7-O-methylflavonoid or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is genkwaflavone or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is acacetin or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is redoxin flavonol or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is 7-hydroxyflavone or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is apigenin 7,4'-dimethyl ether or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is chelidonol or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is schizonepeta tenuifolia or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is quercetin 3,3'-dimethyl ether or a pharmaceutically acceptable salt thereof. In one embodiment, the flavonoid is schizonepeta tenuifolia or a pharmaceutically acceptable salt thereof.

In one embodiment, the flavonoid is a leaf flavonoid or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid, such as quercetin, cyperiflavonoids, taxifolin, flavonoids or flavonols. In one embodiment, the flavonoid is a quercetin or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid, such as leaf flavonoids, cyperiflavonoids, taxifolin, flavonoids or flavonols. In one embodiment, the flavonoid is cyperiflavonoids or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid, such as quercetin, leaf flavonoids, taxifolin, flavonoids or flavonols. In one embodiment, the flavonoid is taxifolin or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid, such as quercetin, acanthin, flavonoids, flavonoids or flavonols. In one embodiment, the flavonoid is flavonoid or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid, such as quercetin, acanthin, taxifolin, flavonoids or flavonols. In one embodiment, the flavonoid is flavonoids or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid, such as quercetin, acanthin, taxifolin, flavonoids or flavonols.

In one embodiment, the flavonoid is flavonoids or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid listed in Table 1. In one embodiment, the flavonoid is quercetin or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid listed in Table 1. In one embodiment, the flavonoid is flavonoids or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid listed in Table 1. In one embodiment, the flavonoid is taxifolin or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid listed in Table 1. In one embodiment, the flavonoid is flavonoids or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid listed in Table 1. In one embodiment, the flavonoid is a flavonol or a pharmaceutically acceptable salt thereof, which is substantially free of another flavonoid listed in Table 1.

In one embodiment, the flavonoid or a pharmaceutically acceptable salt thereof is provided as a substantially pure compound (e.g., at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.9% pure, e.g., as measured by HPLC analysis). In one embodiment, the flavonoid is quercetin or a pharmaceutically acceptable salt thereof and is provided as a substantially pure compound (e.g., at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.9% pure, e.g., as measured by HPLC analysis).

In one embodiment, the flavonoid has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5% or 0.1% of another flavonoid, such as the absence of another flavonoid. In one embodiment, the flavonoid is quercetin and has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5% or 0.1% of another flavonoid, such as the absence of another flavonoid. In one embodiment, the flavonoid is quercetin and has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5% or 0.1% of quercetin present, such as the absence of phylloflavonoids. In one embodiment, the flavonoid has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5% or 0.1% of another plant-derived substance, such as a plant metabolite, a plant lipid or a plant fiber. In one embodiment, the flavonoid is quercetin and has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5% or 0.1% of plant-derived substances such as plant metabolites, plant lipids or plant fibers.

Compositions useful for treating inflammation or inflammatory diseases or conditions may contain one flavonoid (e.g., quercetin) or a plurality of flavonoids. For example, a composition comprising a flavonoid may comprise quercetin (e.g., prepared synthetically or extracted from a natural source) and no other flavonoid is present. Conversely, a composition comprising a flavonoid may also contain a combination of quercetin and closely related analogs or variants thereof, such as the flavonoids shown in Table 1, such as quercetin.

Sesquiterpene lactones Sesquiterpene lactones are a class of colorless, lipophilic sesquiterpenoid compounds containing a lactone ring. These compounds are one of the most common classes of secondary metabolites present in plants and are most commonly found in plant families such as Asteraceae , Cactaceae , Solanaceae , Araceae , and Euphorbiaceae . Polyphenolic compounds are commonly found in higher plants, fungi, and lichens. The biosynthesis of sesquiterpene lactones is known and proceeds from three isoprene units via farnesyl pyrophosphate in the endoplasmic reticulum of plant cells.

In one embodiment, the sesquiterpene lactone is a compound of formula (B): (B) or a pharmaceutically acceptable salt thereof, wherein each of R ^1a and R ^1b is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl, or R ^1a and R ^1b together with the carbon atom to which they are attached form a C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; each of R ⁴ and R ⁵ is independently absent, hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A , or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a heterocyclic ring; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C 6 heteroalkyl, or -OR A ₆ heteroalkyl or -OR ^A ; R ⁷ is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atoms to which they are attached form a heterocyclic ring; R ⁸ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl; and “ " is a single key or double key, and its restriction condition is that when " When " is a double key, each of ^R4 and ^R5 independently does not exist.

In one embodiment, the sesquiterpene lactone is a compound of formula (Bi): (Bi) or a pharmaceutically acceptable salt thereof, wherein each of R ^1a and R ^1b is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl, or R ^1a and R ^1b together with the carbon atom to which they are attached form a C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen or C ₁ -C ₆ alkyl; each of R ⁴ and R ⁵ is independently absent, hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A , or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a heterocyclic ring; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; R ^{R 7} is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atoms to which they are attached form a heterocyclic ring; ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl; and " " is a single key or double key, and its restriction condition is that when " When " is a double key, each of ^R4 and ^R5 independently does not exist.

In one embodiment, R ^1a and R ^1b together form a C ₂ -C ₆ alkenyl. In one embodiment, R ² is a C ₁ -C ₆ alkyl. In one embodiment, R ³ is a C ₁ -C ₆ alkyl. In one embodiment, R ⁴ and R ⁵ together form a heterocyclic ring (e.g., an epoxide ring). -OH. In one embodiment, R ⁴ is -OR ^A . In one embodiment, R ⁴ is -OH. In one embodiment, R ⁶ is hydrogen or -OR ^A . In one embodiment, R ⁷ is hydrogen or -OR ^A . In one embodiment, R ² and R 7 together form a heterocyclic ring. In one embodiment, " " is a single key. In one embodiment, " " is a double key.

In one embodiment, R ^1a and R ^1b together with the carbon atoms to which they are attached form a C ₂ -C ₆ alkenyl group; R ² is a C ₁ -C ₆ alkyl group; R ³ is a C ₁ -C ₆ alkyl group; R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a heterocyclic ring; R ⁶ is hydrogen; R ⁷ is hydrogen; and " " is a single key.

In one embodiment, R ^1a and R ^1b together with the carbon atom to which they are attached form a vinyl group; R ² is a methyl group; R ³ is a methyl group; R ⁴ and R ⁵ together with the carbon atom to which they are attached form an epoxide ring; R ⁶ is hydrogen; R ⁷ is hydrogen; and " " is a single key.

In one embodiment, R ^1a and R ^1b together with the carbon atoms to which they are attached form a C ₂ -C ₆ alkenyl group; R ² is a C ₁ -C ₆ alkyl group; R ³ is a C ₁ -C ₆ alkyl group; each of R ⁴ and R ⁵ is independently absent; R ⁶ is hydrogen; R ⁷ is hydrogen; and " " is a double key.

In one embodiment, the sesquiterpene lactone is a compound of formula (B-ii): (B-ii) or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; R ⁷ is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atom to which they are attached form a heterocyclic ring; and ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl.

In the embodiment of formula (Ci), R ² is C ₁ -C ₆ alkyl; R ³ is C ₁ -C ₆ alkyl; R ⁶ is hydrogen; and R ⁷ is hydrogen. In the embodiment of formula (Ci), R ² is methyl; R ³ is methyl; R ⁶ is hydrogen; and R ⁷ is hydrogen.

In one embodiment, the sesquiterpene lactone is a compound of formula (B-iii): (B-iii) or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; R ⁷ is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atom to which they are attached form a heterocyclic ring; and ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl.

In the embodiment of formula (B-iii), R ² is C ₁ -C ₆ alkyl; R ³ is C ₁ -C ₆ alkyl; R ⁶ is hydrogen; and R ⁷ is hydrogen. In the embodiment of formula (C-ii), R ² is methyl; R ³ is methyl; R ⁶ is hydrogen; and R ⁷ is hydrogen.

In the embodiment of formula (B-iii), ^R2 is _C1 - _C6 alkyl; ^R3 is _C1 - _C6 alkyl; ^R6 is ^-ORA ; ^R7 is hydrogen; and ^RA is hydrogen. In the embodiment of formula (C-ii), ^R2 is methyl; ^R3 is methyl; ^R6 is ^-ORA ; ^R7 is hydrogen; and ^RA is hydrogen.

In one embodiment, the sesquiterpene lactone is a compound shown in Table 2. Table 2 : Exemplary sesquiterpene lactones Compound Structure Parthenolide Costunolide Eupatolide Onopordopicrin Deoxyelepantopin 9α-Hydroxyparthenolide 11β,13-Dihydroparthenolide Lipiferolide Elephantoin

In one embodiment, the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof. In one embodiment, the sesquiterpene lactone is costus lactone or a pharmaceutically acceptable salt thereof. In one embodiment, the sesquiterpene lactone is zearalenolide or a pharmaceutically acceptable salt thereof. In one embodiment, the sesquiterpene lactone is schizonepeta lactone or a pharmaceutically acceptable salt thereof. In one embodiment, the sesquiterpene lactone is schizonepeta lactone or a pharmaceutically acceptable salt thereof. In one embodiment, the sesquiterpene lactone is deoxyschizonepeta lactone or a pharmaceutically acceptable salt thereof.

In one embodiment, the sesquiterpene lactone is 9α-hydroxy parthenolide or a pharmaceutically acceptable salt thereof. In one embodiment, the sesquiterpene lactone is 11β,13-dihydroparthenolide or a pharmaceutically acceptable salt thereof. In one embodiment, the sesquiterpene lactone is aliphatic alcohol lactone or a pharmaceutically acceptable salt thereof. In one embodiment, the sesquiterpene lactone is scutellarin or a pharmaceutically acceptable salt thereof.

In one embodiment, the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof, which is substantially free of costusinolide, zeolite, schizone and deoxyschizone. In one embodiment, the sesquiterpene lactone is costusinolide or a pharmaceutically acceptable salt thereof, which is substantially free of parthenolide, zeolite, schizone and deoxyschizone. In one embodiment, the sesquiterpene lactone is zeolite or a pharmaceutically acceptable salt thereof, which is substantially free of costusinolide, parthenolide, schizone and deoxyschizone. In one embodiment, the sesquiterpene lactone is acridin or a pharmaceutically acceptable salt thereof, which is substantially free of costusinol, zeolite, parthenolide and deoxyspergine. In one embodiment, the sesquiterpene lactone is deoxyspergine or a pharmaceutically acceptable salt thereof, which is substantially free of costusinolide, zeolite, acridin and parthenolide.

In one embodiment, the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof, which is substantially free of another compound shown in Table 2. In one embodiment, the sesquiterpene lactone is costusinolide or a pharmaceutically acceptable salt thereof, which is substantially free of another compound shown in Table 2. In one embodiment, the sesquiterpene lactone is zelanolide or a pharmaceutically acceptable salt thereof, which is substantially free of another compound shown in Table 2. In one embodiment, the sesquiterpene lactone is schizonepeta lactone or a pharmaceutically acceptable salt thereof, which is substantially free of another compound shown in Table 2. In one embodiment, the sesquiterpene lactone is deoxyschizonepeta lactone or a pharmaceutically acceptable salt thereof, which is substantially free of another compound shown in Table 2.

In one embodiment, the sesquiterpene lactone or a pharmaceutically acceptable salt thereof is provided as a substantially pure compound (e.g., at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.9% pure, for example, as measured by HPLC analysis). In one embodiment, the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof, and is provided as a substantially pure compound (e.g., at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.9% pure, for example, as measured by HPLC analysis).

In one embodiment, the sesquiterpene lactone has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5%, or 0.1% of another sesquiterpene lactone. In one embodiment, the sesquiterpene lactone is parthenolide and has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5%, or 0.1% of another sesquiterpene lactone. In one embodiment, the sesquiterpene lactone is parthenolide and has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5%, or 0.1% of costus lactone. In one embodiment, the sesquiterpene lactone has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5%, or 0.1% of another plant material, such as a plant metabolite or a plant lipid. In one embodiment, the sesquiterpene lactone is parthenolide and has less than 10%, 7.5%, 5%, 2.5%, 1%, 0.5% or 0.1% of another plant material, such as a plant metabolite or a plant lipid.

Compositions useful for treating inflammation or inflammatory diseases or conditions may contain one sesquiterpene lactone (e.g., parthenolide) or a plurality of sesquiterpene lactones. For example, a composition comprising a sesquiterpene lactone may contain only parthenolide (e.g., prepared synthetically or extracted from a natural source) and no other sesquiterpene lactone is present. Conversely, a composition comprising a sesquiterpene lactone may also contain a combination of parthenolide and closely related analogs or variants thereof, such as the sesquiterpene lactones shown in Table 1, such as costusinolide.

The flavonoids and sesquiterpene lactones provided herein may contain one or more asymmetric centers and therefore exist as racemates and racemic mixtures, single mirror image isomers, individual non-mirror image isomers, and non-mirror image isomer mixtures. In addition, flavonoids and sesquiterpene lactones may exist in one of many tautomeric forms. All such isomers and tautomeric forms of these compounds are expressly included in the scope. Unless otherwise indicated, when a compound is named or depicted by a structure without specifying stereochemistry and has one or more chiral centers or tautomeric structures, it should be understood to represent all possible stereoisomers or tautomers of the compound. The compounds provided herein may also contain bond linkages (e.g., carbon-carbon bonds, phosphorus-oxygen bonds, or phosphorus-sulfur bonds) or substituents that may restrict bond rotation (e.g., restriction due to the presence of a ring or double bond).

Inflammatory Diseases and Conditions Described herein are methods for treating inflammation or inflammatory diseases or conditions in an individual, tissue, or cell, for example, by administering sesquiterpene lactones and flavonoids. In embodiments, the cell is an isolated cell (e.g., a cell in cell culture or a cell isolated from a tissue or intact organism). In embodiments, the cell is located in a tissue or organ.

Inflammatory diseases or disorders are any diseases or disorders that affect the immune system and can lead to the modulation of inflammatory pathways. Exemplary inflammatory diseases and disorders include skin conditions (e.g., psoriasis, skin allergies, eczema, burns, atopic dermatitis, or abnormal proliferation of hair follicle cells), fibrosis (e.g., renal or pulmonary fibrosis), allergic rhinitis, respiratory distress syndrome, asthma, bronchitis, tendinitis, bursitis, fever, migraine, gastrointestinal conditions (e.g., inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel disease, colonitis, and colorectal cancer), vascular disease (e.g., atherosclerosis), periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, Disease), rheumatic fever, osteoarthritis, autoimmune diseases (e.g., type I diabetes, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis), sarcoidosis, nephrotic syndrome, renal failure, Behcet's syndrome, polymyositis, odontitis, allergies (e.g., delayed or immediate), transplant and graft rejection, graft-versus-host disease (GVHD), conjunctivitis, swelling following injury, myocardial hypoxia, and endotoxin shock syndrome.

Psoriasis is a chronic skin disease that afflicts about 2% of the population. The disease is associated with a rapid turnover (overproliferation) of skin cells, with loss of differentiation, resulting in the formation of silvery white scales on the skin surface. In addition, microvessels become twisted and dilated and an inflammatory reaction occurs, causing the skin to redden. The increased silvery white scales on the contrasting red background produce the unsightly lesions that are unique to psoriasis. Psoriasis most often occurs on the scalp, knees, elbows, hands, and feet, but can affect any part of the skin. The cause of the disease is unknown, but it is believed to have a genetic component, and it has been proposed that the disease is a T-cell mediated autoimmune skin disease. In one embodiment, the inflammatory disease or condition comprises psoriasis.

Skin allergy is a non-specific histological reaction pattern that can be seen in a variety of clinical conditions. Symptoms may include itching, lesions, and in idiopathic cases, urticaria or eczematous papules or plaques. In one embodiment, the inflammatory disease or disorder comprises skin allergy.

Eczema is a general term for many types of skin inflammation (also called dermatitis). The most common form of eczema is atopic eczema or dermatitis. Eczema occurs in people of all races and can affect people of any age, but the condition is most common in infants, with about 85% of people developing it before the age of five. Typically, only about half of the infants affected have eczema permanently resolved by the age of three. In other infants, the condition tends to recur throughout life. People with eczema often have a family history of the condition or other allergic conditions, such as asthma and/or hay fever. Although eczema is not known to be contagious, it is believed to be at least partially hereditary. In one embodiment, the inflammatory disease or disorder comprises eczema.

In the United States alone, approximately 140 million people suffer burns each year. Of these, an estimated 54,000 to 180,000 are hospitalized. A burn is an injury to the skin or other tissue caused by heat, cold, electricity, chemicals, friction, or radiation. Most burns are caused by heat from hot liquids (scalds), solids, or fire. The skin is made up of three main tissue layers: the epidermis, dermis, and subcutaneous tissue. Burns that affect only the outermost layer of skin are called superficial or first-degree burns. These burns appear red, without blisters, and the pain usually lasts about three days. When the injury extends to some underlying skin layers, the injury is called a partial thickness burn or a second degree burn. Blisters usually appear and it is usually painful. Healing may take up to eight weeks and scarring may occur. In a full thickness burn or a third degree burn, the injury extends to all skin layers. There is usually no pain and the burned area is stiff. The burn will not heal normally on its own and a skin graft is required. Fourth degree burns also involve deeper tissues, such as damage to muscles, tendons, or bones. Such burns are usually black and usually result in loss of the burned site. In one embodiment, the inflammatory disease or condition comprises a burn.

Atopic dermatitis is the most common form of eczema. This is a condition that causes dry, itchy, and inflamed skin. The condition is common in young children, but can occur at any age. Atopic dermatitis is a chronic condition that causes attacks throughout the patient's life and is not contagious. People with atopic dermatitis are at risk for food allergies, hay fever, and asthma. Symptoms of atopic dermatitis can include dry skin, chapped skin, itching (pruritus), small, raised bumps, thickening of the skin, darkening of the skin around the eyes, and rough, sensitive skin. In one embodiment, the inflammatory disease or disorder comprises atopic dermatitis.

Fibrosis is a process characterized by the excessive accumulation of extracellular matrix as a response to different types of tissue damage, which can lead to organ dysfunction. The process can be initiated by a variety of different stimuli and pathogenic factors, which trigger the repair cascade that converges on molecular signals responsible for initiating and driving fibrination. Although fibrination can play a defensive role, in some cases, at a certain stage, it can gradually become an uncontrolled, irreversible and self-sustaining process, known as pathological fibrosis. Such fibrosis can occur in any organ in the body, for example, in one or more kidneys (renal fibrosis) or in one or more lungs (pulmonary fibrosis). In one embodiment, the inflammatory disease or disorder comprises fibrosis, such as renal fibrosis and pulmonary fibrosis.

Allergic rhinitis (also known as hay fever) is an allergic reaction that causes sneezing, congestion, itchy nose, and pharyngitis. Pollen, pet dander, mold, and insects can cause hay fever symptoms. Symptoms of hay fever include sneezing, nasal congestion, and irritation of the nose, throat, mouth, and eyes. In one embodiment, the inflammatory disease or condition comprises allergic rhinitis.

Respiratory distress syndrome is a disease associated with increased pulmonary microvascular permeability. The resulting accumulation of protein-rich fluid within the alveoli is a result of damage to the microvascular endothelium and alveolar epithelium; this causes the release of interleukins, resulting in diffuse alveolar damage. Common risk factors for ARDS include: pneumonia, sepsis, aspiration of gastric contents, trauma, pancreatitis, aspiration injury, burns, non-cardiogenic shock, drug overdose, transfusion-related acute lung injury (TRALI), and drowning. The typical pathological features of ARDS have been classically described as three overlapping phases: the exudative or inflammatory phase, the proliferative phase, and the fibrotic phase. In one embodiment, the inflammatory disease or disorder comprises respiratory distress syndrome.

Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. The inflammatory component of asthma is believed to involve a variety of cell types, including mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells, and their biological products. Patients with asthma most commonly experience symptoms of wheezing, shortness of breath, coughing, and chest tightness. In one embodiment, the inflammatory disease or condition comprises asthma.

Bronchitis is an inflammation of the mucous membranes of the trachea and bronchi caused by bacterial and viral infections or by irritation caused by physical and chemical factors. In general, the main symptoms of this disease are cough, sputum, discomfort or pain behind the sternum, shortness of breath, and common cold symptoms accompanying these characteristics. Bronchitis can be divided into two forms according to its duration: acute tracheobronchitis and chronic bronchitis. Chronic bronchitis is bronchitis that lasts for more than two months and worsens for two consecutive years or lasts for three consecutive months and worsens for one year, causing inflammation of the mucous membranes and surrounding tissues. Most patients are adults, and the incidence of bronchitis increases in winter and spring. In one embodiment, the inflammatory disease or condition comprises bronchitis.

Tendonitis is inflammation of the tendon, which refers to inflammatory changes in the tendon tissue. It usually causes degenerative changes in the affected tissue, which may include subsequent calcium deposits. In general, tendonitis can affect any tendon in the body. Since tendonitis is mainly caused by mechanical stress (movement), tendonitis particularly affects certain areas of the body, such as the shoulder, tibia or foot. Tendonitis can also occur in the context of inflammatory rheumatoid diseases, especially Reiter's syndrome, ankylosing spondylitis and arthritis-type psoriasis. In one embodiment, the inflammatory disease or condition comprises tendonitis.

Bursitis is an inflammation of a bursa or protective sac located in or near a patient's joint. Bursitis can be acute, causing sudden, severe pain after an injury, or it can be chronic due to recurrent inflammation in the same area. Most commonly, bursitis is caused by trauma, infection, and crystal deposits. Bursitis is often caused by overuse or injury to the joint from strenuous work or recreation, poor conditioning before exercise or exercise, poor overall posture while working or resting, or due to arthritis or abnormal joint position due to differences in bone length, such as compression of soft tissue structures in the human or animal body. In one embodiment, the inflammatory disease or condition comprises bursitis.

Fever is a commonly used medical indicator characterized by an increase in body temperature above the normal range. In one embodiment, an inflammatory disease or disorder comprises a fever.

Migraine comprises a complex, common neurological condition characterized by severe, intermittent attacks of headache and related features, which may include nausea, vomiting, sensitivity to light, sound or movement. In some patients, headaches are preceded or accompanied by sensory warning signs or symptoms (i.e., aura). In some patients, headaches may be severe and may also be unilateral. Migraine attacks disrupt daily life and cost billions of dollars each year due to absence from work and impaired performance. Migraine is a very prevalent disease worldwide, with approximately 15% of the European population and 12% of the U.S. population suffering from migraine attacks. In addition, migraine has been found to be associated with a variety of psychiatric and medical comorbidities, such as depression and vascular disorders. In one embodiment, an inflammatory disease or disorder comprises migraine.

Inflammatory bowel disease (IBD) is a chronic inflammatory autoimmune condition of the gastrointestinal (GI) tract that presents clinically as ulcerative colitis (UC) or Crohn's disease (CD). CD is a chronic transmural inflammatory disease that may affect any part of the entire GI tract, and UC is an inflammation of the mucosa of the colon. Both conditions are clinically manifested by frequent bowel movements, malnutrition, and dehydration, and disrupt daily activities. CD is often complicated by the presence of malabsorption, strictures, and fistulas, and may require repeated surgeries. Less commonly, UC may be complicated by severe bloody diarrhea and toxic megacolon, also requiring surgery. Both IBD conditions are associated with an increased risk of gastrointestinal malignancies. The etiology of IBD is complex, and many aspects of the pathogenesis remain unclear. In one embodiment, the inflammatory disease or disorder comprises inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis).

Gastritis is a general term for a group of conditions that include inflammation of the stomach lining. The inflammation of gastritis is most often the result of infection with the same bacteria that cause most stomach ulcers or the regular use of certain pain relievers. Drinking too much alcohol can also cause gastritis. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). In some cases, gastritis can lead to an increased risk of ulcers and stomach cancer. In one embodiment, the inflammatory disease or condition comprises gastritis.

Irritable bowel syndrome (IBS) is the most common of all gastrointestinal disorders, affecting 11-14% of adults and accounting for more than 50% of all patients suffering from digestive discomfort. It is believed that only a small number of people with IBS actually seek medical treatment. Patients with IBS present with different symptoms, such as abdominal pain mainly related to defecation, alternating diarrhea and constipation, bloating, flatulence, and excess mucus in the stool. Many possible causes of IBS have been proposed, but none of them are fully accepted. These hypotheses include a Western diet lacking fiber, intestinal motility dysfunction, abnormal pain perception, abnormal psychological or behavioral or psychophysiological responses to stress. In one embodiment, the inflammatory disease or condition comprises IBS.

Colorectal cancer (CRC) (also called intestinal cancer, colon cancer, or rectal cancer) is cancer that develops in the colon or rectum (part of the large intestine). Signs and symptoms may include blood in the stool, changes in bowel movements, weight loss, and fatigue. Most colorectal cancers are caused by aging and lifestyle factors, with only a few cases due to an underlying genetic condition. Risk factors include diet, obesity, smoking, and lack of physical activity. Another risk factor is inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis. Some genetic conditions that can cause colorectal cancer include familial adenomatous polyposis and hereditary non-polyposis colorectal cancer; however, these conditions account for less than 5% of cases. Colorectal cancer typically begins as a benign tumor, often in the form of a polyp, which becomes cancerous over time. In one embodiment, the inflammatory disease or disorder comprises colorectal cancer.

Atherosclerosis is a chronic disease that causes the innermost layer (intima) of the aorta or middle arteries to thicken. This reduces blood flow and can lead to ischemia and tissue damage to organs supplied by the affected blood vessels. Atherosclerosis is the leading cause of heart disease, including myocardial infarction, stroke, and peripheral arterial disease. The disease begins with the accumulation of lipoproteins, primarily low-density lipoproteins (LDL), in the extracellular matrix of blood vessels. These LDL particles aggregate and promote oxidative modification. Oxidized LDL is toxic and causes damage to blood vessels. Atherosclerosis represents a response to this trauma in the form of inflammation and fibrosis. In one embodiment, the inflammatory disease or disorder comprises atherosclerosis.

Polyarteritis nodosa (PAN) is a necrotic inflammation of systemic blood vessels (vasculitis) affecting medium-sized muscular arteries, often involving the arteries of the kidneys and other internal organs, but usually sparing the pulmonary circulation. The small arterial aneurysms are strung together like beads of a rosary, making this "rosary syndrome" an important diagnostic feature of vasculitis. PAN is sometimes associated with infection with the hepatitis B or C viruses. The condition can occur in infants. In one embodiment, the inflammatory disease or disorder comprises periarteritis nodosa.

Thyroiditis is an inflammation of the thyroid gland. There are many different signs and symptoms of thyroiditis, none of which are specific to this disease. Many of the symptoms mimic those of other diseases, so thyroiditis can sometimes be difficult to diagnose. Common symptoms of hypothyroidism appear when there is slow, long-term damage to the thyroid cells, and can include fatigue, weight gain, feeling "foggy," depression, dry skin, and constipation. Other, more rare symptoms include swelling in the legs, dull pain, and decreased concentration. If the damage to the thyroid cells is acute, thyroid hormone from the gland can leak into the bloodstream, which can cause symptoms of thyroid poisoning, which are similar to those of hyperthyroidism. These symptoms include weight loss, irritability, anxiety, insomnia, rapid heart rate, and fatigue. Elevated levels of thyroid hormone in the bloodstream cause both conditions, but thyrotoxicosis is the term used with thyroiditis because the thyroid gland is not overactive as in the case of hyperthyroidism. In one embodiment, the inflammatory disease or disorder comprises thyroiditis.

Aplastic anemia is a serious hematological condition in which the body cannot make adequate numbers of blood cells. Aplastic anemia is associated with cancer and various cancer syndromes. Blood cells are produced in the bone marrow from stem cells that reside in the bone marrow. Aplastic anemia results in a deficiency of all types of blood cells: red blood cells, white blood cells, and platelets. The disease most often occurs in people in their teens and twenties, but it is also common in older adults. It can be caused by genetics, immune disorders, or exposure to chemicals, drugs, or radiation. However, in about half of cases, the cause is unknown. In one embodiment, the inflammatory disease or condition comprises aplastic anemia.

Hodgkin's disease (also known as Hodgkin's lymphoma (HL)) is a type of lymphoma in which the cancer originates from a specific type of white blood cell called a lymphocyte, in which multinucleated Reed-Sternberg cells (RS cells) are present in the patient's lymph nodes. Symptoms may include fever, sweating, and weight loss. Typically, painless enlarged lymph nodes appear in the neck, under the arms, or in the groin. About half of Hodgkin's lymphoma cases are caused by the Epstein-Barr virus (EBV) and these cases are usually of the classic form. Other risk factors include a family history of the condition and having HIV/AIDS. In one embodiment, the inflammatory disease or disorder comprises Hodgkin's disease.

Rheumatic fever (RF) is an inflammatory disease that can affect the heart, joints, skin, and brain. The disease usually develops two to four weeks after a streptococcal throat infection. Signs and symptoms include fever, multiple joint pain, involuntary muscle movements, and occasionally a characteristic non-itching rash called erythema marginale. The heart is affected in about half of cases. Damage to the heart valves, called rheumatic heart disease (RHD), usually occurs after recurring attacks, but can sometimes occur after a single attack. Damaged valves may lead to heart failure, atrial flutter, and valve infection. In one embodiment, the inflammatory disease or condition comprises rheumatic fever.

Osteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and underlying bone, affecting one in seven adults in the United States. Osteoarthritis is believed to be the fourth leading cause of disability in the world. The most common symptoms are joint pain and stiffness. Other symptoms may include joint swelling, reduced range of motion, and when the back is affected, weakness or numbness in the arms and legs. The joints most commonly affected are the two joints near the end of the fingers and the joint at the base of the thumb, the knee and hip joints, and the joints of the neck and lower back. Unlike some other types of arthritis, it only affects the joints and not the internal organs. In one embodiment, the inflammatory disease or condition comprises osteoarthritis.

Type 1 diabetes (T1D) (formerly known as juvenile diabetes) is an autoimmune disease that develops when the cells that produce insulin (beta cells) are destroyed by the immune system, resulting in high blood sugar levels. Common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Other symptoms may include blurred vision, fatigue, and slow healing of wounds. Symptoms usually appear within a short period of time, usually only about a few weeks. The underlying mechanism involves autoimmune destruction of the insulin-producing beta cells in the pancreas. In one embodiment, the inflammatory disease or condition comprises type 1 diabetes.

Myasthenia gravis (MG) is a long-term autoimmune neuromuscular disease that causes varying degrees of skeletal muscle weakness. The muscles most commonly affected are those of the eyes, face, and those responsible for swallowing. Myasthenia gravis can cause double vision, drooping eyelids, difficulty speaking, and difficulty walking. Attacks can be sudden. Affected individuals often have an enlarged thymus gland or a thymoma. In one embodiment, the inflammatory disease or condition comprises myasthenia gravis.

Rheumatoid arthritis (RA) is a long-term autoimmune disease that primarily affects the joints. The disease usually causes heat, swelling, and pain in the joints. The pain and stiffness usually worsen after rest. Most commonly, the wrists and hands are affected, with the same joints on both sides of the body usually involved. The disease can also affect other parts of the body, including the skin, eyes, lungs, heart, nerves, and blood. This can lead to low red blood cell counts, inflammation around the lungs, and inflammation around the heart. Fever and lack of energy may also occur. In one embodiment, the inflammatory disease or condition comprises rheumatoid arthritis.

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary from person to person and can be mild to severe. Common symptoms include joint pain and swelling, fever, chest pain, hair loss, mouth sores, swollen lymph nodes, feeling tired, and a red rash that is most common on the face. There are usually periods of illness called flare-ups and periods of remission with few symptoms. The cause of SLE is not known. It is believed that the disease involves a combination of genetic and environmental factors. In one embodiment, the inflammatory disease or condition comprises systemic lupus erythematosus.

Multiple sclerosis (MS) is one of the most common demyelinating diseases in which the insulating coverings of nerve cells in the brain and spinal cord are damaged. This damage destroys the ability of parts of the nervous system to transmit signals, leading to a range of signs and symptoms including physical, psychological, and sometimes psychiatric problems. Specific symptoms may include double vision, visual loss, muscle weakness, and difficulty with sensation or coordination. MS takes several forms in which new symptoms occur as isolated attacks (relapsing forms) or accumulate over time (progressive forms). Although the cause is unclear, the underlying mechanism is believed to be destruction of the immune system or failure of cells that produce myelin. In one embodiment, the inflammatory disease or disorder comprises multiple sclerosis.

Sarcoidosis is a disease that involves abnormal collections of inflammatory cells that form masses called granulomas. The disease usually begins in the lungs, skin, or lymph nodes. Although any organ can be affected, the eyes, liver, heart, and brain are less commonly affected. Signs and symptoms depend on the organs involved. Usually, no or only mild symptoms are found. When sarcoidosis affects the lungs, wheezing, coughing, shortness of breath, or chest pain may occur. In one embodiment, the inflammatory disease or disorder comprises sarcoidosis.

Nephrotic syndrome is a collection of symptoms caused by kidney damage. This includes the presence of protein in the urine, low serum protein levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infection, and high blood pressure. Causes include many kidney diseases, such as focal segmental glomerulosclerosis, membranous nephropathy, and minimal lesion disease. Nephrotic syndrome can also occur as a complication of diabetes or lupus. In one embodiment, an inflammatory disease or disorder comprises nephrotic syndrome.

Kidney failure (also called end-stage renal disease) is a medical condition in which the kidneys can no longer adequately filter waste products from the blood and function less than 15% of normal levels. Kidney failure is classified as acute, which develops quickly and resolves, and chronic, which develops slowly and is usually irreversible. Symptoms may include swollen legs, feeling tired, vomiting, loss of appetite, and confusion. In one embodiment, the inflammatory disease or disorder comprises kidney failure.

Behçet's disease (BD) is an inflammatory disorder that affects many parts of the body. The most common symptoms include painful sores on the lining of the mouth and other parts of the body, inflammation of the eyes, and arthritis. The sores can last from a few days to a week or more. Less common are inflammation of the brain or spinal cord, blood clots, aneurysms, or blindness. Often, symptoms come and go. In one embodiment, the inflammatory disease or disorder comprises Behçet's disease.

Polymyositis is a chronic muscle inflammation (inflammatory myopathy) that is related to dermatomyositis and inclusion body myositis. Inflammation in polymyositis is primarily found in the endomysial layer of skeletal muscle, while dermatomyositis is characterized primarily by inflammation of the perimysial layer of skeletal muscle. In one embodiment, the inflammatory disease or disorder comprises polymyositis.

Gingivitis is a non-destructive disease that causes inflammation of the gums. In general, the most common form of gingivitis and the most common form of periodontal disease is a response to bacterial biofilms (also called plaque) attached to the tooth surfaces, called plaque-induced gingivitis. Most forms of gingivitis are plaque-induced. In one embodiment, the inflammatory disease or disorder comprises gingivitis.

Graft versus host disease (GVHD) is a syndrome characterized by inflammation in various organs. GVHD is commonly associated with bone marrow transplants and stem cell transplants. The white blood cells of the donor's immune system that remain within the donated tissue (the graft) recognize the recipient (the host) as foreign (non-self). The white blood cells present within the transplanted tissue then attack the cells within the recipient, resulting in GVHD. This should not be confused with transplant rejection, which occurs when the transplant recipient's immune system rejects the transplanted tissue; GvHD occurs when the white blood cells of the donor's immune system reject the recipient. In one embodiment, the inflammatory disease or condition comprises GVHD.

Conjunctivitis (also called pink eye) is an inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. The disease causes the eye to appear pink or reddish. Pain, burning, scratching, or itching may occur. The affected eye may experience increased tearing or a "gummy shut" in the morning. Swelling of the white part of the eye may also occur. In cases caused by allergies, itching is more common. Conjunctivitis can affect one eye or both eyes. In one embodiment, the inflammatory disease or condition comprises conjunctivitis.

Myocardial hypoxia involves a decrease in blood flow to the heart muscle due to a buildup of atherosclerotic plaque in the heart's arteries. Myocardial hypoxia is the most common cardiovascular disease. Common symptoms are chest pain or discomfort that may spread to the shoulders, arms, back, neck, or jaw. The disease may occasionally feel like heartburn. Typically, symptoms develop with exercise or emotional stress, last for less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms occur. In most cases, the first symptom is a heart attack. In one embodiment, the inflammatory disease or condition comprises myocardial hypoxia.

Endotoxin shock syndrome (also known as toxic shock syndrome (TSS)) is an uncommon but life-threatening illness caused by a toxic endotoxin (TSS-1) produced by the bacterium Staphylococcus aureus. The infection is caused by bacteria entering the body through an opening in the skin, such as a cut or wound, or from improper skin surgery, skin burns, and skin infections. No significant differences were found in the prevalence of toxin production and colonization by age or geographic region, while the prevalence in the population studied was 26%. Symptoms of TSS include rash, headache, fever, vomiting, diarrhea, including neurological and central nervous system disorders and organ failure. In one embodiment, the inflammatory disease or disorder comprises endotoxin shock syndrome.

In one embodiment, the inflammatory disease or condition is a skin condition. For example, the dermatological disease or condition can be atopic dermatitis, psoriasis, eczema, or skin allergy. In one embodiment, the skin condition is atopic dermatitis. In one embodiment, the skin condition is psoriasis. In one embodiment, the skin condition is eczema. In one embodiment, the skin condition is skin allergy.

Combination Therapy Combination therapy comprising flavonoids and sesquiterpene lactones is described herein and is suitable for treating inflammation or inflammatory diseases or conditions. Combination therapy can be administered in a single formulation or in separate formulations. In one embodiment, flavonoids and sesquiterpene lactones are administered in a single pharmaceutical composition. In one embodiment, flavonoids and sesquiterpene lactones are administered in separate pharmaceutical compositions. In the case of separate formulations, flavonoids and sesquiterpene lactones can be administered simultaneously or sequentially. In one embodiment, flavonoids and sesquiterpene lactones are administered simultaneously. In one embodiment, flavonoids and sesquiterpene lactones are administered sequentially. For example, flavonoids can be administered before sesquiterpene lactones or after sesquiterpene lactones.

In some embodiments, the administration of flavonoids and sesquiterpene lactones has a synergistic or additive effect. For example, the administration of flavonoids and sesquiterpene lactones can have an additive effect, where the therapeutic effect of the flavonoids and sesquiterpene lactones is the sum of the effects of each of the components individually. In contrast, the administration of flavonoids and sesquiterpene lactones can have a synergistic effect, where the therapeutic effect of the flavonoids and sesquiterpene lactones is greater than the sum of the individual components. The synergistic effect of the combination of flavonoids and sesquiterpene lactones may be greater than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately by 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more. In one embodiment, the synergistic effect of the combination of flavonoids and sesquiterpene lactones is greater than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately by 5% to 75%.

In one embodiment, the synergistic effect of the combination of flavonoids and sesquiterpene lactones is 10% greater than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately. In one embodiment, the synergistic effect of the combination of flavonoids and sesquiterpene lactones is 25% greater than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately. In one embodiment, the synergistic effect of the combination of flavonoids and sesquiterpene lactones is 50% greater than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately. In one embodiment, the synergistic effect of the combination of flavonoids and sesquiterpene lactones is 75% greater than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately.

The synergistic effect of the combination of flavonoids and sesquiterpene lactones can be 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 40 times, 50 times, 75 times, 100 times, 200 times, 500 times or more than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately. In one embodiment, the synergistic effect of the combination of flavonoids and sesquiterpene lactones is 2 to 100 times greater than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately. In one embodiment, the synergistic effect of the combination of flavonoids and sesquiterpene lactones is 5 to 50 times greater than the sum of the effects of the flavonoids and sesquiterpene lactones administered separately.

In one aspect, the amount of flavonoids and the amount of sesquiterpene lactones are selected so that the molar concentration of flavonoids is higher than the molar concentration of sesquiterpene lactones. For example, the molar concentration of flavonoids is higher than the molar concentration of sesquiterpene lactones by more than 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 40 times, 50 times, 75 times, 100 times, 200 times, or 500 times. In one embodiment, the molar concentration of flavonoids is higher than the molar concentration of sesquiterpene lactones by more than 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times. In one embodiment, the molar concentration of flavonoids is 2 to 20 times higher than the molar concentration of sesquiterpene lactones. In one embodiment, the molar concentration of flavonoids is 5 to 10 times higher than the molar concentration of sesquiterpene lactones. In one embodiment, the molar concentration of flavonoids is about 5 times higher than the molar concentration of sesquiterpene lactones. In one embodiment, the molar concentration of flavonoids is about 10 times higher than the molar concentration of sesquiterpene lactones. In one embodiment, the molar concentration of flavonoids is about 15 times higher than the molar concentration of sesquiterpene lactones.

In another aspect, the combination of flavonoids and sesquiterpene lactones results in a decrease in inflammation in an individual or cell, such as the level of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a). For example, administration of a combination of flavonoids and sesquiterpene lactones results in a decrease in inflammation in an individual or cell, such as the level of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a), compared to the inflammation (e.g., the level of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a)) produced when a sesquiterpene lactone is administered alone to an individual or cell. In one embodiment, inflammation (e.g., levels of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a)) in a subject or cell is reduced following administration of a combination of a sesquiterpene lactone and a flavonoid, e.g., by about 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, as compared to the inflammation (e.g., levels of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a)) produced when the sesquiterpene lactone is administered alone.

In another aspect, the combination of flavonoids and sesquiterpene lactones reduces inflammation in an individual or cell, such as the level of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a). For example, administration of a combination of flavonoids and sesquiterpene lactones can reduce inflammation in an individual or cell, such as the level of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a), compared to the inflammation produced when flavonoids are administered alone to an individual or cell, such as the level of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a). In one embodiment, inflammation (e.g., levels of inflammatory interleukins (e.g., IL-6, IL-1b, and TNF-a)) in a subject or cell is reduced following administration of a combination of a sesquiterpene lactone and a flavonoid, e.g., by about 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, as compared to the inflammation (e.g., levels of inflammatory interleukins) produced when the flavonoid is administered alone.

In another aspect, the combination of flavonoids and sesquiterpene lactones increases the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) in an individual or cell. For example, administration of a combination of flavonoids and sesquiterpene lactones can increase the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) in an individual or cell compared to the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) produced when sesquiterpene lactones are administered alone to an individual or cell. In one embodiment, the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) in a subject or cell is increased following administration of a combination of a sesquiterpene lactone and a flavonoid, e.g., by about 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) produced when the sesquiterpene lactone is administered alone.

In another aspect, the combination of flavonoids and sesquiterpene lactones increases the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) in an individual or cell. For example, administration of a combination of flavonoids and sesquiterpene lactones can increase the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) in an individual or cell compared to the level of anti-inflammatory interleukins produced when flavonoids are administered alone to an individual or cell. In one embodiment, the level of anti-inflammatory interleukins (e.g., IL-4 and IL-10) in a subject or cell is increased following administration of a combination of a sesquiterpene lactone and a flavonoid, e.g., by about 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to the level of inflammatory interleukins produced when the flavonoid is administered alone.

In one embodiment, the flavonoid is administered in an amount that provides a concentration of between 0.1 µM and 500 µM in a subject or cell. In one embodiment, the flavonoid is administered in an amount that provides a concentration of between 0.5 µM and 100 µM in a subject or cell. In one embodiment, the flavonoid is administered in an amount that provides a concentration of between 1 µM and 100 µM in a subject or cell. In one embodiment, the flavonoid is administered in an amount that provides a concentration of between 1 µM and 50 µM in a subject or cell. In one embodiment, the flavonoid is administered in an amount that provides a concentration of between 1 µM and 25 µM in a subject or cell. In one embodiment, the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.01 µM and 50 µM in a subject or cell. In one embodiment, the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.1 µM and 25 µM in a subject or cell. In one embodiment, the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.1 µM and 10 µM in a subject or cell. In one embodiment, the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.1 µM and 5 µM in a subject or cell. In one embodiment, the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.1 µM and 2.5 µM in a subject or cell.

In one embodiment, the flavonoid is administered at a dose providing a concentration of between 0.1 μM and 500 μM in a subject or cell and the sesquiterpene lactone is administered at a dose providing a concentration of between 0.01 μM and 50 μM in a subject or cell. In one embodiment, the flavonoid is administered at a dose providing a concentration of between 1 μM and 100 μM in a subject or cell and the sesquiterpene lactone is administered at a dose providing a concentration of between 0.1 μM and 25 μM in a subject or cell. In one embodiment, the flavonoid is administered in an amount that provides a concentration of between 1 µM and 25 µM in a subject or cell and the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.1 µM and 2.5 µM in a subject or cell.

Pharmaceutical Compositions The present invention provides methods for treating a subject suffering from inflammation or an inflammatory disease or condition comprising administering a flavonoid, a sesquiterpene lactone, or a combination thereof.

Although it is possible to administer flavonoids (e.g., compounds of Table 1) or sesquiterpene lactones (e.g., compounds of Table 2) alone, it is preferred to administer the compound in the form of a pharmaceutical composition or formulation in which the compound is combined with one or more pharmaceutically acceptable diluents, excipients, or carriers. The compounds according to the present invention may be formulated for administration in any suitable manner for human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical formulation may be active itself, or may be a predrug that is, for example, capable of being converted into an active compound in a physiological environment. Regardless of the selected route of administration, the compounds of the present invention that can be used in a suitable hydrated form and/or the pharmaceutical composition of the present invention are formulated into pharmaceutically acceptable dosage forms as described below or by other methods known to those skilled in the art.

The amount and concentration of the compound of the present invention (e.g., flavonoids (e.g., compounds of Table 1) or sesquiterpene lactones (e.g., compounds of Table 2)) in the pharmaceutical composition and the amount of the pharmaceutical composition administered to an individual can be selected based on clinically relevant factors, such as medically relevant individual characteristics (e.g., age, weight, sex, other medical conditions and the like), the solubility of the compound in the pharmaceutical composition, the potency and activity of the compound, and the mode of administration of the pharmaceutical composition. For additional information on routes of administration and dosage regimens, the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

Thus, another aspect of the present invention provides a pharmaceutically acceptable composition comprising a therapeutically effective amount or a preventive effective amount of a flavonoid (e.g., a compound of Table 1) or a sesquiterpene lactone (e.g., a compound of Table 2), which is formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical composition of the present invention can be specifically formulated for administration in solid or liquid form, including forms suitable for oral or parenteral administration, such as by oral administration or by subcutaneous, intramuscular or intravenous injection in the form of, for example, a sterile solution or suspension. However, in some embodiments, the compounds of the present invention can be simply dissolved or suspended in sterile water. In some embodiments, the pharmaceutical preparation is non-pyrogenic, i.e., it does not raise the patient's body temperature.

As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" mean administration of a compound other than direct administration into the central nervous system such that the compound enters the patient's system and thereby undergoes metabolism and other similar processes, e.g., subcutaneous administration.

The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, stabilizer, formulator, solvent or encapsulating material, which is involved in carrying or transporting the antagonist of the present invention from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, red safflower oil, sesame oil, teff oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, taffy oil, flower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) ascorbic acid; (17) pyrogen-free water; (18) isotonic saline; (19) Ringer's solution solution); (20) ethanol; (21) phosphate buffered solutions; (22) cyclodextrins, such as Captisol®; and (23) other nontoxic compatible substances used in pharmaceutical formulations, such as antioxidants and antimicrobial agents.

As explained above, certain embodiments of the compounds described herein may contain basic functional groups, such as amines, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this regard, the term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately reacting the purified compounds of the present invention in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, and laurylsulfonate and the like (see, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm . Sci . 66 : 1-19).

In other cases, the compounds of the invention may contain one or more acidic functional groups and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic and organic base addition salts of the compounds of the invention, such as flavonoids (e.g., compounds of Table 1) or sesquiterpene lactones (e.g., compounds of Table 2). These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in free acid form with a suitable base (e.g., hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation), ammonia or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali metal salts or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines suitable for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperidine and the like (see, e.g., Berge et al., supra).

Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate) as well as coloring agents, release agents, coating agents, sweetening, flavoring and fragrance agents, preservatives and antioxidants may also be present in the composition. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants such as ascorbic acid palmitate, butylated hydroxymethoxyphenyl (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

Pharmaceutically acceptable carriers as well as wetting agents, emulsifiers, lubricants, coloring agents, release agents, coating agents, sweeteners, flavoring agents, aromas, preservatives, antioxidants and other additional components may be present in an amount between about 0.001% and 99% of the compositions described herein. For example, the pharmaceutically acceptable carriers and wetting agents, emulsifiers, lubricants, coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, antioxidants and other additional components can be about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1% or more of the composition described herein. %, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 85%, about 90%, about 95%, or about 99% is present.

The pharmaceutical composition of the present invention may be in a form suitable for oral administration, such as a liquid or solid oral dosage form. In some embodiments, the liquid dosage form comprises a suspension, solution, syrup, emulsion, beverage, elixir or syrup. In some embodiments, the solid dosage form comprises a capsule, tablet, powder, dragee or powder. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dose. The pharmaceutical composition may contain, in addition to flavonoids (e.g., compounds in Table 1) or sesquiterpene lactones (e.g., compounds in Table 2), a pharmaceutically acceptable carrier, and may further contain one or more pharmaceutically acceptable excipients, such as stabilizers (e.g., binders, such as polymers (e.g., precipitation inhibitors)), diluents, adhesives, and lubricants, as appropriate.

In some embodiments, the compositions described herein comprise a liquid dosage form for oral administration, such as a solution or suspension. In other embodiments, the compositions described herein comprise a solid dosage form for oral administration that can be directly compressed into a tablet. In addition, the tablet may include other medicinal or pharmaceutical agents, carriers and/or adjuvants. Exemplary pharmaceutical compositions include compressed tablets (e.g., directly compressed tablets), for example, comprising a flavonoid (e.g., a compound of Table 1) or a sesquiterpene lactone (e.g., a compound of Table 2) or one or more of their pharmaceutically acceptable salts.

The formulations of the present invention include formulations suitable for parenteral administration. The formulations are preferably presented in unit dosage form and can be prepared by any method known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier substance to produce a single dosage form will vary depending on the host being treated, the specific mode of administration. The amount of active ingredient that can be combined with a carrier substance to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally speaking, this amount (in percentage) will be in the range of about 1% to about 99%, preferably about 5% to about 70%, and most preferably about 10% to about 30% of the active ingredient. Pharmaceutical compositions of the present invention suitable for parenteral administration include a combination of a compound of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, such compositions may contain antioxidants, buffers, bacteriostats, solutes or suspending or thickening agents that render the formulation isotonic with the blood of the intended recipient.

In some embodiments, the compounds of the present invention, such as flavonoids (e.g., compounds of Table 1), are provided in the form of a composition in combination with a sesquiterpene lactone (e.g., compound of Table 2). For example, a flavonoid (e.g., compound of Table 1) can be combined with a sesquiterpene lactone (e.g., compound of Table 2) to prepare a fixed dose composition. The fixed dose composition can be formulated for oral administration, for example, in a solid dosage form or a liquid dosage form. In some embodiments, the liquid dosage form comprises a suspension, a solution, a syrup, an emulsion, a drink, an elixir, or a syrup. In some embodiments, the solid dosage form comprises a capsule, a tablet, a dragee, or a powder.

The combination therapies described herein may involve formulations of component agents for different routes of administration or for the same route of administration. For example, both flavonoids and sesquiterpene lactones may be formulated for oral administration. In another embodiment, the flavonoids are formulated for oral administration and the sesquiterpene lactones are formulated for parenteral administration. In another embodiment, the flavonoids are formulated for parenteral administration and the sesquiterpene lactones are formulated for oral administration. In one embodiment, the flavonoids and sesquiterpene lactones are formulated as a fixed dose combination (e.g., in a liquid dosage form or a solid dosage form, such as a capsule or tablet). In some embodiments, the flavonoids and sesquiterpene lactones are formulated as a fixed-dose combination for oral administration (e.g., in a liquid dosage form or a solid dosage form, such as a capsule or tablet).

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, p-hydroxybenzoic acid esters, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the compounds of the present invention (e.g., flavonoids and sesquiterpene lactones), it may be necessary to slow the absorption of drugs injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The rate of absorption of the drug depends on its dissolution rate, which in turn depends on the size of the crystals and the crystalline form. Alternatively, delayed absorption of parenteral administration forms of the compounds of the present invention is achieved by dissolving or suspending the compound in an oily vehicle.

In some embodiments, it may be advantageous to administer the flavonoids or sesquiterpene lactones of the present invention in a sustained manner. It will be appreciated that any formulation that provides a sustained absorption profile may be used. In certain embodiments, sustained absorption may be achieved by combining the compounds of the present invention with other pharmaceutically acceptable ingredients, diluents, or carriers that slow their release profile into the systemic circulation.

Administration routes Those skilled in the art will appreciate that the flavonoids and sesquiterpene lactones described herein and other agents used in the methods described herein and related compositions thereof can be administered to an individual in various forms depending on the selected administration route. Exemplary administration routes for the compositions used in the methods described herein include topical, enteral or parenteral administration. Topical administration includes, but is not limited to, epidermal, inhalation, enema, eye drops, ear drops, and administration through the mucosa in the body. Enteral administration includes oral administration, rectal administration, vaginal administration, and gastric feeding tube. Parenteral administration includes intravenous, intraarterial, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, intraarticular, subcapsular, subarachnical, intraspinal, epidural, intracerebral stem, intraperitoneal, subcutaneous, intramuscular, transepithelial, transnasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

In certain embodiments of the present invention, the compositions described herein comprising flavonoids and sesquiterpene lactones are administered orally. In other embodiments of the present invention, the compositions described herein comprising flavonoids and sesquiterpene lactones are administered systemically. In other embodiments of the present invention, the compositions described herein comprising flavonoids and sesquiterpene lactones are administered topically. In certain embodiments of the present invention, the compositions described herein comprising flavonoids are administered orally. In certain embodiments of the present invention, the compositions described herein comprising sesquiterpene lactones are administered orally. In other embodiments of the present invention, the compositions described herein comprising flavonoids are administered systemically. In other embodiments of the present invention, the compositions described herein comprising sesquiterpene lactones are administered systemically. In certain embodiments of the present invention, the compositions described herein comprising flavonoids are administered topically. In certain embodiments of the invention, the compositions comprising sesquiterpene lactones described herein are administered topically. In other embodiments of the invention, the compositions comprising flavonoids described herein are administered intravenously. In other embodiments of the invention, the compositions comprising sesquiterpene lactones described herein are administered intravenously.

In one embodiment, the compositions comprising quercetin described herein are administered orally in combination with parthenolide. In one embodiment, the compositions comprising quercetin described herein are administered orally before or after the oral administration of parthenolide. In other embodiments of the invention, the compositions comprising quercetin described herein are administered topically (e.g., transdermally). In one embodiment, the compositions comprising quercetin described herein are administered topically in combination with parthenolide. In one embodiment, the compositions comprising quercetin described herein are administered systemically before or after the administration of parthenolide.

For intravenous, intraperitoneal or intrathecal delivery or direct injection, the composition must be sterile and fluid to the extent that the composition can be delivered by syringe. In addition to water, the carrier may be an isotonic buffered saline solution, ethanol, a polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol and the like) and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the desired particle size in the case of a dispersion and by the use of a surfactant. In many cases, it is preferred to include an isotonic agent, for example, a sugar, a polyol (e.g., mannitol or sorbitol) and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

The choice of route of administration will depend on whether a local or systemic effect is to be achieved. For example, for a local effect, the composition may be formulated for topical administration and applied directly to the site where its effect is desired. For a systemic, long-term effect, the composition may be formulated for enteral administration and provided via the digestive tract. For systemic, immediate and/or short-term effects, the composition may be formulated for parenteral administration and provided by a route other than via the digestive tract.

Dosage The flavonoid and sesquiterpene lactone compositions described herein can be formulated into acceptable dosage forms by known methods known to those skilled in the art. Actual dosage levels of the active ingredients (e.g., flavonoids or sesquiterpene lactones, such as quercetin or parthenolide) in the compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular individual, composition, and mode of administration without being toxic to the individual. The selected dosage level will depend upon a variety of pharmacokinetic factors, including the activity of the particular composition of the invention being employed; the route of administration; the time of administration; the rate of absorption of the particular agent being employed; the duration of the treatment; other drugs, substances and/or materials used in combination with the particular composition being employed; the age, sex, weight, condition, general health and previous medical history of the individual being treated; and like factors well known in the medical art. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the composition required. For example, the physician or veterinarian could begin administering the flavonoids and/or sesquiterpene lactones of the invention used in the composition at levels lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of the composition of the present invention will be the amount of the substance in the minimum dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described herein. Preferably, the effective daily dose of the therapeutic composition can be administered as two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form.

Preferred therapeutic dosage levels of the compositions administered (e.g., orally or by injection) daily to a subject suffering from a disease or disorder described herein (e.g., inflammation or an inflammatory disease or disorder) are between about 0.1 mg/kg and about 1000 mg/kg (e.g., about 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg or 1000 mg/kg). Preferred prophylactic dosage levels for daily administration (e.g., orally, topically, or systemically) of the composition to an individual are between about 0.1 mg/kg and about 1000 mg/kg (e.g., about 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, The dose may be titrated (e.g., the dose may be increased gradually until signs of toxicity occur, such as headache, diarrhea, or nausea).

The frequency of treatment may also vary. A subject may be treated one or more times per day (e.g., once, twice, three times, four times or more) or every few hours (e.g., about every 2, 4, 6, 8, 12, or 24 hours). The flavonoid and/or sesquiterpene lactone concentration may be administered once or twice every 24 hours. The duration of treatment may be of varying duration, such as two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days or more, two weeks, one month, two months, four months, six months, eight months, ten months, or more than one year. For example, treatment may be twice a day for three days, twice a day for seven days, twice a day for ten days. Treatment cycles can be repeated at intervals, such as weekly, bimonthly, or monthly, separated by periods of no treatment. Treatment can be a single treatment or can last as long as the life of the individual (e.g., many years).

In some embodiments, the dosage of flavonoids (e.g., compounds of Table 1) is between about 5 mg/kg and about 100 mg/kg (e.g., about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, or about 100 mg/kg). In some embodiments, the dosage of flavonoids (e.g., compounds of Table 1) is between about 10 mg/kg and about 50 mg/kg (e.g., about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, or about 50 mg/kg).

In some embodiments, the dosage of flavonoids (e.g., compounds of Table 1) is from about 0.1 mg to about 5 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg). In some embodiments, the dosage of flavonoids (e.g., compounds of Table 1) is between about 0.01 mg/kg and about 10 mg/kg (e.g., about 0.01 mg/kg, about 0.025 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg). In some embodiments, the dosage of flavonoids (e.g., compounds of Table 1) is between about 0.1 mg/kg and about 5 mg/kg (e.g., about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, or about 5 mg/kg).

In some embodiments, the course of treatment of flavonoids (e.g., compounds of Table 1) is between about 1 day and about 24 weeks. In some embodiments, the course of treatment of flavonoids (e.g., compounds of Table 1) is at least weekly (e.g., once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week) throughout the treatment. In some embodiments, the course of treatment of flavonoids (e.g., compounds of Table 1) is daily throughout the treatment.

In some embodiments, the dosage of a sesquiterpene lactone (e.g., a compound of Table 2) is between about 5 mg/kg and about 100 mg/kg (e.g., about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, or about 100 mg/kg). In some embodiments, the dosage of a sesquiterpene lactone (e.g., a compound of Table 2) is between about 10 mg/kg and about 50 mg/kg (e.g., about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, or about 50 mg/kg).

In some embodiments, the dose of a sesquiterpene lactone (e.g., a compound of Table 2) is from about 0.1 mg to about 5 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg). In some embodiments, the dose of a sesquiterpene lactone (e.g., a compound of Table 2) is between about 0.01 mg/kg and about 10 mg/kg (e.g., about 0.01 mg/kg, about 0.025 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg). In some embodiments, the dose of a sesquiterpene lactone (e.g., a compound of Table 2) is between about 0.1 mg/kg and about 5 mg/kg (e.g., about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, or about 5 mg/kg).

In some embodiments, the course of treatment with a sesquiterpene lactone (e.g., a compound of Table 2) is between about 1 day and about 24 weeks. In some embodiments, the course of treatment with a sesquiterpene lactone (e.g., a compound of Table 2) is administered at least weekly (e.g., once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week) throughout the course of treatment. In some embodiments, the course of treatment with a sesquiterpene lactone (e.g., a compound of Table 2) is administered daily throughout the course of treatment.

Patient Selection and Monitoring The methods of the invention described herein require administration of a combination of flavonoids and sesquiterpene lactones. Thus, patients and/or individuals may be selected for treatment with flavonoids and sesquiterpene lactones to treat an inflammatory disease or condition by first assessing the patient and/or individual to determine whether the individual suffers from an inflammatory disease or condition. An individual may be assessed as suffering from an inflammatory disease or condition using methods known in the art. For example, an individual may also be monitored after administration of a compound described herein (e.g., flavonoids and sesquiterpene lactones) or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adult. In some embodiments, the subject has an acute form of inflammation or an inflammatory disease or condition. In some embodiments, the subject has a chronic form of inflammation or an inflammatory disease or condition. In some embodiments, the subject has been diagnosed with an inflammatory disease or condition.

In some embodiments, the subject is untreated. In some embodiments, the subject has been previously treated for inflammation or an inflammatory disease or condition. For example, the subject may have received immunotherapy. In some embodiments, the subject is suffering from an inflammatory disease or condition. In some embodiments, the subject has been treated with an agent other than a flavonoid or sesquiterpene lactone described herein and is suffering from a recurring inflammatory disease or condition.

In some embodiments, the individual suffers from a comorbid condition such as heart disease, coronary artery disease, cardiomyopathy, diabetes, obesity, hypertension, cancer, cerebrovascular disease, chronic kidney disease, chronic liver disease, cystic fibrosis, immunodeficiency, and tuberculosis.

In some embodiments, the methods described herein further comprise analyzing a biopsy sample from the individual at least once or receiving an analysis result of a biopsy sample from the individual at least once before the end of the treatment. In some embodiments, the biopsy sample is analyzed for the level of interleukins, antibodies or other allergy markers.

Additional Agents In some embodiments, additional therapeutic agents may be administered with the compositions of the invention for the treatment of inflammation or an inflammatory disease or disorder, or any symptom or associated condition thereof. When a combination therapy is used, one or more additional therapeutic agents may be administered as separate formulations or may be combined with any of the compositions described herein.

For example, any of the methods described herein may further comprise administering a therapeutically effective amount of an additional agent along with the flavonoid or sesquiterpene lactone. Exemplary additional agents include immunotherapy, vaccines, anti-inflammatory agents, pain relievers, mucolytic agents, cancer therapy, antifungal agents, antibacterial agents, bronchodilators, or vasodilators.

In some embodiments, the additional agent is an anti-inflammatory agent. For example, the anti-inflammatory agent can be an angiotensin converting enzyme 2 (ACE-2) inhibitor (e.g., lisinopril, benazepril, captopril, enalapril, fosinopril, moexipril, perindopril, or quinapril), a corticosteroid (e.g., corticosterone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, or hydrocorticosterone), or a nonsteroidal anti-inflammatory drug (NSAID). (for example, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, or indomethacin).

In some embodiments, the additional agent is a cancer therapy. In some embodiments, the cancer therapy agent is selected from methotrexate, 5-fluorouracil, doxorubicin, vincristine, bleomycin, vinblastine, dacarbazine, toposide, cisplatin, epirubicin, and sorafenib tosylate.

The compositions and methods described herein may include an immunomodulator. In one embodiment, the immunomodulator is an anti-inflammatory agent described herein, for example, for treating or preventing a disease or condition, such as a cancer or fibrotic disorder described herein. The compositions and methods may include one, two, three or more anti-inflammatory agents (e.g., AHCM agents, microenvironment modulators, immune checkpoint inhibitors, or additional therapies, such as cancer or antifibrotic chemotherapy), alone or in combination with one or more therapeutic agents described herein.

In one embodiment, an anti-inflammatory agent is an agent that blocks, inhibits or reduces inflammation or signaling from an inflammatory signaling pathway. In one embodiment, the anti-inflammatory agent inhibits or reduces the activity of one or more of any one of the following: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, interferons (IFNs) (e.g., TNF-α, TNF-β, TNF-RI, TNF-RII); CD23, CD30, CD40L, CXCL-1, EGF, G-CSF, GDNF, PDGF-BB, RANTES/CCL5, IKK, NF-kB, TLR2, TLR3, TLR4, TL5, TLR6, TLR7, TLR8, TLR9 and/or any cognate receptors thereof.

In one embodiment, the anti-inflammatory agent is IL-1 or an IL-1 receptor antagonist, such as anakinra (KINIRET®), rilonacept, or canakinumab.

In one embodiment, the anti-inflammatory agent is IL-6 or an IL-6 receptor antagonist, such as an anti-IL-6 antibody or an anti-IL-6 receptor antibody, such as tocilizumab (ACTEMRA®), olokizumab, clazakizumab, sarilumab, sirukumab, siltuximab, or ALX-0061.

In one embodiment, the anti-inflammatory agent is a TNF-α antagonist, for example, an anti-TNFα antibody, such as infliximab (REMICADE®), golimumab (SIMPONI®), adalimumab (HUMIRA®), certolizumab pegol (CIMZIA®), or etanercept.

In one embodiment, the anti-inflammatory agent is a corticosteroid. Exemplary corticosteroids include, but are not limited to, corticosterone (hydrocorticosterone, hydrocorticosterone sodium phosphate, hydrocorticosterone sodium succinate, ALA-CORT®, HYDROCORT ACETATE®, hydrocortisone phosphate (LANACORT®, SOLU-CORTEF®), decadron, (dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), methylprasidronate (6-methylprasidronate, methylprasidronate acetate, methylprasidronate sodium succinate, DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL®, SOLU-MEDROL®), prasidronate (DELTA-CORTEF®, ORAPRED®, PEDIAPRED®, PRELONE®), and prasidronate (DELTASONE®, LIQUID PRED®, METICORTEN®, ORASONE®), and bisphosphonates such as pamidronate (AREDIA®) and zoledronic acid (ZOMETA®).

In another embodiment, the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug (NSAID). Exemplary anti-inflammatory agents (e.g., NSAIDs) include, but are not limited to, aspirin, ibuprofen, naproxen, celecoxib, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, oxaprozin, piroxicam, sulindac, and tolmetin. In one embodiment, the anti-inflammatory agent is an immunoselective anti-inflammatory derivative (ImSAID).

Combined administration may be carried out by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

Examples 1. A method for reducing the level of inflammatory cytokines in a cell or an individual, wherein the method comprises administering to the cell or individual a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of inflammatory cytokines in the cell or the individual. 2. A method for reducing the level of inflammatory cytokines in a cell, wherein the method comprises administering to the cell a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of inflammatory cytokines in the cell. 3. A method for reducing the level of inflammatory interleukins in an individual, wherein the method comprises administering to the individual a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of inflammatory interleukins in the individual. 4. The method of any one of Examples 1 or 3, wherein the individual is a mammal. 5. The method of any one of Examples 1 to 3, wherein the inflammatory interleukin is selected from IL-6, IL-1b and TNF-a. 6. The method of any one of Examples 1 to 3, wherein the inflammatory interleukin is IL-6. 7. The method of any one of Examples 1 to 3, wherein the inflammatory interleukin is IL-1b. 8. The method of any one of Examples 1 to 3, wherein the inflammatory interleukin is TNF-a. 9. The method of any one of embodiments 1 to 3 or 5 to 8, wherein the level of the inflammatory cytokine is reduced by about 10%, 25%, 50%, 75%, 90%, 95% or more, for example relative to a reference standard. 10. The method of any one of embodiments 1 to 3 or 5 to 8, wherein the level of the inflammatory cytokine is reduced by about 10%, for example relative to a reference standard. 11. The method of any one of embodiments 1 to 3 or 5 to 8, wherein the level of the inflammatory cytokine is reduced by about 25%, for example relative to a reference standard. 12. The method of any one of embodiments 1 to 3 or 5 to 8, wherein the level of the inflammatory cytokine is reduced by about 50%, for example relative to a reference standard. 13. The method of any one of embodiments 1 to 3 or 5 to 8, wherein the level of the inflammatory interleukin is reduced by about 75%, for example relative to a reference standard. 14. The method of any one of embodiments 1 to 3 or 5 to 8, wherein the level of the inflammatory interleukin is reduced by about 90%, for example relative to a reference standard. 15. The method of any one of embodiments 1 to 3 or 5 to 8, wherein the level of the inflammatory interleukin is reduced by about 95%, for example relative to a reference standard. 16. A method of increasing the level of an anti-inflammatory interleukin in a cell or individual, wherein the method comprises administering to the cell or individual a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of the anti-inflammatory interleukin in the cell or individual. 17. A method of increasing the level of an anti-inflammatory interleukin in a cell, wherein the method comprises administering to the cell a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of an anti-inflammatory interleukin in the cell. 18. A method of increasing the level of an anti-inflammatory interleukin in an individual, wherein the method comprises administering to the individual a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of an anti-inflammatory interleukin in the individual. 19. The method of any one of embodiments 16 or 18, wherein the individual is a mammal. 20. The method of any one of embodiments 16 to 18, wherein the anti-inflammatory interleukin is selected from IL-4 and IL-10. 21. The method of any one of embodiments 16 to 18, wherein the anti-inflammatory interleukin is IL-4. 22. The method of any one of embodiments 16 to 18, wherein the anti-inflammatory interleukin is IL-10. 23. The method of any one of embodiments 16 to 18 or 20 to 22, wherein the level of the anti-inflammatory interleukin is increased by about 5%, 10%, 25%, 50%, 75%, 90%, 95% or more, for example relative to a reference standard. 24. The method of any one of embodiments 16 to 18 or 20 to 22, wherein the level of the anti-inflammatory interleukin is increased by about 5%, for example relative to a reference standard. 25. The method of any one of embodiments 16 to 18 or 20 to 22, wherein the level of the anti-inflammatory interleukin is increased by about 10%, for example relative to a reference standard. 26. The method of any one of embodiments 16 to 18 or 20 to 22, wherein the level of the anti-inflammatory interleukin is increased by about 25%, for example relative to a reference standard. 27. The method of any one of embodiments 16 to 18 or 20 to 22, wherein the level of the anti-inflammatory interleukin is increased by about 50%, for example relative to a reference standard. 28. The method of any one of embodiments 16 to 18 or 20 to 22, wherein the level of the anti-inflammatory interleukin is increased by about 75%, for example relative to a reference standard. 29. The method of any one of embodiments 16 to 18 or 20 to 22, wherein the level of the anti-inflammatory interleukin is increased by about 90%, for example relative to a reference standard. 30. The method of any one of embodiments 16 to 18 or 20 to 22, wherein the level of the anti-inflammatory interleukin is increased by about 95%, for example relative to a reference standard. 31. A method of reducing the level of an allergy marker in a cell or subject, wherein the method comprises administering to the cell or subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of the allergy marker in the cell or subject. 32. A method of reducing the level of an allergy marker in a cell, wherein the method comprises administering to the cell a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of the allergy marker in the cell. 33. A method of reducing the level of an allergy marker in a subject, wherein the method comprises administering to the subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing the level of an allergy marker in the subject. 34. The method of any one of embodiments 31 or 33, wherein the subject is a mammal. 35. The method of any one of embodiments 31 to 33, wherein the allergy marker is selected from IL-13, IL-14, INF-g and serum IgE. 36. The method of any one of embodiments 31 to 33, wherein the allergy marker is IL-13. 37. The method of any one of embodiments 31 to 33, wherein the allergy marker is IL-14. 38. The method of any one of embodiments 31 to 33, wherein the allergy marker is INF-g. 39. The method of any one of embodiments 31 to 33, wherein the allergy marker is serum IgE. 40. The method of any one of embodiments 31 to 33 or 35 to 39, wherein the level of the allergy marker is reduced by about 10%, 25%, 50%, 75%, 90%, 95% or more, e.g. relative to a reference standard. 41. The method of any one of embodiments 31 to 33 or 35 to 39, wherein the level of the allergy marker is reduced by about 10%, e.g. relative to a reference standard. 42. The method of any one of embodiments 31 to 33 or 35 to 39, wherein the level of the allergy marker is reduced by about 25%, e.g. relative to a reference standard. 43. The method of any one of embodiments 31 to 33 or 35 to 39, wherein the level of the allergy marker is reduced by about 50%, e.g. relative to a reference standard. 44. The method of any one of embodiments 31 to 33 or 35 to 39, wherein the level of the allergy marker is reduced by about 75%, e.g., relative to a reference standard. 45. The method of any one of embodiments 31 to 33 or 35 to 39, wherein the level of the allergy marker is reduced by about 90%, e.g., relative to a reference standard. 46. The method of any one of embodiments 31 to 33 or 35 to 39, wherein the level of the allergy marker is reduced by about 95%, e.g., relative to a reference standard. 47. A method of inducing expression of anti-inflammatory macrophages in a cell or subject, wherein the method comprises administering to the cell or subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby inducing expression of anti-inflammatory macrophages in the cell or subject. 48. A method of inducing the expression of anti-inflammatory macrophages in a cell, wherein the method comprises administering to the cell a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby inducing the expression of anti-inflammatory macrophages in the cell. 49. A method of inducing the expression of anti-inflammatory macrophages in an individual, wherein the method comprises administering to the individual a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby inducing the expression of anti-inflammatory macrophages in the individual. 50. The method of any one of embodiments 47 or 49, wherein the individual is a mammal. 51. The method of any one of embodiments 47 to 49, wherein the anti-inflammatory macrophage is an M2 macrophage. 52. The method of any one of embodiments 47 to 49 or 51, wherein the M2 macrophages secrete anti-inflammatory interleukins (e.g., IL-10). 53. A method for improving skin health in a cell or an individual, wherein the method comprises administering to the cell or the individual a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby improving skin health in the cell or the individual. 54. A method for improving skin health in a cell, wherein the method comprises administering to the cell a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby improving skin health in the cell. 55. A method of improving skin health in a subject, wherein the method comprises administering to the subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby improving skin health in the subject. 56. The method of any of embodiments 53 or 55, wherein the subject is a mammal. 57. A method of reducing inflammation in a cell or subject, wherein the method comprises administering to the cell or subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing inflammation in the cell or subject. 58. A method of reducing inflammation in a cell, wherein the method comprises administering to the cell a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing inflammation in the cell. 59. A method of reducing inflammation in an individual, wherein the method comprises administering to the individual a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing inflammation in the individual. 60. The method of any one of embodiments 57 or 59, wherein the individual is a mammal. 61. The method of any one of embodiments 57 to 59, wherein the inflammation is skin inflammation or epithelial cell inflammation. 62. A method of treating a skin condition in a cell or subject, wherein the method comprises administering to the cell or subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby treating the skin condition in the cell or subject. 63. A method of treating a skin condition in a cell, wherein the method comprises administering to the cell a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby treating the skin condition in the cell. 64. A method of treating a skin condition in a subject, wherein the method comprises administering to the subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby treating the skin condition in the subject. 65. The method of any one of embodiments 62 or 65, wherein the subject is a mammal. 66. The method of any one of embodiments 62 to 64, wherein the skin condition is selected from atopic dermatitis, psoriasis, and skin allergies. 67. A method of treating local inflammation in a subject, wherein the method comprises administering to the subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby treating the local inflammation in the subject. 68. The method of embodiment 67, wherein the subject is a mammal. 69. The method of embodiment 67, wherein the local inflammation comprises urticaria or a rash. 70. A method of treating an inflammatory disease or condition in a cell or subject, wherein the method comprises administering to the cell or subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby treating the inflammatory disease or condition in the cell or subject. 71. A method of treating an inflammatory disease or condition in a cell, wherein the method comprises administering to the cell a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby treating the inflammatory disease or condition in the cell. 72. A method of treating an inflammatory disease or condition in a subject, wherein the method comprises administering to the subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby treating the inflammatory disease or condition in the subject. 73. The method of any one of embodiments 70 or 72, wherein the subject is a mammal. 74. The method of any one of embodiments 70 to 72, wherein the inflammatory disease or condition comprises rheumatoid arthritis. 75. A method of reducing inflammation or a symptom of an inflammatory disease or condition in a subject, wherein the method comprises administering to the subject a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone, thereby reducing inflammation or a symptom of an inflammatory disease or condition in the subject. 76. The method of embodiment 75, wherein the subject is a mammal. 77. The method of embodiment 75, wherein the symptom comprises swelling, irritation, redness, itching, hives, or sneezing. 78. The method of embodiment 75, wherein the symptom comprises swelling. 79. The method of embodiment 75, wherein the symptom comprises irritation. 80. The method of embodiment 75, wherein the symptom comprises redness. 81. The method of embodiment 75, wherein the symptom comprises itching. 82. The method of embodiment 75, wherein the symptom comprises urticaria. 83. The method of embodiment 75, wherein the symptom comprises sneezing. 84. The method of any of the preceding embodiments, wherein one of the flavonoid and the sesquiterpene lactone comprises an AHR agonist, an NRF2 agonist, or a PPARg agonist. 85. The method of any of the preceding embodiments, wherein one of the flavonoid and the sesquiterpene lactone comprises an AHR agonist. 86. The method of any of the preceding embodiments, wherein one of the flavonoid and the sesquiterpene lactone comprises an NRF2 agonist. 87. The method of any of the preceding embodiments, wherein one of the flavonoid and the sesquiterpene lactone comprises a PPARg agonist. 88. The method of any of the preceding embodiments, wherein each of the flavonoid and the sesquiterpene lactone independently comprises an AHR agonist, an NRF2 agonist, or a PPARg agonist. 89. The method of any of the preceding embodiments, wherein each of the flavonoid and the sesquiterpene lactone independently comprises an AHR agonist. 90. The method of any of the preceding embodiments, wherein each of the flavonoid and the sesquiterpene lactone independently comprises an NRF2 agonist. 91. The method of any of the preceding embodiments, wherein each of the flavonoid and the sesquiterpene lactone independently comprises a PPARg agonist. 92. The method of any of the preceding embodiments, wherein the sesquiterpene lactone has a structure of formula (Bi): (Bi) or a pharmaceutically acceptable salt thereof, wherein: R ^1a and R ^1b are each independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl, or R ^1a and R ^1b together with the carbon atom to which they are attached form a C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁴ and R ⁵ are each independently absent, hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A , or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a heterocyclic ring; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; R ^{R 7} is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atoms to which they are attached form a heterocyclic ring; ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl; and " " is a single key or double key, and its restriction condition is that when " " is a double bond, each of R ⁴ and R ⁵ is independently absent. 93. The method of Example 92, wherein each of R ^1a and R ^1b is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl. 94. The method of Example 92, wherein each of R ^1a and R ^1b is independently hydrogen. 95. The method of Example 92, wherein each of R ^1a and R ^1b is independently C ₁ -C ₆ alkyl. 96. The method of Example 92, wherein each of R ^1a and R ^1b is independently C ₁ -C ₆ heteroalkyl. 97. The method of Example 92, wherein R ^1a and R ^1b together with the carbon atom to which they are attached form a C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. 98. The method of Example 92, wherein R ^1a and R ^1b together with the carbon atom to which they are attached form a C ₂ -C ₆ alkenyl. 99. The method of Example 92, wherein R ^1a and R ^1b together with the carbon atom to which they are attached form a C ₂ -C ₆ alkynyl. 100. The method of Example 92, wherein each of R ^1a and R ^1b is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl, or R ^1a and R ^1b together with the carbon atom to which they are attached form a C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. 101. The method of Example 92, wherein R ² is hydrogen or C ₁ -C ₆ alkyl. 102. The method of Example 92, wherein R ² is hydrogen. 103. The method of Example 92, wherein R ² is C ₁ -C ₆ alkyl. 104. The method of Example 92, wherein R ³ is hydrogen or C ₁ -C ₆ alkyl. 105. The method of Example 92, wherein R ³ is hydrogen. 106. The method of Example 92, wherein R ³ is C ₁ -C ₆ alkyl. 107. The method of Example 92, wherein each of R ⁴ and R ⁵ is independently absent, hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, or -OR ^A. 108. The method of Example 92, wherein each of R ⁴ and R ⁵ is independently absent. 109. The method of Example 92, wherein each of R ⁴ and R ⁵ is independently hydrogen. 110. The method of Example 92, wherein each of R ⁴ and R ⁵ is independently C ₁ -C ₆ alkyl. 111. The method of Example 92, wherein each of R ⁴ and R ⁵ is independently C ₁ -C ₆ heteroalkyl. 112. The method of Example 92, wherein each of R ⁴ and R ⁵ is independently -OR ^A. 113. The method of Example 92, wherein R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a heterocyclic ring. 114. The method of Example 92, wherein each of R ⁴ and R ⁵ is independently absent, hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, or -OR ^A , or R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a heterocyclic ring. 115. The method of Example 92, wherein R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, or -OR ^A . 116. The method of Example 92, wherein R ⁶ is hydrogen. 117. The method of Example 92, wherein R ⁶ is C ₁ -C ₆ alkyl. 118. The method of Example 92, wherein R ⁶ is C ₁ -C ₆ heteroalkyl. 119. The method of Example 92, wherein R ⁶ is -OR ^A . 120. The method of Example 92, wherein R ⁷ is hydrogen or -OR ^A . 121. The method of Example 92, wherein R ⁷ is hydrogen. 122. The method of Example 92, wherein R ⁷ is -OR ^A . 123. The method of Example 92, wherein R ² and R ⁷ together with the carbon atom to which they are attached form a heterocyclic ring. 124. The method of Example 92, wherein R ⁷ is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atom to which they are attached form a heterocyclic ring. 125. The method of Example 92, wherein ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl. 126. The method of Example 92, wherein ^RA is hydrogen. 127. The method of Example 92, wherein ^RA is C ₁ -C ₆ alkyl. 128. The method of Example 92, wherein ^RA is -C(O)-C ₁ -C ₆ alkyl. 129. The method of Example 92, wherein ^RA is C(O)-C ₂ -C ₆ alkenyl. 130. The method of Example 92, wherein ^RA is cycloalkyl. 131. The method of Example 92, wherein " " is a single key or double key, and its restriction condition is that when " When " is a double bond, each of ^R4 and ^R5 is independently absent. 132. The method of Example 92, wherein " 133. The method of Example 92, wherein " 134. The method of Example 92, wherein " 135. The method of Example 92, wherein " " is a double bond and each of R ⁴ and R ⁵ is independently non-existent. 136. The method as in any of the foregoing embodiments, wherein the compound of formula (Bi) is selected from parthenolide, costusinolide, zeantolide, schizonepetalide and deoxyschizonepetalide or a pharmaceutically acceptable salt thereof. 137. The method as in any of the foregoing embodiments, wherein the compound of formula (Bi) is parthenolide or a pharmaceutically acceptable salt thereof. 138. The method as in any of the foregoing embodiments, wherein the compound of formula (Bi) is costusinolide or a pharmaceutically acceptable salt thereof. 139. The method as in any of the foregoing embodiments, wherein the compound of formula (Bi) is zeantolide or a pharmaceutically acceptable salt thereof. 140. The method of any of the preceding embodiments, wherein the compound of formula (Bi) is picropicrin or a pharmaceutically acceptable salt thereof. 141. The method of any of the preceding embodiments, wherein the compound of formula (Bi) is deoxyspermatin or a pharmaceutically acceptable salt thereof. 142. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is a compound of formula (Bi): (Ci) or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; R ⁷ is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atoms to which they are attached form a heterocyclic ring; and ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl. 143. The method of Example 142, wherein R ² is hydrogen or C ₁ -C ₆ alkyl. 144. The method of Example 142, wherein R ² is hydrogen. 145. The method of Example 142, wherein R ² is C ₁ -C ₆ alkyl. 146. The method of Example 142, wherein R ³ is hydrogen or C ₁ -C ₆ alkyl. 147. The method of Example 142, wherein R ³ is hydrogen. 148. The method of Example 142, wherein R ³ is C ₁ -C ₆ alkyl. 149. The method of Example 142, wherein R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A. 150. The method of Example 142, wherein R ⁶ is hydrogen. 151. The method of Example 142, wherein R ⁶ is C ₁ -C ₆ alkyl. 152. The method of Example 142, wherein R ⁶ is C ₁ -C ₆ heteroalkyl. 153. The method of Example 142, wherein R ⁶ is -OR ^A . 154. The method of Example 142, wherein R ⁷ is hydrogen or -OR ^A . 155. The method of Example 142, wherein R ⁷ is hydrogen. 156. The method of Example 142, wherein R ⁷ is -OR ^A . 157. The method of Example 142, wherein R ² and R ⁷ together with the carbon atoms to which they are attached form a heterocyclic ring. 158. The method of Example 142, wherein ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl. 159. The method of Example 142, wherein ^RA is hydrogen. 160. The method of Example 142, wherein ^RA is C ₁ -C ₆ alkyl. 161. The method of Example 142, wherein ^RA is -C(O)-C ₁ -C ₆ alkyl. 162. The method of Example 142, wherein ^RA is C(O)-C ₂ -C ₆ alkenyl. 163. The method of Example 142, wherein ^RA is cycloalkyl. 164. The method of Example 142, wherein R ² is C ₁ -C ₆ alkyl; R ³ is C ₁ -C ₆ alkyl; R ⁶ is hydrogen; and R ⁷ is hydrogen. 165. The method of Example 142, wherein R ² is methyl; R ³ is methyl; R ⁶ is hydrogen; and R ⁷ is hydrogen. 166. The method of any one of the preceding embodiments, wherein the sesquiterpene lactone is a compound of formula (C-iii): (C-iii) or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; R ⁷ is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atom to which they are attached form a heterocyclic ring; and ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl. 167. The method of Example 166, wherein R ² is hydrogen or C ₁ -C ₆ alkyl. 168. The method of Example 166, wherein R ² is hydrogen. 169. The method of Example 166, wherein R ² is C ₁ -C ₆ alkyl. 170. The method of Example 166, wherein R ³ is hydrogen or C ₁ -C ₆ alkyl. 171. The method of Example 166, wherein R ³ is hydrogen. 172. The method of Example 166, wherein R ³ is C ₁ -C ₆ alkyl. 173. The method of Example 166, wherein R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A. 174. The method of Example 166, wherein R ⁶ is hydrogen. 175. The method of Example 166, wherein R ⁶ is C ₁ -C ₆ alkyl. 176. The method of Example 166, wherein R ⁶ is C ₁ -C ₆ heteroalkyl. 177. The method of Example 166, wherein R ⁶ is -OR ^A . 178. The method of Example 166, wherein R ⁷ is hydrogen or -OR ^A . 179. The method of Example 166, wherein R ⁷ is hydrogen. 180. The method of Example 166, wherein R ⁷ is -OR ^A . 181. The method of Example 166, wherein R ² and R ⁷ together with the carbon atoms to which they are attached form a heterocyclic ring. 182. The method of Example 166, wherein ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl. 183. The method of Example 166, wherein ^RA is hydrogen. 184. The method of Example 166, wherein ^RA is C ₁ -C ₆ alkyl. 185. The method of Example 166, wherein ^RA is -C(O)-C ₁ -C ₆ alkyl. 186. The method of Example 166, wherein ^RA is C(O)-C ₂ -C ₆ alkenyl. 187. The method of Example 166, wherein ^RA is cycloalkyl. 188. The method of Example 166, wherein R ² is C ₁ -C ₆ alkyl; R ³ is C ₁ -C ₆ alkyl; R ⁶ is hydrogen; and R ⁷ is hydrogen. 189. The method of Example 166, wherein R ² is methyl; R ³ is methyl; R ⁶ is hydrogen; and R ⁷ is hydrogen. 190. The method of Example 166, wherein R ² is C ₁ -C ₆ alkyl; R ³ is C ₁ -C ₆ alkyl; R ⁶ is -OR ^A ; R ⁷ is hydrogen; and ^RA is hydrogen. 191. The method of Example 166, wherein R ² is methyl; R ³ is methyl; R ⁶ is -OR ^A ; R ⁷ is hydrogen; and ^RA is hydrogen. 192. The method of any of the preceding examples, wherein the sesquiterpene lactone is selected from parthenolide, costusinolide, zearalenolide and schizonepeta lactone or a pharmaceutically acceptable salt thereof. 193. The method of any of the preceding examples, wherein the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof. 194. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is costus lanolin or a pharmaceutically acceptable salt thereof. 195. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is zearalenolide or a pharmaceutically acceptable salt thereof. 196. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is schizonepeta lactone or a pharmaceutically acceptable salt thereof. 197. The method of any of the preceding embodiments, wherein the flavonoid has the structure of formula (A): or a pharmaceutically acceptable salt thereof, wherein: ^R1 and ^R2 are independently hydrogen or ^ORA ; ^R3 is hydrogen or ^ORA ; ^R4 is hydrogen or ^-ORA ; ^RA is hydrogen, _C1 - _C6 alkyl or cycloalkyl; and " " is a single bond or a double bond. 198. The method of Example 197, wherein each of R ¹ and R ² is independently hydrogen or OR ^A . 199. The method of Example 197, wherein each of R ¹ and R ² is independently hydrogen. 200. The method of Example 197, wherein each of R ¹ and R ² is independently OR ^A . 201. The method of Example 197, wherein R ³ is hydrogen or OR ^A . 202. The method of Example 197, wherein R ³ is hydrogen. 203. The method of Example 197, wherein R ³ is OR ^A . 204. The method of Example 197, wherein R ⁴ is hydrogen or OR ^A . 205. The method of Example 197, wherein R ⁴ is hydrogen. 206. The method of Example 197, wherein R ⁴ is OR ^A. 207. The method of Example 197, wherein ^RA is hydrogen, C ₁ -C ₆ alkyl or cycloalkyl. 208. The method of Example 197, wherein ^RA is hydrogen. 209. The method of Example 197, wherein ^RA is C ₁ -C ₆ alkyl. 210. The method of Example 197, wherein ^RA is cycloalkyl. 211. The method of Example 197, wherein " 212. The method of embodiment 197, wherein " 213. The method of Example 197, wherein " " is a double bond. 214. A method as in any of the foregoing embodiments, wherein the flavonoid is selected from quercetin, leaf flavonoids, acanthus flavonoids, taxifolin, flavonoids and flavonols or pharmaceutically acceptable salts thereof. 215. A method as in any of the foregoing embodiments, wherein the flavonoid is quercetin or a pharmaceutically acceptable salt thereof. 216. A method as in any of the foregoing embodiments, wherein the flavonoid is leaf flavonoids or a pharmaceutically acceptable salt thereof. 217. A method as in any of the foregoing embodiments, wherein the flavonoid is acanthus flavonoids or a pharmaceutically acceptable salt thereof. 218. A method as in any of the foregoing embodiments, wherein the flavonoid is taxifolin or a pharmaceutically acceptable salt thereof. 219. A method as in any of the preceding embodiments, wherein the flavonoids are flavonoids and flavonols or their pharmaceutically acceptable salts. 220. A method as in any of the preceding embodiments, wherein the flavonoids are flavonols or their pharmaceutically acceptable salts. 221. A method as in any of the preceding embodiments, wherein the flavonoids are selected from quercetin, flavonoids, taxifolin, flavonoids and flavonols or their pharmaceutically acceptable salts. 222. A method as in any of the preceding embodiments, wherein the flavonoids are quercetin, flavonoids or their pharmaceutically acceptable salts. 223. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of a molar amount of the flavonoid alone used in the combination, wherein X ₁ is 1, 1.25, 1.5, 1.75, 2, 2.5 or greater. 224. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of a molar amount of the flavonoid alone used in the combination, wherein X ₁ is 1. 225. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of a molar amount of the flavonoid alone used in the combination, wherein X ₁ is 1.25. 226. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of a molar amount of the flavonoid alone used in the combination, wherein X ₁ is 1.5. 227. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of the molar amount of the flavonoid alone used in the combination, wherein X ₁ is 1.75. 228. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of the molar amount of the flavonoid alone used in the combination, wherein X ₁ is 2. 229. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X 1 times greater than the efficacy of the molar amount of the flavonoid alone used in the combination, wherein X ₁ is 2.5. 230. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of the molar amount of the sesquiterpene lactone alone used in the combination, wherein X ₁ is ₁ , 1.25, 1.5, 1.75, 2, 2.5 or more. 231. The method of any of the preceding embodiments, wherein the potency of the combination is at least X ₁ times greater than the potency of a molar amount of the sesquiterpene lactone alone used in the combination, wherein X ₁ is 1. 232. The method of any of the preceding embodiments, wherein the potency of the combination is at least X 1 times greater than the potency of a molar amount of the sesquiterpene lactone alone used in the combination, wherein X ₁ is 1.25. 233. The method of any of the preceding embodiments, wherein the potency of the combination is at least X ₁ times greater than the potency of a molar amount of the sesquiterpene lactone alone used in the combination, wherein X ₁ is 1.5. 234. The method of any of the preceding embodiments, wherein the potency of the combination is at least X ₁ times greater than the potency of a _{molar amount of the sesquiterpene lactone alone used in the combination, wherein X 1 is} 1.75. 235. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of the molar amount of the sesquiterpene lactone alone used in the combination, wherein X ₁ is 2. 236. The method of any of the preceding embodiments, wherein the efficacy of the combination is at least X ₁ times greater than the efficacy of the molar amount of the sesquiterpene lactone alone used in the combination, wherein X ₁ is 2.5. 237. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is parthenolide and the flavonoid is quercetin. 238. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is synthetically prepared. 239. The method of any of the preceding embodiments, wherein the flavonoid is synthetically prepared. 240. The method of any of the preceding embodiments, wherein the sesquiterpene lactone and/or the flavonoid is extracted from a natural source (e.g., a plant). 241. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is extracted from a natural source (e.g., a plant). 242. The method of any of the preceding embodiments, wherein the flavonoid is extracted from a natural source (e.g., a plant). 243. The method of any of the preceding embodiments, wherein the flavonoid is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof. 244. The method of embodiment 243, wherein the flavonoid is substantially pure. 245. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 99.9% of another compound. 246. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 50% of another compound. 247. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 55% of another compound. 248. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 60% of another compound. 249. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 65% of another compound. 250. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 70% of another compound. 251. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 75% of another compound. 252. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 80% of another compound. 253. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 85% of another compound. 254. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 90% of another compound. 255. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 95% of another compound. 256. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 99% of another compound. 257. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 99.9% of another compound. 258. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition, and the pharmaceutical composition comprises less than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 99.9% of another flavonoid, such as a flavonoid listed in Table 1, or a pharmaceutically acceptable salt thereof. 259. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition, and the pharmaceutical composition comprises less than about 50% of another flavonoid, such as a flavonoid listed in Table 1, or a pharmaceutically acceptable salt thereof. 260. The method of any of the preceding embodiments, wherein the flavonoid is provided as a pharmaceutical composition, and the pharmaceutical composition comprises less than about 55% of another flavonoid, such as a flavonoid listed in Table 1, or a pharmaceutically acceptable salt thereof. 261. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 60% of another flavonoid, such as a flavonoid listed in Table 1 or a pharmaceutically acceptable salt thereof. 262. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 65% of another flavonoid, such as a flavonoid listed in Table 1 or a pharmaceutically acceptable salt thereof. 263. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 70% of another flavonoid, such as a flavonoid listed in Table 1 or a pharmaceutically acceptable salt thereof. 264. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 75% of another flavonoid, such as a flavonoid listed in Table 1 or a pharmaceutically acceptable salt thereof. 265. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 80% of another flavonoid, such as a flavonoid listed in Table 1 or a pharmaceutically acceptable salt thereof. 266. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 85% of another flavonoid, such as a flavonoid listed in Table 1 or a pharmaceutically acceptable salt thereof. 267. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 90% of another flavonoid, such as a flavonoid listed in Table 1, or a pharmaceutically acceptable salt thereof. 268. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 95% of another flavonoid, such as a flavonoid listed in Table 1, or a pharmaceutically acceptable salt thereof. 269. The method of any of the foregoing embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 99% of another flavonoid, such as a flavonoid listed in Table 1, or a pharmaceutically acceptable salt thereof. 270. The method of any of the foregoing embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 99.9% of another flavonoid, such as a flavonoid listed in Table 1 or a pharmaceutically acceptable salt thereof. 271. The method of any of the foregoing embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 99.9% of a plant-derived substance. 272. The method of any of the foregoing embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 50% of a plant-derived substance. 273. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 55% plant-derived substances. 274. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 60% plant-derived substances. 275. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 65% plant-derived substances. 276. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 70% plant-derived substances. 277. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 75% plant-derived substances. 278. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 80% plant-derived substances. 279. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 85% plant-derived substances. 280. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 90% plant-derived substances. 281. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 95% plant-derived substances. 282. The method of any of the preceding embodiments, wherein the flavonoid is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 99% plant-derived substances. 283. The method of any of the preceding embodiments, wherein the flavonoid is provided in the form of a pharmaceutical composition and the pharmaceutical composition comprises less than about 99.5% plant-derived material. 284. The method of any of the preceding embodiments, wherein the flavonoid is provided in the composition in the absence of quercetin, flavonoids, flavonoids, taxifolin, flavonoids, or flavonols, or pharmaceutically acceptable salts thereof. 285. The method of any of the preceding embodiments, wherein the flavonoid is provided in the composition in the absence of quercetin, or pharmaceutically acceptable salts thereof. 286. The method of any of the preceding embodiments, wherein the flavonoid is provided in the composition in the absence of flavonoids, or pharmaceutically acceptable salts thereof. 287. The method of any of the preceding embodiments, wherein the flavonoid is provided in the combination in the absence of quercetin or a pharmaceutically acceptable salt thereof. 288. The method of any of the preceding embodiments, wherein the flavonoid is provided in the combination in the absence of taxifolin or a pharmaceutically acceptable salt thereof. 289. The method of any of the preceding embodiments, wherein the flavonoid is provided in the combination in the absence of flavonol or a pharmaceutically acceptable salt thereof. 290. The method of any of the preceding embodiments, wherein the flavonoid is provided in the combination in the absence of quercetin or a pharmaceutically acceptable salt thereof. 291. The method of any of the preceding embodiments, wherein the flavonoid is quercetin or a pharmaceutically acceptable salt thereof. 292. The method of Example 291, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of flavonoids, cyperitoyltransferone, taxifolin, flavonoids or flavonols or a pharmaceutically acceptable salt thereof. 293. The method of Example 291, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of flavonoids or a pharmaceutically acceptable salt thereof. 294. The method of Example 291, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of cyperitoyltransferone or a pharmaceutically acceptable salt thereof. 295. The method of embodiment 291, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of taxifolin or a pharmaceutically acceptable salt thereof. 296. The method of embodiment 291, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of flavonoids or a pharmaceutically acceptable salt thereof. 297. The method of embodiment 291, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of flavonol or a pharmaceutically acceptable salt thereof. 298. The method of any one of embodiments 291 to 297, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 90%, 95%, 99% or 99.9% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. 299. The method of any one of embodiments 291 to 297, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 90% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. 300. The method of any one of embodiments 291 to 297, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 95% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. 301. The method of any one of embodiments 291 to 297, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 99% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. 302. The method of any one of embodiments 291 to 297, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 99.9% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. 303. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof. 304. The method of embodiment 303, wherein the sesquiterpene lactone is substantially pure. 305. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 99.9% of another compound. 306. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 50% of another compound. 307. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 55% of another compound. 308. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 60% of another compound. 309. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 65% of another compound. 310. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 70% of another compound. 311. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 75% of another compound. 312. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 80% of another compound. 313. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 85% of another compound. 314. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 90% of another compound. 315. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 95% of another compound. 316. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 99% of another compound. 317. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 99.9% of another compound. 318. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 99.9% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2 or a pharmaceutically acceptable salt thereof. 319. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition and the pharmaceutical composition comprises less than about 50% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2 or a pharmaceutically acceptable salt thereof. 320. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 55% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 321. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 60% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 322. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 65% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 323. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 70% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 324. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 75% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 325. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 80% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 326. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 85% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 327. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 90% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 328. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 95% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 329. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition, and the pharmaceutical composition comprises less than about 99% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 330. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition, and the pharmaceutical composition comprises less than about 99.9% of another sesquiterpene lactone, such as a sesquiterpene lactone listed in Table 2, or a pharmaceutically acceptable salt thereof. 331. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided as a pharmaceutical composition, and the pharmaceutical composition comprises less than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 99.9% of a plant-derived substance. 332. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 50% plant-derived substances. 333. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 55% plant-derived substances. 334. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 60% plant-derived substances. 335. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 65% plant-derived substances. 336. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 70% plant-derived substances. 337. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 75% plant-derived substances. 338. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 80% plant-derived substances. 339. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 85% plant-derived substances. 340. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 90% plant-derived substances. 341. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 95% plant-derived substances. 342. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 99% plant-derived substances. 343. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in a pharmaceutical composition and the pharmaceutical composition comprises less than about 99.9% plant-derived substances. 344. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in the combination in the absence of costunolide, zeantolide, schizone and deoxyschizone or a pharmaceutically acceptable salt thereof. 345. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in the combination in the absence of costunolide or a pharmaceutically acceptable salt thereof. 346. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in the combination in the absence of zeantolide or a pharmaceutically acceptable salt thereof. 347. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in the combination in the absence of schizone or a pharmaceutically acceptable salt thereof. 348. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is provided in the combination in the absence of deoxyspergillus or a pharmaceutically acceptable salt thereof. 349. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof. 350. The method of embodiment 349, wherein the parthenolide or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of costusinolide, zearalenolide, schizonepetacin and deoxyspergillus or a pharmaceutically acceptable salt thereof. 351. The method of embodiment 349, wherein the parthenolide or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of costusinolide or a pharmaceutically acceptable salt thereof. 352. The method of embodiment 349, wherein the parthenolide or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of zearalenolide or a pharmaceutically acceptable salt thereof. 353. The method of embodiment 349, wherein the parthenolide or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of schizonepetavirus or a pharmaceutically acceptable salt thereof. 354. The method of embodiment 349, wherein the parthenolide or a pharmaceutically acceptable salt thereof is provided in the combination in the absence of deoxyspergillus or a pharmaceutically acceptable salt thereof. 355. The method of any one of embodiments 349 to 354, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 90%, 95%, 99% or 99.9% of another compound listed in Table 1, or a pharmaceutically acceptable salt thereof. 356. The method of any one of embodiments 349 to 344, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in a pharmaceutical composition, and the pharmaceutical composition comprises less than about 90% of another compound listed in Table 1, or a pharmaceutically acceptable salt thereof. 357. The method of any one of embodiments 349 to 354, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 95% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. 358. The method of any one of embodiments 349 to 354, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 99% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. 359. The method of any one of embodiments 349 to 354, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 99.9% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. 360. The method of any of the preceding embodiments, wherein each of parthenolide and quercetin is formulated independently as a pharmaceutical composition. 361. The method of any of the preceding embodiments, wherein the parthenolide and quercetin are formulated together as a pharmaceutical composition. 362. The method of any of the preceding embodiments, wherein each of the parthenolide and quercetin is provided (e.g., administered) to the subject simultaneously. 363. The method of embodiment 362, wherein each of the parthenolide and quercetin is provided (e.g., administered) to the subject sequentially. 364. The method of embodiment 362, wherein the parthenolide is provided (e.g., administered) to the subject prior to the quercetin. 365. The method of embodiment 362, wherein the quercetin is provided (e.g., administered) to the individual prior to the parthenolide. 366. The method of any of the preceding embodiments, wherein the sesquiterpene lactone and the flavonoid are formulated for topical, systemic, or oral administration. 367. The method of any of the preceding embodiments, wherein the sesquiterpene lactone and the flavonoid are formulated for topical administration. 368. The method of any of the preceding embodiments, wherein the sesquiterpene lactone and the flavonoid are formulated for systemic administration. 369. The method of any of the preceding embodiments, wherein the sesquiterpene lactone and the flavonoid are formulated for oral administration. 370. The method of any of the preceding embodiments, wherein the flavonoid is administered in an amount that provides a concentration of between 0.1 µM and 500 µM in the subject or cell. 371. The method of any of the preceding embodiments, wherein the flavonoid is administered in an amount that provides a concentration of between 0.1 µM and 500 µM in the subject. 372. The method of any of the preceding embodiments, wherein the flavonoid is administered in an amount that provides a concentration of between 0.1 µM and 500 µM in the cell. 373. The method of any of the preceding embodiments, wherein the flavonoid is administered in an amount that provides a concentration of between 1 µM and 25 µM in the subject or cell. 374. The method of any of the preceding embodiments, wherein the flavonoid is administered in an amount that provides a concentration of between 1 µM and 25 µM in the subject. 375. The method of any of the preceding embodiments, wherein the flavonoid is administered in an amount that provides a concentration of between 1 µM and 25 µM in a cell. 376. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.01 µM and 25 µM in the subject or cell. 377. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.01 µM and 25 µM in the subject. 378. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.01 µM and 25 µM in the cell. 379. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.1 µM and 5 µM in the subject or cell. 380. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.1 µM and 5 µM in the subject. 381. The method of any of the preceding embodiments, wherein the sesquiterpene lactone is administered in an amount that provides a concentration of between 0.1 µM and 5 µM in the cell. 382. The method of any of the preceding embodiments, wherein the ratio of the amount of flavonoids to the sesquiterpene lactones in the combination is between 200:1 and 1:1. 383. The method of embodiment 382, wherein the ratio of the amount of flavonoids to the sesquiterpene lactones in the combination is between 50:1 and 1:1. 384. The method of any of embodiments 382 to 383, wherein the ratio of the amount of flavonoids to the sesquiterpene lactones in the combination is between 50:1 and 2:1. 385. The method of any of embodiments 382 to 384, wherein the ratio of the amount of flavonoids to the sesquiterpene lactones in the combination is between 25:1 and 2:1. 386. The method of any of the preceding embodiments, wherein: (i) the flavonoid is quercetin or a pharmaceutically acceptable salt thereof; (ii) the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof; and (iii) the molar amount of the flavonoid in the combination is between 20 and 5 times greater than the molar amount of the sesquiterpene lactone. 387. The method of any of the preceding embodiments, further comprising administering an additional agent. 388. The method of any of the preceding embodiments, wherein the subject is a mammal (e.g., a human). 389. The method of any of the preceding embodiments, wherein the inflammation is present in an inflamed organ, tissue, or cell in the subject. 390. The method of embodiment 389, wherein the inflamed organ is selected from the group consisting of skin, brain, spinal cord, eye, skin, lung, heart, pancreas, large intestine, small intestine, stomach, liver, gall bladder, kidney or spleen. 391. The method of embodiment 389, wherein the inflamed organ is skin. 392. The method of embodiment 389, wherein the inflamed organ is brain. 393. The method of embodiment 389, wherein the inflamed organ is spinal cord. 394. The method of embodiment 389, wherein the inflamed organ is eye. 395. The method of embodiment 389, wherein the inflamed organ is skin. 396. The method of embodiment 389, wherein the inflamed organ is lung. 397. The method of Example 389, wherein the inflamed organ is the large intestine. 398. The method of Example 389, wherein the inflamed organ is the small intestine. 399. The method of Example 389, wherein the inflamed organ is the stomach. 400. The method of Example 389, wherein the inflamed organ is the liver. 401. The method of Example 389, wherein the inflamed organ is the gallbladder. 402. The method of Example 389, wherein the inflamed organ is the kidney. 403. The method of Example 389, wherein the inflamed organ is the spleen. 404. The method of Example 389, wherein the inflamed tissue is selected from the group consisting of lung tissue, tracheal tissue, intestinal tissue, skin tissue, pancreatic tissue, vascular tissue, mucosal tissue, kidney tissue, brain tissue, nervous tissue or heart tissue. 405. The method of Example 389, wherein the inflamed tissue is lung tissue. 406. The method of Example 389, wherein the inflamed tissue is tracheal tissue. 407. The method of Example 389, wherein the inflamed tissue is intestinal tissue. 408. The method of Example 389, wherein the inflamed tissue is skin tissue. 409. The method of Example 389, wherein the inflamed tissue is pancreatic tissue. 410. The method of Example 389, wherein the inflamed tissue is vascular tissue. 411. The method of Example 389, wherein the inflamed tissue is mucosal tissue. 412. The method of Example 389, wherein the inflamed tissue is kidney tissue. 413. The method of Example 389, wherein the inflamed tissue is brain tissue. 414. The method of Example 389, wherein the inflamed tissue is neural tissue. 415. The method of Example 389, wherein the inflamed tissue is cardiac tissue.

Examples The following examples are provided to further illustrate some embodiments of the present invention, but are not intended to limit the scope of the present invention. It will be understood by its exemplary nature that other procedures, methods or techniques known to those skilled in the art may be used instead.

Example 1 : In vitro assays to determine the anti-inflammatory properties of exemplary compounds - THP1 interleukin secretion assay AhR, NRF2 or PPARG agonism is known to cause downstream inhibition of secretion of various inflammatory interleukins (e.g., TNFa, IL6). Given the observation of AhR, NRF2 or PPARG agonism, the purpose of this example was to demonstrate the ability of quercetin and parthenolide, alone or in combination, to affect various downstream functional inflammatory processes.

Human THP-1 cells were plated and differentiated into macrophages by treatment with phorbol 12-myristate 13-acetate and β-hydroxyethanol for 72 hours. The differentiated THP-1 macrophages were then stimulated with IFN-γ (20 ng/mL) and LPS (50 ng/mL) to induce inflammatory responses and co-treated with parthenolide and/or quercetin at 0, 0.2, 0.5, 2, 5, 10 μM. Various secreted interleukins were measured from the culture medium using the Ella automated immunoassay system (ProteinSimple).

Parthenolide alone (0-5 μM) caused a dose-dependent inhibition of TNFa secretion, with a maximum TNFa inhibition of 1.3% seen at 5 μM. Quercetin alone (0-10 μM) also caused a dose-dependent inhibition of TNFa secretion, with a maximum TNFa inhibition of 38.1% seen at 10 μM. When screened in combination at certain concentrations, parthenolide and quercetin had a synergistic effect, causing greater TNFa inhibition than the maximum effect of each compound alone. For example, the combination of parthenolide (5 μM) and quercetin (0.2-10 μM) resulted in complete inhibition of TNFa to 0%.

Example 2 : In vitro assays to determine the anti-inflammatory properties of exemplary compounds - Interleukin secretion assay of primary T cells CD4+CD25- T-responder cells T cells can be isolated from human PBMCs (STEMCELL Technologies, Catalog No. 70025) using the CD4+CD127lowCD25+ Regulatory T Cell Isolation Kit (Catalog No. 18063, STEMCELL Technologies). For interleukin release by CD4+ T-responder cells, cells can be plated at 25,000/well in a V-bottom 96-well plate and exposed to IL-2 (100 U/mL) to trigger interleukin secretion. The ability of parthenolide and quercetin (5 μM + 5 μM) to block interleukin secretion can be assessed. Interleukin panel analysis can be performed using the Ella automated immunoassay system (ProteinSimple).

Example 3 : Oxazolinone - induced dermatitis mouse model : Experimental design and results The purpose of this example was to demonstrate the combined anti-inflammatory effect of topical application of parthenolide or quercetin on oxazolinone-induced ear swelling (allergic contact dermatitis model) in mice. Male BALB/c mice weighing 22 ± 2 g were used and randomly divided into groups of 5 mice each. The sham group did not receive oxazolinone sensitization and challenge, but received PBS plus treatment with vehicle (acetone:ethanol 1:1). All other groups of animals were sensitized on day 0 by application of oxazolidinone (100 μL, 1.5% in acetone) onto the surface of their previously shaved abdomens and challenged seven (7) days later with oxazolidinone (1%, 20 μL/ear). 20 μL of vehicle, dexamethasone (5 mg/mL; anti-inflammatory positive control), or a combination of parthenolide (0.5 to 3 mg/mL) + quercetin (1.8 to 10.8 mg/mL) were applied topically to the anterior and posterior surfaces of the right ear 30 minutes before and 15 minutes after oxazolidinone challenge. The left ear was not stimulated and served as a control treatment.

The thickness of the right and left ears of each mouse was measured 24 hours after the oxazolidinone challenge as an indicator of inflammation. The right ears were collected and snap-frozen for analysis of interleukin gene expression. Each compound was evaluated by calculating the percentage of interleukin gene expression compared to the vehicle control, where the lower the percentage, the greater the anti-inflammatory effect of the compound.

Vehicle-treated ears showed an increase in oxadiazine-stimulated ear thickness to 0.42 mm. Dexamethasone-treated ears showed a 29% decrease in thickness compared to vehicle-treated ears. Parthenolide + quercetin-treated ears showed a 20% decrease in thickness compared to vehicle-treated ears ( Figure 1 ).

Compared with the sham treated group, the mice treated with vehicle showed an increase in the expression of oxazolidinone-induced Il1b, Il4, Il6, Il11, Il13 and Tnfa. Topical treatment with dexamethasone effectively reduced the expression of Il1b, Il4, Il6, Il11, Il13 and Tnfa genes to 5%, 24%, 33%, 55%, 20% and 14% of vehicle control, respectively. Dexamethasone increased the expression of Ifng gene to 445% of vehicle control. Topical treatment with parthenolide + quercetin reduced Il1b, Il4, Il6, Il11, Il13, Tnfa to <1%, <1%, 50%, 50%, 6%, 47% of vehicle control, respectively ( Table 3 ). Table 3. Fold changes in gene expression in the ears of mice topically stimulated with oxazolidinone and treated with vehicle, dexamethasone, or a combination of quercetin + parthenolide Interleukin gene Dexamethasone ( % of vehicle control ) Parthenolide + Quercetin ( % of vehicle control ) Il1b 5% <1% Il4 twenty four% <1% Il6 33% 50% Il11 55% 50% Il13 20% 6% Tnf 14% 47%

Example 4 : LPS -induced systemic inflammation mouse model: experimental design and results C57Bl/6 male mice aged 6 to 8 weeks and weighing 22 ± 2 g were randomly divided into groups of 5 to 6 mice each. Sham-treated animals were injected intraperitoneally with PBS only. All other groups were injected intraperitoneally with vehicle control, dexamethasone (5 mg/kg), or a combination of parthenolide + quercetin (4 mg/kg + 9 mg/kg) 1 hour before injection of LPS (1 mg/kg), an agent known to trigger systemic inflammation. After LPS injection, blood was collected at different time points: 30 minutes, 2 hours, 4 hours and 24 hours, and the processed serum or plasma was used for further interleukin analysis via LUMINEX or Ella automated immunoassay system (ProteinSimple).

In LPS-injected mice, dexamethasone reduced MIP1-β, CXCL1, and TNFa levels to 29%, 57%, and 12% of vehicle, respectively, at 4 hours. In LPS-injected mice, parthenolide + quercetin reduced MIP1-β, CXCL1, and TNFa levels to 73%, 63%, and 55% of vehicle, respectively (Figures 2A to 2C).

INCORPORATION BY REFERENCE AND EQUIVALENTS All patents, published applications, and references cited herein are incorporated by reference in their entirety. Although exemplary embodiments have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made herein without departing from the scope of the embodiments covered by the appended claims.

Figure 1 is a graph depicting the results of ear thickness measurements of oxazolinone stimulated ears or unstimulated control ears after topical treatment with vehicle, dexamethasone (control), or parthenolide + quercetin. Figures 2A to 2C are graphs showing the levels of certain interleukins (Figure 2A - MIP1-β, Figure 2B - CXCL1, Figure 2C - TNFa) in mice pre-injected with vehicle, dexamethasone (control), or parthenolide + quercetin for 1 hour and then injected with LPS.

Claims (38)

A composition for reducing inflammation in a mammal comprising a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone. The composition of claim 2, wherein the inflammation is skin inflammation or epithelial cell inflammation. A composition for treating a skin condition in a cell or an individual, comprising a combination of: (i) a flavonoid; and (ii) a sesquiterpene lactone. The composition of claim 3, wherein the skin condition is selected from atopic dermatitis, psoriasis and skin allergy. The composition of any of the preceding claims, wherein one of the flavonoid and the sesquiterpene lactone comprises an AHR agonist, an NRF2 agonist, or a PPARg agonist. A composition as claimed in any of the preceding claims, wherein one of the flavonoid and the sesquiterpene lactone independently comprises an AHR agonist, an NRF2 agonist or a PPARg agonist. The composition of any of the preceding claims, wherein the sesquiterpene lactone has a structure of formula (Ci): (C) or a pharmaceutically acceptable salt thereof, wherein: R ^1a and R ^1b are each independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl, or R ^1a and R ^1b together with the carbon atoms to which they are attached form a C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; R ² is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁴ and R ⁵ are each independently absent, hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A , or R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a heterocyclic ring; R ⁶ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl or -OR ^A ; R ^{R 7} is hydrogen or -OR ^A , or R ² and R ⁷ together with the carbon atoms to which they are attached form a heterocyclic ring; ^RA is hydrogen, C ₁ -C ₆ alkyl, -C(O)-C ₁ -C ₆ alkyl, C(O)-C ₂ -C ₆ alkenyl or cycloalkyl; and " " is a single key or double key, and its restriction condition is that when " When " is a double key, each of ^R4 and ^R5 independently does not exist. The composition of any of the preceding claims, wherein the compound of formula (C-i) is selected from the compounds in Table 2. A composition as claimed in any of the preceding claims, wherein the sesquiterpene lactone is selected from parthenolide, costunolide, eupatolide and onopordopicrin or a pharmaceutically acceptable salt thereof. A composition as claimed in any of the preceding claims, wherein the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof. The composition of any of the preceding claims, wherein the flavonoid has a structure of formula (Ai): or a pharmaceutically acceptable salt thereof, wherein: ^R1 and ^R2 are independently hydrogen or ^ORA ; ^R3 is hydrogen or ^ORA ; ^R4 is hydrogen or ^-ORA ; ^RA is hydrogen, _C1 - _C6 alkyl or cycloalkyl; and " " is a single key or a double key. The composition of any of the preceding claims, wherein the compound of formula (A-i) is selected from the compounds in Table 1. The composition of any of the preceding claims, wherein the flavonoid is selected from quercetin, myricetin, taxifolin, fisetin and kaempferol or a pharmaceutically acceptable salt thereof. The composition of any of the preceding claims, wherein the flavonoid is quercetin, phylloxetine or a pharmaceutically acceptable salt thereof. The composition of any of the preceding claims, wherein the flavonoid is quercetin or a pharmaceutically acceptable salt thereof. The composition of any of the preceding claims, wherein the potency of the combination is at least _X1 times greater than the potency of the molar amount of the flavonoid alone used in the combination, wherein _X1 is 1, 1.25, 1.5, 1.75, 2, 2.5 or greater. A composition as claimed in any of the preceding claims, wherein the potency of the combination is at least _X1 times greater than the potency of the molar amount of the sesquiterpene lactone alone used in the combination, wherein _X1 is 1, 1.25, 1.5, 1.75, 2, 2.5 or greater. A composition as claimed in any preceding claim, wherein the sesquiterpene lactone is parthenolide and the flavonoid is quercetin. A composition as claimed in any of the preceding claims, wherein the flavonoids are provided in the composition in the absence of quercetin, flavonoids, flavonoids, taxifolin, flavonoids or flavonols or pharmaceutically acceptable salts thereof. A composition as claimed in any of the preceding claims, wherein the sesquiterpene lactone is provided in the composition in the absence of costunolide, zearalenolide, sciatolic acid and deoxyelepantopin or a pharmaceutically acceptable salt thereof. A composition as claimed in any of the preceding claims, wherein the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof. A composition as claimed in claim 21, wherein the parthenolide or a pharmaceutically acceptable salt thereof is provided in the composition in the absence of costusinolide, zearalenolide, schizonepetacin and deoxyschizonepetacin or a pharmaceutically acceptable salt thereof. The composition of any one of claims 21 to 22, wherein the quercetin or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, and the pharmaceutical composition comprises less than about 90%, 95%, 99% or 99.9% of another compound listed in Table 1 or a pharmaceutically acceptable salt thereof. A composition as claimed in any of the preceding claims, wherein each of parthenolide and quercetin is independently formulated in the form of a pharmaceutical composition. A composition as claimed in any of the preceding claims, wherein the parthenolide and quercetin are formulated together in the form of a pharmaceutical composition. The composition of any of the preceding claims, wherein each of the parthenolide and quercetin is provided (eg, administered) to the subject simultaneously. The composition of claim 26, wherein each of the parthenolide and quercetin is provided (eg, administered) sequentially to the subject. The composition of claim 26, wherein the parthenolide is provided to (eg, administered to) the subject before the quercetin. The composition of claim 26, wherein the quercetin is provided to (eg, administered to) the subject prior to the parthenolide. The composition of any of the preceding claims, wherein the sesquiterpene lactone and the flavonoid are formulated for topical, systemic or oral administration. The composition of any of the preceding claims, wherein the flavonoid is administered in an amount to provide a concentration of between 0.1 µM and 500 µM in the subject or cell. A composition as claimed in any of the preceding claims, wherein the ratio of the amount of flavonoid to the amount of sesquiterpene lactone in the composition is between 200:1 and 1:1. A composition as claimed in any of the preceding claims, wherein: (i) the flavonoid is quercetin or a pharmaceutically acceptable salt thereof; (ii) the sesquiterpene lactone is parthenolide or a pharmaceutically acceptable salt thereof; and (iii) the molar amount of the flavonoid in the composition is between 20 and 5 times greater than the molar amount of the sesquiterpene lactone. The composition of any of the preceding claims, further comprising administration of an additional agent. The composition of any preceding claim, wherein the mammal is a human. The composition of any of the preceding claims, wherein the inflammation is present in an inflamed organ, tissue or cell in a subject. The composition of claim 36, wherein the inflamed organ is selected from the group consisting of skin, brain, spinal cord, eye, skin, lung, heart, pancreas, large intestine, small intestine, stomach, liver, gall bladder, kidney or spleen. The composition of claim 37, wherein the inflamed tissue is selected from the group consisting of lung tissue, tracheal tissue, intestinal tissue, skin tissue, pancreatic tissue, vascular tissue, mucosal tissue, kidney tissue, brain tissue, nervous tissue or heart tissue.