WO2012068539A1

WO2012068539A1 - Use and composition of quercetin-3'-o-sulfate for therapeutic treatment

Info

Publication number: WO2012068539A1
Application number: PCT/US2011/061523
Authority: WO
Inventors: Michael Paul Chang; May Dean-Ming Lee
Original assignee: Limerick Biopharma, Inc.
Priority date: 2010-11-19
Filing date: 2011-11-18
Publication date: 2012-05-24

Abstract

The present invention relates generally to the use and composition of quercetin-3'-O-sulfate for therapeutic treatment. In particular, methods for reducing or eliminating a side effect associated with, or increasing the effectiveness of, the administration of a therapeutic agent, using quercetin-3'-O-sulfate or a pharmaceutically acceptable salt thereof as an adenosine A₃ receptor antagonist, are described. In addition, methods for the treatment and prevention of metabolic disorders and other diseases, using quercetin-3'-O-sulfate or a pharmaceutically acceptable salt thereof, are described. Related compositions in discrete dosage form and kits are also described.

Description

USE AND COMPOSITION OF QUERCETIN-3'-0-SULFATE FOR THERAPEUTIC

TREATMENT

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority under 35 USC § 119(e) to

U.S. Provisional Patent Application No. 61/415,566 filed on 19 November 2010, and to U.S. Provisional Patent Application No. 61/508,255 filed on 15 July 2011, both of which are herein incorporated in full by reference for all purposes.

BACKGROUND

Field

The present invention relates generally to the use and composition of quercetin-3'-0-sulfate for therapeutic treatment. Description of the Related Art

Polyphenols such as flavonoids have been shown to have beneficial health effects. In particular, polyphenols can provide beneficial effects by lowering the side effects of co-administered therapeutic agents. Side effects are often associated with the administration of a therapeutic agent. Side effects may be CNS side effects, renal side effects, urogenital side effects, hepatic side effects, pancreatic side effects, or gastrointestinal side effects, to name a few. People are always searching for ways to reduce or eliminate side effects. One way is to develop new therapeutic agents with fewer side effects. Other ways include searching for adjunctive therapy to reduce or eliminate the side effects of existing therapeutic agents. For example, Tacrolimus (TAC), a calcineurin inhibitor, is a potent immunosuppressant which has significantly advanced the success of transplantation through control of rejection episodes. However, TAC induces hyperglycemia, renal vasoconstriction, glomerular filtration rate (GFR) reduction and other side effects. One way to eliminate or reduce TAC induced side effects is to develop adjunct therapy, through administration of another agent. Therefore, there is a need to find compounds that will reduce or eliminate side effects of co-administered therapeutic agents. In addition, there is a continued need to find compounds that can be used in the treatment and prevention of metabolic disorders and other diseases, such as diabetes mellitus. Diabetes mellitus has become one of the most prevalent diseases in industrialized countries. In the United States alone, about 23.6 million people (about 8% of the population) have diabetes with an additional 57 million people at risk. Because of such a large prevalence and impact upon the health and economy of a society, diabetes is a subject of intense interest by academics and pharmaceutical industry.

Insulin is a hormone that is produced by beta cells of the islets of Langerhans in the pancreas, and functions to facilitate glucose uptake in the cells. In Type 1 diabetes, a majority of beta cells are destroyed and rendered nonfunctional by autoimmune inflammation resulting in no insulin production. Triggers for the autoimmune response are not yet known, but it has been contemplated that viruses and environmental factors in genetically susceptible individuals play a factor.

Type 2 diabetes is characterized by the onset of insulin resistance or reduced sensitivity in peripheral tissues in combination with impaired insulin secretion. The impaired insulin secretion results from progressive degeneration and dysfunction of pancreatic alpha and beta cells as well as a significant reduction in cell mass, and is typically associated with obese conditions. Obesity is now a world wide epidemic, and is one of the most serious contributors to increased morbidity and mortality. Obesity, which is an excess of body fat relative to lean body mass, is a chronic disease. Obesity is also a multiple etiology problem. The prevalence of obesity has risen significantly in the past decade in the United States and many other developed countries.

Obesity is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, stroke, hyperlipidemia, some cancers, type 2 diabetes, coronary heart disease, hypertension, numerous other major illnesses, and overall mortality from all causes. Weight reduction and improved control of lipid, blood pressure, and sugar levels is critical for the obese patient. BRIEF SUMMARY

In brief, the present invention relates generally to the use and composition of quercetin-3'-0-sulfate for therapeutic treatment. In particular, the present invention is directed to the use of quercetin-3'-0-sulfate for reducing or eliminating a side effect associated with, or increasing the effectiveness of, the administration of a therapeutic agent. In addition, the present invention is directed to the use of quercetin-3'-0-sulfate for the treatment and prevention of metabolic disorders and other diseases. In particular, the use of quercetin-3'-0-sulfate for modulating lipid, cholesterol, triglyceride, insulin or glucose levels. In addition, the present invention is also directed to the use of quercetin-3'-0-sulfate as a selective adenosine A₃ receptor antagonist.

In one embodiment, a method for selectively inhibiting adenosine A₃ receptor activity in an animal is provided, the method comprising administering to the animal an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

In another embodiment, a method for reducing or eliminating a side effect associated with, or increasing the effectiveness of, the administration of a therapeutic agent to an animal is provided, the method comprising administering to the animal an effective amount of an adenosine A₃ receptor antagonist, wherein the adenosine A₃ receptor antagonist is quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

In another embodiment, a method for reducing or eliminating a side effect associated with, or increasing the effectiveness of, the administration of a therapeutic agent to an animal is provided, the method comprising administering to the animal an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

In further embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt is in isolated and purified form. For example, in certain embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 98%, or the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99%, or the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99.7%.

In other further embodiments, the pharmaceutically acceptable salt is a sodium sulfate salt or a potassium sulfate salt.

In other further embodiments, the therapeutic agent is an immunosuppressant, antiviral, antibiotic, antineoplastic, amphetamine, antihypertensive, vasodilator, barbiturate, membrane stabilizer, cardiac stabilizer, glucocorticoid, antilipedemic, antiglycemic, cannabinoid, antidepressant, antineuroleptic, antiinfective, immunomodulator or chemotherapeutic agent. In certain embodiments, the therapeutic agent is an immunosuppressant. In certain embodiments, the therapeutic agent is a calcineurin inhibitor. In certain embodiments, the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, voclosporin, or hydrocortisone. In certain embodiments, the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, or voclosporin. In particular embodiments, the therapeutic agent is tacrolimus. In other particular embodiments, the therapeutic agent is cyclosporin. In certain embodiments, the therapeutic agent is an antilipedimic agent. In certain embodiments, the therapeutic agent is an HMG-CoA inhibitor. In certain embodiments, the therapeutic agent is lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin. In certain embodiments, the therapeutic agent is an antihyperglycemic agent. In certain embodiments, the therapeutic agent is glyburide, glipizide, gliclazide, glimepride, a meglitinide, repaglinide, netaglinide, a biguanide, metformin, a thiazolidinedione, an a-glucosidase inhibitor, acarbose, miglitol, glucagon, somatostatin, or diazoxide. In certain embodiments, the therapeutic agent is metformin. In certain embodiments, the therapeutic agent is a thiazolidinedione.

In other further embodiments, the therapeutic agent is insulin.

In other further embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt and the therapeutic agent are administered to the animal separately. In other further embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt and the therapeutic agent are administered to the animal simultaneously.

In other further embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt is administered to the animal before or concurrently with the administration of the therapeutic agent.

In other further embodiments, the side effect is renal vasoconstriction, hyperglycemia, nephrotoxicity, renal function impairment, creatinine increase, proteinuria, hematuria, hypertension, renal allograft rejection, urinary tract infection, oliguria, cystitis haemorrhagic, hemolytic-uremic syndrome or micturition disorder, hepatic necrosis, hepatotoxicity, fatty liver, venooclusive liver disease, diarrhea, nausea, constipation, vomiting, dyspepsia, anorexia, or a combination thereof. In certain embodiments, the side effect is hyperglycemia.

In other further embodiments, the side effect is calcineurin inhibitor induced hyperglycemia, new onset diabetes after transplantation, reduced kidney function, proteinuria, hematuria, hypertension or graft failure. In certain embodiments, the side effect is tacrolimus induced hyperglycemia, new onset diabetes after transplantation, reduced kidney function, proteinuria, hematuria, hypertension or graft failure.

In other further embodiments, the side effect is calcineurin induced renal vasoconstriction. In certain embodiments, the side effect is tacrolimus induced renal vasoconstriction.

In another embodiment, a composition in discrete dosage form is provided comprising quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

In further embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt is in isolated and purified form. For example, in certain embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 98%, or the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99%, or the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99.7%. In other further embodiments, the pharmaceutically acceptable salt is a sodium sulfate salt or a potassium sulfate salt.

In other further embodiments, the composition is formulated for oral administration. In certain embodiments, the composition is in the form of a tablet or capsule.

In other further embodiments, the composition further comprises a therapeutic agent. In certain embodiments, the therapeutic agent is an immunosuppressant, antiviral, antibiotic, antineoplastic, amphetamine, antihypertensive, vasodilator, barbiturate, membrane stabilizer, cardiac stabilizer, glucocorticoid, antilipedemic, antiglycemic, cannabinoid, antidepressant, antineuroleptic, antiinfective, immunomodulator or chemotherapeutic agent. In certain embodiments, the therapeutic agent is an immunosuppressant. In certain embodiments, the therapeutic agent is a calcineurin inhibitor. In certain embodiments, the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, voclosporin, or hydrocortisone. In certain embodiments, the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, or voclosporin. In particular embodiments, the therapeutic agent is tacrolimus. In other particular embodiments, the therapeutic agent is cyclosporin. In certain embodiments, the therapeutic agent is an antilipedimic agent. In certain embodiments, the therapeutic agent is an HMG-CoA inhibitor. In certain embodiments, the therapeutic agent is lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin. In certain embodiments, the therapeutic agent is an antihyperglycemic agent. In certain embodiments, the therapeutic agent is glyburide, glipizide, gliclazide, glimepride, a meglitinide, repaglinide, netaglinide, a biguanide, metformin, a thiazolidinedione, an a-glucosidase inhibitor, acarbose, miglitol, glucagon, somatostatin, or diazoxide. In certain embodiments, the therapeutic agent is metformin. In certain embodiments, the therapeutic agent is a thiazolidinedione.

In other further embodiments, the therapeutic agent is insulin.

In another embodiment, a kit is provided comprising: (a) quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof; (b) a therapeutic agent; and (c) instructions for use of the quercetin-3'-0-sulfate or pharmaceutically acceptable salt, the therapeutic agent, or both.

In other further embodiments, the therapeutic agent is an immunosuppressant, antiviral, antibiotic, antineoplastic, amphetamine, antihypertensive, vasodilator, barbiturate, membrane stabilizer, cardiac stabilizer, glucocorticoid, antilipedemic, antiglycemic, cannabinoid, antidepressant, antineuroleptic, antiinfective, immunomodulator or chemotherapeutic agent. In certain embodiments, the therapeutic agent is an immunosuppressant. In certain embodiments, the therapeutic agent is a calcineurin inhibitor. In certain embodiments, the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, voclosporin, or hydrocortisone. In certain embodiments, the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, or voclosporin. In particular embodiments, the therapeutic agent is tacrolimus. In other particular embodiments, the therapeutic agent is cyclosporin. In certain embodiments, the therapeutic agent is an antilipedimic agent. In certain embodiments, the therapeutic agent is an HMG-CoA inhibitor. In certain embodiments, the therapeutic agent is lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin. In certain embodiments, the therapeutic agent is an antihyperglycemic agent. In certain embodiments, the therapeutic agent is glyburide, glipizide, gliclazide, glimepride, a meglitinide, repaglinide, netaglinide, a biguanide, metformin, a thiazolidinedione, an a-glucosidase inhibitor, acarbose, miglitol, glucagon, somatostatin, or diazoxide. In certain embodiments, the therapeutic agent is metformin. In certain embodiments, the therapeutic agent is a thiazolidinedione. In other further embodiments, the therapeutic agent is insulin.

In another embodiment, a method of modulating lipid, cholesterol, triglyceride, insulin or glucose levels in a subject is provided, the method comprising administering to the subject an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

In other further embodiments, the method comprises treating a disease selected from diabetes, hyperglycemia, impaired wound healing, neuropathy, insulin resistance, hyperinsulinemia, hypoinsulinemia, hypertension, hyperlipidemia, hypertriglyceridemia, hyperchlesterolemia, microvascular retinopathy, vascular stenosis, inflammation, hydronephrosis, chronic kidney disease, nonalcoholic fatty liver disease, metabolic syndrome and pancreatitis. In particular embodiments, the disease is diabetes. In other particular embodiments, the disease is hyperglycemia. In other particular embodiments, the disease is insulin resistance. In other particular embodiments, the disease is hyperinsulinemia. In other particular embodiments, the disease is hyperlipidemia.

In other further embodiments, the ratio of high density lipoproteins (HDL) concentration to low density lipoproteins (LDL) concentration in the blood of the subject is increased.

In other further embodiments, the method further comprises administering to the subject a compound that decreases lipid levels in the subject. In certain embodiments, the compound that decreases lipid levels comprises clofibrate, gemfibrozil, fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, cholestyrine, colestipol, probucol, ascorbic acid, asparaginase, clofibrate, colestipol, fenofibrate, or omega-3 fatty acid.

In other further embodiments, the method further comprises administering to the subject a compound that decreases glucose levels in the subject. In certain embodiments, the compound that decreases glucose levels comprises glipizide, exenatide, incretins, sitagliptin, pioglitizone, glimepiride, rosiglitazone, metformin, exantide, vildagliptin, sulfonylurea, glucosidase inhibitor, biguanide, repaglinide, acarbose, troglitazone, or nateglinide.

These and other aspects of the invention will be apparent upon reference to the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows that quercetin-3'-0-sulfate (Q-3 '-sulfate) reduces plasma triglyceride levels in C57BL/6 mice over 13 days of daily treatment.

Figure 2 shows that quercetin-3'-0-sulfate reduces liver triglyceride levels in C57BL/6 mice over 13 days of daily treatment.

Figure 3 shows that quercetin-3'-0-sulfate reduces fed plasma glucose levels in ZDF rats over four weeks of daily treatment.

Figure 4 shows that quercetin-3'-0-sulfate maintains higher fed and fasting insulin level following four weeks of daily treatment.

Figure 5 shows that quercetin-3'-0-sulfate improves glucose tolerance in ZDF rats following four weeks of daily treatment.

Figure 6 shows that quercetin-3'-0-sulfate reduces glycated hemoglobin levels (% HbAlc levels) in ZDF rats following four weeks of daily treatment.

Figure 7 shows that effective doses of quercetin-3'-0-sulfate increases pancreatic insulin levels following four weeks of daily treatment.

Figure 8 shows that quercetin-3'-0-sulfate does not increase terminal liver triglyceride following four weeks of daily treatment, contrary to Rosiglitazone.

Figure 9 shows that quercetin-3'-0-sulfate in combination with Metformin improves glucose tolerance in ZDF rats following two weeks of daily treatment. DETAILED DESCRIPTION

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details.

Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is as "including, but not limited to".

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range.

An "average" as used herein is preferably calculated in a set of normal subjects, this set being at least about 3 subjects, at least about 5 subjects, at least about 10 subjects, at least about 25 subjects, or at least about 50 subjects.

The terms "effective amount" or "pharmaceutically effective amount" refer to a nontoxic but sufficient amount of the agent to provide the desired biological, therapeutic, and/or prophylactic result. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

By "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.The term "subject," "patient" or "individual" as used herein in reference to individuals suffering from a disorder, and the like, encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In some embodiments of the methods and compositions provided herein, the mammal is a human.

The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

The term "pharmaceutical composition," as used herein, refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.

The term "carrier" as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of the compound into cells or tissues.

The term "pharmaceutically acceptable excipient," includes vehicles, adjuvants, or diluents or other auxiliary substances, such as those conventional in the art, which are readily available to the public. For example, pharmaceutically acceptable auxiliary substances include pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like.

As used herein, "percent," "percentage" or the symbol "%" means the percent of the component indicated in the composition based on the amount of the carrier present in the composition, on a weight/weight (w/w), weight/volume (w/v) or volume/volume (v/v), as indicated with respect to any particular component, all based on the amount of the carrier present in the composition. Thus, different types of carriers may be present in an amount of up to 100% as indicated, which does not preclude the presence of the API, the amount of which may be indicated as a % or as a certain number of mg present in the composition or a certain number of mg/mL present, where the % or mg/mL is based on the amount of the total carrier present in the composition. Certain types of carriers may be present in combination to make up 100% of the carrier.

I. Introduction

In brief, the present invention relates generally to the use and composition of quercetin-3'-0-sulfate for therapeutic treatment.

In particular, as noted above, the present invention is directed to the use of quercetin-3'-0-sulfate as a selective adenosine A₃ receptor antagonist. Accordingly, in general embodiments, a method for selectively inhibiting adenosine A₃ receptor activity in an animal is provided, the method comprising administering to the animal an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

In addition, as noted above, in other particular embodiments, the present invention is directed to the use of quercetin-3'-0-sulfate as a side effect modulator. A "side effect modulator" as used herein includes agents that reduce or eliminate one or more side effects of one or more substances. Accordingly, in certain embodiments, a method for reducing or eliminating a side effect associated with the administration of a therapeutic agent to an animal is provided, the method comprising administering to the animal an effective amount of an adenosine A₃ receptor antagonist, wherein the adenosine A₃ receptor antagonist is quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. In other certain embodiments, a method for reducing or eliminating a side effect associated with the administration of a therapeutic agent to an animal is provided, the method comprising administering to the animal an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

Furthermore, as also noted above, in other more particular embodiments, the present invention is directed to the use of quercetin-3'-0-sulfate for the treatment and prevention of metabolic disorders and other diseases. In particular, the use of quercetin-3'-0-sulfate for modulating lipid, cholesterol, triglyceride, insulin or glucose levels.

II. Quercetin-3'-0-sulfate

As noted above, the methods and compositions of the present invention utilize quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

As used herein, "pharmaceutically acceptable salt" includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, /?-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.

In certain embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt is in insolated and purified form. The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

For example, in certain embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity greater than 98%, 98.5%, 99%, 99.5%, 99.7%, 99.8%, 99.9%, 99.99%, 99.999% or greater. In some embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 98%. In some embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99%. In some embodiments, the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99.7%. III. Adenosine Receptor Binding

There are four known subtypes of adenosine receptors (ARs), referred to as Ai, A₂A, A_2B and A₃, each of which has a unique pharmacological profile, tissue distribution and effector coupling. All four subtypes are members of the superfamily of G-protein-coupled receptors. Adenosine A₃ receptors are the most recently identified AR subtype.

In some embodiments, quercetin-3 '-0-sulfate is an adenosine receptor antagonist. In some embodiments, quercetin-3 '-0-sulfate blocks an animal adenosine A₃ receptor. In some embodiments, quercetin-3 '-0-sulfate blocks a human adenosine A₃ receptor. In some embodiments, quercetin-3 '-0-sulfate preferentially inhibits adenosine A₃ receptor versus other adenosine receptor subtypes at clinically relevant concentrations.

Adenosine is an endogenous mediator of afferent arteriole vasoconstriction and glomerular filtration rate (GFR) reduction. In kidney transplant patients, a calcineurin inhibitor (CNI) such as tacrolimus elevates adenosine plasma levels. Such elevation is caused by inhibition of adenosine kinase activity. By blocking the adenosine A₃ receptor, quercetin-3 '-0-sulfate protects against tacrolimus induced vasoconstriction and GFR reduction in animals such as rats and human. The ability of quercetin-3 '-0-sulfate to attenuate CNI -mediated vasoconstriction and GFR reduction reflects short-term (acute) effects of CNI exposure; quercetin-3 '-0-sulfate may attenuate kidney damage caused by chronic CNI exposure that contributes to parenchymal damage, including tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and other pathologic changes. Quercetin-3 '-0-sulfate may also attenuate kidney damage caused by chronic CNI exposure that leads to proteinuria, elevated serum creatinine, and elevated FGF-23.

In some embodiments, quercetin-3 '-0-sulfate reduces calcineurin inhibitor induced vasoconstriction. In some embodiments, quercetin-3 '-0-sulfate reduces tacrolimus induced vasoconstriction. In some embodiments, quercetin-3 '-0- sulfate reduces calcineurin inhibitor induced GFR reduction. In some embodiments, quercetin-3 '-0-sulfate reduces tacrolimus induced GFR reduction. In some embodiments, quercetin-3 '-0-sulfate reduces calcineurin inhibitor induced kidney damage. In some embodiments, quercetin-3'-0-sulfate reduces tacrolimus induced kidney damage. In some embodiments, the kidney damage is induced by chronic CNI exposure that contributes to parenchymal damage, including tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and/or other pathologic changes. In some embodiments, the kidney damage is induced by chronic CNI exposure that leads to proteinuria, elevated serum creatinine, and/or elevated FGF-23.

IV. Substances Whose Effects are Enhanced and/or Whose Side Effects are

Diminished When Combined with Quercetin-3'-0-sulfate or a Pharmaceutically

Acceptable Salt Thereof

In certain embodiments, the invention provides compositions and methods to reduce or eliminate one or more side effects of a substance. The substance may be produced in the subject in a normal or abnormal condition (e.g., beta amyloid in Alzheimer's disease). The substance may be an agent that is introduced into an animal, e.g., a therapeutic agent (e.g., an immunosuppressive to decrease rejection in organ transplant). It will be appreciated that some therapeutic agents are also agents produced naturally in an animal, and the two groups are not mutually exclusive. In some embodiments, the compositions and methods retain or enhance a desired effect of the substance, e.g., a peripheral effect. The methods and compositions of the invention apply to any therapeutic agent for which it is desired to reduce one or more side effects of the agent and/or enhance one or more of the therapeutic effects of the agent. In some embodiments, the compositions and methods of the invention utilize an immunomodulator such as an immunosuppressive agent. In some embodiments, the immunosuppressive agent is a calcineurin inhibitor. In some embodiments, the immunosuppressive is a non-calcineurin inhibitor. It will be appreciated that some agents that have primarily an immunosuppressive effect also have other therapeutic effects, while some agents that have primarily a non-immunosuppressive therapeutic effect also provide some degree of immunosuppression. The invention encompasses these therapeutic agents as well.

Hence, in some embodiments, the methods and compositions of the present invention can be used to modulate the effects of one or more of a variety of therapeutic agents. In some embodiments, the dosage of the therapeutic agent will be modulated according to the effect of the side effect modulator. For instance, less therapeutic agent may be needed to reach optimal effect when co-administered with the side effect modulator. In other embodiments, co-administering the side effect modulator with a therapeutic agent will allow for chronically administering the drug without drug escalation and/or without dependence on the drug. In another embodiment, co-administering the side effect modulator will allow for the elimination of a therapeutic agent from a physiological compartment.

The "side effect" of the therapeutic agent for which modulation is sought may be any effect associated with the agent that occurs in addition to the therapeutic effect. In some embodiments, the compositions and methods of the invention are used to decrease undesirable side effects and or increase desirable side effects or therapeutic effects of a therapeutic agent. Side effects are often specific to the agent, and are well- known in the art for various therapeutic agents. The effect may be acute or chronic. The effect may be biochemical, cellular, at the tissue level, at the organ level, at the multi-organ level, or at the level of the entire organism. The effect may manifest in one or more objective or subjective manners, any of which may be used to measure the effect. Exemplary side effects include hypogonadism (e.g., lowered testosterone), vasoconstriction and hyperglycemia associated with some therapeutic agents, e.g., immunosuppressants agents such as calcineurin inhibitors, e.g., tacrolimus. In some embodiments, the side effect is a renal and/or urogenital side effect, for example, nephrotoxicity, renal function impairment, creatinine increase, proteinuria, hematuria, hypertension, renal allograft rejection, urinary tract infection, oliguria, cystitis haemorrhagic, hemolytic-uremic syndrome or micturition disorder, as well as other effects mentioned herein, or combinations thereof. In some embodiments, the side effect is a hepatic, pancreatic and/or gastrointestinal side effect such as necrosis, hepatotoxicity, fatty liver, venooclusive liver disease, diarrhea, nausea, constipation, vomiting, dyspepsia, anorexia, or LFT abnormal, as well as other effects mention herein, or combinations thereof. In some embodiments, the side effect is selected from calcineurin inhibitor induced new onset diabetes after transplantation, reduced kidney function, proteinuria, hematuria, hypertension and graft failure (such as, tacrolimus induced new onset diabetes after transplantation, reduced kidney function, proteinuria, hematuria, hypertension and graft failure). In some embodiments, the side effect is calcineurin induced renal vasoconstriction (such as, tacrolimus induced renal vasoconstriction).

A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

The term "in need of treatment" encompasses both therapeutic and prophylactic treatment. Thus, for example, and animal would be in need of treatment if the treatment would provide a prophylactic benefit, for instance where the animal is at risk of developing a disease or condition.

The term "physiological compartment" as used herein includes physiological structures, such as organs or organ groups or the fetal compartment, or spaces whereby a physiological or chemical barrier exists to exclude compounds or agents from the internal portion of the physiological structure or space. Such physiological compartments include organs such as kidney and pancreas, and internal structures contained within organs, such as the ovaries and testes.

Therapeutic agents that may be used in compositions and methods of the invention include immunosuppressive agents, such as calcineurin inhibitors (e.g. tacrolimus, sirolimus, and the like), other immunomodulators, antivirals, antibiotics, antineoplastics, amphetamines, antihypertensives, vasodilators, barbiturates, membrane stabilizers, cardiac stabilizers, glucocorticoids, antilipedemics, antiglycemics, cannabinoids, antidipressants, antineuroleptics, chemotherapeutic agents, antiinfectives and non-steriodal anti-inflammatory drugs (NSAIDS), as well as tolerogen, immunostimulants, drugs acting on the blood and the blood-forming organs, hematopoietic agents, growth factors, minerals and vitamins, anticoagulants, thrombolytics, antiplatelet drugs, hormones, hormone antagonists, pituitary hormones, thyroid and antithyroid drugs, estrogen and progestin, androgen, adrenocorticotropic hormones, adrenocortical steroids and synthetic analogs, insulin, oral hypoglycemic agents, calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, and other compounds. Therapeutic agents of use in the invention are further described in U.S. Patent Publication No. US2006/0111308, in particular at paragraphs [0123] - [0164]; and PCT Publication No. WO/06055672, in particular at paragraphs [00109] - [00145].

In some embodiments the therapeutic agent whose side effect is reduced and/or whose effectiveness is improved in the presence of the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is an immunosuppressant. The immunosuppressants can be a cyclosporin (Neoral, Sandimmune, SangCya), an azathioprine (Imuran), a corticosteroid such as prednisolone (Deltasone, Orasone), basiliximab (Simulect), daclizumab (Zenapax), muromonab CD3 (Orthoclone OKT3), tacrolimus (Prograf®), ascomycin, pimecrolimus (Elidel), azathioprine (Imuran), glatiramer acetate (Copaxone), mycophenolate (CellCept), methadone, sirolimus (Rapamune), voclosporin or hydrocortisone.

In some embodiments the therapeutic agent is a calcineurin inhibitor such as tacrolimus (Prograf®).

The therapeutic agent can be a selective estrogen receptor modulator (SERM), such as tamoxifen.

The therapeutic agent can be an antilipidemic agent such as an HMG- CoA inhibitor such as lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin.

The therapeutic agent can be an antihyperglycemic agent (antiglycemic, hypoglycemic agent) such as glyburide, glipizide, gliclazide, or glimepride; a meglitinide such as repaglinide or netaglinide, a biguanide such as metformin, a thiazolidinedione, an a-glucosidase inhibitor such as acarbose or miglitol, glucagon, somatostatin, or diazoxide.

The therapeutic agent can be, in some embodiments, a cannabinoid. The therapeutic agent can be an antidepressant. In some embodiments, antidepressants cause the side effects of high blood sugar and diabetes. The compounds and methods of the invention can be used, for example to reduce these side effects. In some embodiments the therapeutic agent is an antidepressant selected from the group of aripiprazone (Abilify), nefazodone (Serzone), escitalopram oxalate (Lexapro), sertraline (Zoloft), escitalopram (Lexapro), fluoxetine (Prozac), bupropion (Wellbutrin, Zyban), paroxetine (Paxil), venlafaxine (Effexor), trazodone (Desyrel), amitriptyline (Elavil), citalopram (Celexa), duloxetine (Cymbalta), mirtazapine (Remeron), nortriptyline (Pamelor), imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Adapin), trimipramine (Surmontil), amoxapine (Asenidin), desipramine (Norpramin), maprotiline (Ludiomil), protryptiline (Vivactil), citalopram (Celexa), fluvoxamine (Luvox), phenelzine (Nardil), trancylpromine (Parnate), selegiline (Eldepryl).

In some embodiments, the therapeutic agent is an antineuropathic agent such as gabapentin.

The therapeutic agent can be an anticonvulsant. In some cases, it can be an anticonvulsant that also has efficacy in the treatment of pain. The therapeutic agent can be, for example, acetazolamide (Diamox), carbamazepine (Tegretol), clobazam (Frisium), clonazepam (Klonopin/Rivotril), clorazepate (Tranxene-SD), diazepam (Valium), divalproex sodium (Depakote), ethosuximide (Zarontin), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), lorezepam (Ativan), mephenytoin (Mesantoin), metharbital (Gemonil), methsuximide (Celontin). Methazolamide (Neptazane), oxcarbazepine (Trileptal), phenobarbital, phenytoin (Dilantin/Epanutin), phensuximide (Milontin), pregabalin (Lyrica), primidone (Mysoline), sodium valproate (Epilim), stiripentol (Diacomit), tiagabine (Gabitril), topiramate (Topamax), trimethadione (Tridione), valproic acid (Depakene/Convulex), vigabatrin (Sabril), zonisamide (Zonegran), or cefepime hydrochloride (Maxipime). In some embodiments, the compositions and methods of the invention utilize an antihypertensive agent. In some embodiments, the compositions and methods of the invention utilize an immunosuppressive agent. The therapeutic agent may also be a chemotherapeutic agent, a vasodilator, a cardiac glycoside, a diuretic agent, a bronchodilator, a corticosteroid, a sedative-hypnotic, an antiepileptic drug, a general anesthetic, a skeletal muscle relaxant, an antipsychotic agent, an anti-hyperlipidemic agent, a non-steroidal antiinflammatory drug, an antidiabetic agent, an antimicrobial agent, an antifungal agent, an antiviral agent, or an antiprotozoal agent. It will be appreciated that there is some overlap between these groups, e.g., some agents that have primarily an immunosuppressive effect also have other therapeutic effects, while some agents that have primarily a non-immunosuppressive effect also provide some degree of analgesia. The invention encompasses these therapeutic agents as well. Additional suitable drugs may be found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.

In some embodiments, the therapeutic agent is an immunomodulator, e.g., an immunosuppressive agent such as a calcineurin inhibitor. In some embodiments, the compositions and methods of the invention utilize cyclosporin A (CsA). In some embodiments, the compositions and methods of the invention utilize tacrolimus. In some embodiments, the calcineurin inhibitor is tacrolimus analog. In some embodiments, the tacrolimus analog is selected from the group consisting of meridamycin, 31-O-Demethyl-FK506; L-683,590, L-685,818; 32-0-(l- hydroxyethylindol-5-yl)ascomycin; ascomycin; C18-OH-ascomycin; 9-deoxo-31-0- demethyl-FK506; L-688,617; A-l 19435; AP1903; rapamycin; dexamethasone-FK506 heterodimer; 13-O-demethyl tacrolimus; and FK 506-dextran conjugate. In some embodiments, the immunosuppressive agent is sirolimus, tacrolimus, mycophenolate, methadone, cyclosporin, prednisone, voclosporin or hydrocortisone. V. Compositions In certain embodiments, the invention provides compositions in discrete dosage form comprising quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. The term "discrete dosage form" as used herein refers to physically discrete units suited as unitary dosages for the individuals to be treated. That is, the compositions are formulated into discrete dosage units each containing a predetermined, "unit dosage" of an active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

As disclosed herein, in certain embodiments, such compositions may be utilized to reduce or eliminate a side effect of one or more therapeutic agents. Accordingly, in certain embodiments, the quercetin-3 '-0-sulfate or a pharmaceutically acceptable salt thereof and the therapeutic agent are co-administered. "Coadministration," "administered in combination with," and their grammatical equivalents, as used herein, encompasses administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present, and combinations thereof.

In some embodiments, the invention provides a composition containing a therapeutic agent and quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, where the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to decrease a side effect of the therapeutic agent by a measurable amount, compared to the side effect without the quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof, when the composition is administered to an animal. In some embodiments, a side effect of the therapeutic agent is decreased by an average of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95%, compared to the side effect without the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. In some embodiments, a side effect is substantially eliminated compared to the side effect without the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. "Substantially eliminated" as used herein encompasses no measurable or no statistically significant side effect (one or more side effects) of the therapeutic agent, when administered in combination with the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

In some embodiments, the quercetin-3'-0 -sulfate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to decrease a side effect of the therapeutic agent by a measurable amount and to increase a therapeutic effect of the therapeutic agent by a measurable amount, compared to the side effect and therapeutic effect without the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof when the composition is administered to an animal. In some embodiments, a therapeutic effect of the therapeutic agent is increased by an average of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95%, compared to the therapeutic effect without the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. An "average" as used herein is preferably calculated in a set of normal human subjects, this set being at least about 3 human subjects, preferably at least about 5 human subjects, preferably at least about 10 human subjects, even more preferably at least about 25 human subjects, and most preferably at least about 50 human subjects.

In some embodiments, the invention provides a composition that contains quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and a therapeutic agent. In some embodiments, the concentration of the therapeutic agent is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v in the composition. In some embodiments, the concentration of the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001 ) w/w, w/v or v/v in the composition.

In some embodiments, the concentration of the therapeutic agent is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v in the composition. In some embodiments, the concentration of the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is greater than 90%>, 80%>, 70%>, 60%>, 50%>, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v in the composition.

In some embodiments, the concentration of the therapeutic agent is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10%> w/w, w/v or v/v. v/v in the composition. In some embodiments, the concentration of the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%), approximately 1% to approximately 10%> w/w, w/v or v/v. v/v in the composition.

In some embodiments, the concentration of the therapeutic agent is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9%> w/w, w/v or v/v in the composition. In some embodiments, the concentration of the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1%) to approximately 0.9%> w/w, w/v or v/v in the composition.

In some embodiments, the amount of the therapeutic agent is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g in the composition. In some embodiments, the amount of the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g in the composition.

In some embodiments, the amount of the therapeutic agent is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, , 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g in the composition. In some embodiments, the amount of the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, , 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g in the composition.

In some embodiments, the amount of the therapeutic agent is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5- 4 g, or 1-3 g in the composition. In some embodiments, the amount of the quercetin-3'- O-sulfate or a pharmaceutically acceptable salt thereof is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g in the composition.

In some embodiments, a molar ratio of the therapeutic agent to the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof can be 0.0001:1 to 1:1. Without limiting the scope of the invention, the molar ratio of one or more of the therapeutic agents to the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof can be about 0.0001:1 to about 10:1, or about 0.001:1 to about 5:1, or about 0.01:1 to about 5: 1, or about 0.1:1 to about 2:1, or about 0.2:1 to about 2:1, or about 0.5:1 to about 2: 1 , or about 0.1:1 to about 1:1. Without limiting the scope of the present invention, the molar ratio of one or more of the therapeutic agents to the quercetin-3'- O-sulfate or a pharmaceutically acceptable salt thereof can be about 0.03xl0^"5:l, 0.04xl0^"5:l, 0.1xl0^"5:l, 0.2xl0^"5:l, 0.3xl0^"5:l, 0.4xl0^"5:l, 0.5xl0^"5:l, 0.8xl0^"5:l, 0.1xl0^"4:l, 0.2xl0^"4:l, 0.3xl0^"4:l, 0.4xl0^"4:l, 0.5xl0^"4:l, 0.8xl0^"4:l, 0.1xl0^"3:l, 0.2x10^" ³:1, 0.3xl0^"3:l, 0.4xl0^"3:l, 0.5xl0^"3:l, 0.8xl0^"3:l, 0.1xl0^~2:l, 0.2xl0^~2:l, 0.3xl0^~2:l, 0.4xl0^~2:l, 0.5xl0^"2:l, 0.6xl0^"2:l, 0.8xl0^"2:l, 0.01:1, 0.1:1; 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 2:1, 3:1, 4:1, or 5:1.

As further disclosed herein, in certain embodiments, compositions comprising quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be utilized in the treatment and prevention of metabolic disorders and other diseases. In particular, such compositions may be utilized for modulating lipid, cholesterol, triglyceride, insulin or glucose levels.

In some embodiments, the quercetin-3'-0 -sulfate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to exert a therapeutic effect and decrease hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia, and/or one or more symptoms thereof, by a measurable amount, compared to no treatment. In some embodiments, the measurable amount is by an average of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95%, compared to no treatment. In some embodiments, the measurable amount is by an average of at least about 5%, about 10%>, about 15%, or about 20%, compared to no treatment.

In some embodiments, the symptom of hyperglycemia, hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia that is reduced upon administration of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof includes, but are not limited to, xanthoma, skin lesion, pancreatitis, enlargement of liver and spleen, chest pain, heart attack or a combination thereof.

In some embodiments, the symptom of hyperglycemia that is reduced includes, but is not limited to, glucosuria, polyphagia, polyuria, polydipsia, loss of consciousness, blurred vision, headaches, coma, ketoacidosis, decrease in blood volume, decrease in renal blood flow, accelerated lipolysis, weight loss, stomach problems, intestinal problems, poor wound healing, dry mouth, nausea, vomiting, dry skin, itchy skin, impotence, hypeventilation, ketoanemia, fatigue, weakness on one side of the body, hallucinations, impairment in cognitive function, increase sadness, anxiety, recurrent genital infections, increase sugar in urine, retinopathy, nepropathy, arteriosclerotic disorders, cardiac arrhythmia, stupor, susceptibility to infection, neuropathy, nerve damages causing cold feet, nerve damage causing insensitive feet and loss of hair. In some embodiments, the symptom of hyperglycemia is glucosuria.

"Substantially eliminated" as used herein encompasses no measurable or no statistically significant symptom (one or more symptoms) of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia as disclosed herein. The amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof for use in such compositions may be equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

Alternatively, the amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof for use in such compositions may be more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

The amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof for use in such compositions may be in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof for use in such compositions may be in the range of about 1-1000 mg, about 10-1000 mg, about 50-1000 mg, about 100-1000 mg, about 1-500 mg, about 5-500 mg, about 50-500 mg, about 100-500 mg, about 200-1000 mg, about 200-800 mg, or about 200-700 mg. Quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may present in an amount of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some embodiments, the compositions disclosed herein further include a pharmaceutical excipient. In some embodiments, the quercetin-3'-0 -sulfate or a pharmaceutically acceptable salt thereof may be administered to an animal alone or in combination with one or more other agents of one or more other forms to have a biological effect on lipid, triglyceride or glucose levels in the animal. Such combination may comprise agents including but not limited to chemical compounds, nucleic acids (i.e., DNA, R A), proteins, peptides, peptidomimetics, peptoids, or any other forms of a molecule. The agents in a combination may be administered to an animal simultaneously or sequentially. These agents in a combination may be of any category of agents mentioned herein, and may interact with each other in a synergistic or additive manner to exert a biological effect or effects. The synergy between the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and the agents can potentially allow a reduction in the dose required for each agent, leading to a reduction in the side effects and enhancement of the clinical utility of these agents.

In other embodiments, compositions comprise quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof with a compound that lowers lipid levels (i.e. lipid-lowering compound). The lipid- lowering compound may be present in an amount sufficient to exert an therapeutic effect and the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be present in an amount sufficient to decrease hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and/or one or more symptoms thereof by a measurable amount, compared to treatment without the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof when administered to an animal.

The symptom measured may be any symptom as described herein. In some embodiments, the symptom that is reduced includes, but is not limited to, xanthoma, skin lesion, pancreatitis, enlargement of liver and spleen, chest pain, heart attack or a combination thereof. The measurable amount may be an average of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95% as described herein.

A lipid-lowering compound may be a compound that lowers the level of cholesterol in a subject (i.e. cholesterol-lowering compound). Cholesterol-lowering compounds include, but are not limited to, clofibrate, gemfibrozil, and fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, cholestyrine, colestipol or probucol.

A lipid-lowering compound may be a compound that lowers the level of triglyceride in a subject (i.e. triclyceride-lowering compounds). Triglyceride-lowering compounds include, but are not limited to, ascorbic acid, asparaginase, clofibrate, colestipol, fenofibrate mevastatin, pravastatin, simvastatin, fluvastatin, or omega-3 fatty acid. A lipid-lowering compound may also be a compound that lowers the level of LDL-cholesterol in a subject.

Atorvastatin (marketed under the name Lipitor, Lipidra, Aztor, Torvatin, Sortis, Torvast, Torvacard, Totalip, Tulip, Xarator, Atorpic, Liprimar, Atorlip and other names), is a member of the drug class known as statins, used for lowering blood cholesterol. Atorvastatin inhibits the rate-determining enzyme located in hepatic tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and other mevalonate derivatives. This lowers the amount of cholesterol produced which in turn lowers the total amount of LDL cholesterol. As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. It is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol. In clinical trials, adding ezetimibe (Zetia) to Lipitor lowered cholesterol more effectively than Vytorin (ezetimibe + simvastatin). Atorvastatin is indicated as an adjunct to diet for the treatment of dyslipidemia, specifically hypercholesterolaemia. It has also been used in the treatment of combined hyperlipidemia (Rossi S, editor. Australian Medicines Handbook 2006).

Atorvastatin calcium tablets are currently marketed by Pfizer under the trade name Lipitor®, in tablets (10, 20, 40 or 80 mg) for oral administration. Tablets are white, elliptical, and film coated. Pfizer also packages the drug in combination with other drugs, such as is the case with its Caduet. Lipitor In most cases, the recommended Lipitor dosage for patients who are just starting the medication is Lipitor 10 mg to 20 mg once a day; however, some people may start on Lipitor 40 mg once a day if their cholesterol is extremely high. The recommended Lipitor dosage for children ages 10 to 17 is begins at Lipitor 10 mg once a day; the maximum recommended dose for children is Lipitor 20 mg.

Drugs that decrease triglyceride level include but are not limited to ascorbic acid, asparaginase, clofibrate, colestipol, fenofibrate mevastatin, pravastatin, simvastatin, fluvastatin, or omega-3 fatty acid. Drugs that decrease LDL cholesterol level include but are not limited to clofibrate, gemfibrozil, and fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, cholestyrine, colestipol or probucol.

In some embodiments, compositions comprise quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof wherein the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to decrease the concentration of lipid including but not limited to cholesterol and triglyceride in a physiological compartment by a measurable amount, compared to the concentration without the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof when the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered to an animal. The measurable amount may be an average of at least about 5%, 10%, 15%, 20%, or more than 20%. In some embodiments, the physiological compartment is a lipid accumulating cell or cell membrane including but not limited to macrophage, muscle cell, or adipocyte. In other embodiments, the physiological compartment is a pancreatic islet cell including β cell. In still other embodiments, the physiological compartment is a hepatocyte. Other examples of physiological compartments include, but are not limited to, blood, brain, liver, lymph nodes, spleen, Peyer's patches, intestines, lungs, heart, pancreas and kidney.

The concentration of one or more of the lipid-lowering compounds and/or quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

Alternatively, the concentration of one or more of the lipid-lowering compounds and/or quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In other embodiments, compositions comprise quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof with a compound that lowers glucose levels (i.e. a glucose-lowering compound).

The glucose-lowering compound may be present in an amount sufficient to exert a therapeutic effect and the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be present in an amount sufficient to decrease hyperglycemia and/or one or more symptoms thereof by a measurable amount, compared to treatment without the quercetin-3 '-0-sulfate or a pharmaceutically acceptable salt thereof when the composition is administered to an animal. The measurable amount may be an average of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95%.

The symptom of hyperglycemia may be any symptom as described herein including, but not limited to, glucosuria, polyphagia, polyuria, polydipsia, loss of consciousness, blurred vision, headaches, coma, ketoacidosis, decrease in blood volume, decrease in renal blood flow, accelerated lipolysis, weight loss, stomach problems, intestinal problems, poor wound healing, dry mouth, nausea, vomiting, dry skin, itchy skin, impotence, hypeventilation, ketoanemia, fatigue, weakness on one side of the body, hallucinations, impairment in cognitive function, increase sadness, anxiety, recurrent genital infections, increase sugar in urine, retinopathy, nepropathy, arteriosclerotic disorders, cardiac arrhythmia, stupor, susceptibility to infection, neuropathy, nerve damages causing cold feet, nerve damage causing insensitive feet and loss of hair. In one embodiment, the symptom of hyperglycemia is glucosuria.

Glucose-lowering compounds include, but are not limited to, glipizide, exenatide, incretins, sitagliptin, pioglitizone, glimepiride, rosiglitazone, metformin, exantide, vildagliptin, sulfonylurea, glucosidase inhibitor, biguanide, repaglinide, acarbose, troglitazone, nateglinide, or a variant thereof.

The medication class of thiazolidinedione (also called glitazones) has been used as an adjunctive therapy for hyperglycemia and diabetes mellitus (type 2) and related diseases. Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), specifically PPARy (gamma). The normal ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes. Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include but are not limited to Rosiglitazone (Avandia) and Pioglitazone (Actos). For pioglitazone, the oral dosage for monotherapy is 15-30 mg once daily; if response is inadequate, the dosage may be increased in increments up to 45 mg once daily. The maximum recommended dose is 45 mg once daily. For combination therapy, the maximum recommended dose is 45 mg/day.

Drugs that decrease glucose level include but are not limited to glipizide, exenatide, incretins, sitagliptin, pioglitizone, glimepiride, rosiglitazone, metformin, exantide, vildagliptin, sulfonylurea, glucosidase inhibitor, biguanide, repaglinide, acarbose, troglitazone, and nateglinide.

The concentration of one or more of the glucose-lowering compounds and/or quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001 % w/w, w/v or v/v.

Alternatively, the concentration of one or more of the glucose-lowering compounds and/or quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

When the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and the lipid or glucose lowering compounds are used in combination, both components may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

A. Pharmaceutical Compositions

The compositions comprising quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof of the invention are usually administered in the form of pharmaceutical compositions. The therapeutic agents described above are also administered in the form of pharmaceutical compositions. When quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and a therapeutic agent are used in combination, both components may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

This invention further provides pharmaceutical compositions that contain, as the active ingredient, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof which acts as a side effect modulator, a therapeutic agent or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

Such compositions are prepared in a manner well known in the pharmaceutical art.

Pharmaceutical compositions for oral administration

Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre- gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the therapeutic agent and/or quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof and to minimize precipitation of the therapeutic agent and/or quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, .epsilon.- caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N- alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

The oral formulation can be an aqueous liquid for oral administration, or may be a solid formulation that is produced by drying the aqueous composition, for example by freeze-drying or lyophilization. Once the aqueous composition is dried, it can be handled, for example, as a dried powder. The dried powder can be further formulated into oral pharmaceutical compositions as described herein.

Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. Pharmaceutical compositions for injection

The forms in which the compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof and/or the therapeutic agent in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Other pharmaceutical compositions

Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for inhalation, topical (e.g., transdermal) delivery, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

B. Kits

The invention also provides kits. The kits include quercetin-3 '-0-sulfate or a pharmaceutically acceptable salt thereof and a therapeutic agent that has a side effect, in suitable packaging. The kits may include quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, in suitable packaging. Other components that may be included are written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. In some embodiments, the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and the therapeutic agent are provided as separate compositions in separate containers within the kit. In some embodiments, the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and the therapeutic agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. VI. Methods

In certain embodiments, the invention provides methods, including methods of treatment, methods of decreasing the concentration of a substance in a physiological compartment, methods of enhancing a therapeutic effect of a substance, and methods of reducing a side effect of a substance. The term "animal" or "animal subject" as used herein includes humans as well as other mammals. The methods generally involve the administration of one or more drugs for the treatment of one or more diseases. Combinations of agents can be used to treat one disease or multiple diseases or to modulate the side-effects of one or more agents in the combination.

The term "treating" and its grammatical equivalents as used herein include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

In certain embodiments, the invention provides a method for reducing or eliminating a side effect associated with the administration of a therapeutic agent to an animal, comprising administering to the animal an effective amount of quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof as a side effect modulator. In some embodiments, the side effect modulator reduces or eliminates a plurality of side effects of the therapeutic agent. In some embodiments the animal is a mammal, e.g., a human.

In certain embodiments, the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and the therapeutic agent are co-administered. Typically, the therapeutic agent is present in the composition in an amount sufficient to produce a therapeutic effect, and the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is present in the composition in an amount sufficient to reduce a side effect of the therapeutic agent. In some embodiments, the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is present in an amount sufficient to decrease a side effect of the therapeutic agent by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or substantially eliminate a side effect compared to the effect without the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. Administration of the therapeutic agent and the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be any suitable means. If the agents are administered as separate compositions, they may be administered by the same route or by different routes. If the agents are administered in a single composition, they may be administered by any suitable route. In some embodiments, the agents are administered as a single composition by oral administration. In some embodiments, the agents are administered as a single composition by transdermal administration. In some embodiments, the agents are administered as a single composition by injection.

The methods of the invention may be used for treatment of any suitable condition, e.g., diseases of the heart, circulation, lipoprotein metabolism, hemostasis and thrombosis, respiratory system, kidney, gastrointestinal tract, endocrine system, reproductive system, or hemopoeitic system, where one or more therapeutic agents are used that have a side effect. For example, in some embodiments, the methods of the invention include the treatment of hypertension in an animal by administering to an animal in need of treatment an effective amount of an antihypertensive and an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof that reduces or eliminates a side effect of the hypertensive. Another exemplary embodiment is the treatment of graft rejection in an animal by administering to an animal in need of prevention or treatment an effective amount of an immunosuppressive agent, e.g., an calcineurin inhibitor such as sirolimus or tacrolimus, and an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof that reduces or eliminates a side effect or endocrine effect of the immunosuppressive agent. Another exemplary embodiment is the prevention of organ rejection in an animal by administering to an animal that has received or will receive an organ transplant an effective amount of a calcineurin inhibitor such as tacrolimus or a tacrolimus analog and an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof that reduces or eliminates a side effect, e.g., a hyperglycemic effect or a side effect of the calcineurin inhibitor.

When a therapeutic agent and quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof that reduces or eliminates a side effect of the therapeutic agent are used in combination, any suitable ratio of the two agents, e.g., molar ratio, wt/wt ratio, wt/volume ratio, or volume/volume ratio, as described herein, may be used.

In some embodiments of the methods of the invention, the invention provides a method of treating a condition by administering to an animal suffering from the condition an effective amount of tacrolimus and an amount of quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof sufficient to change the concentration of tacrolimus in a physiological compartment. In some embodiments of the methods of the invention the physiological compartment is selected from the group consisting of blood, lymph nodes, spleen, peyer's patches, lungs, heart, kidney, pancreas, liver, and gull bladder. In some embodiments, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof decrease the clearance of tacrolimus from a compartment where the drug is exerting therapeutic effect.

The methods of the invention involve the administration of quercetin-3'- O-sulfate or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutic agent that produces a side effect is administered in combination with quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof that reduces a side effect of the therapeutic agent. In some embodiments, other agents are also administered, e.g., other therapeutic agents. When two or more agents are coadministered, they may be co-administered in any suitable manner, e.g., as separate compositions, in the same composition, by the same or by different routes of administration.

In some embodiments, the quercetin-3'-0 -sulfate or a pharmaceutically acceptable salt thereof is administered in a single dose. In some embodiments, the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In one embodiment the therapeutic agent is an immunosuppressive. In another embodiment the immunosuppressive compound and quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof are administered together about once per day to about 6 times per day. In another embodiment the administration of the immunosuppressive compound and quercetin-3'- O-sulfate or a pharmaceutically acceptable salt thereof continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary, e.g., intravenous administration of immunosuppressive in a post-operative situation.

An effective amount of quercetin-3 '-O-sulfate or a pharmaceutically acceptable salt thereof and an effective amount of a drug may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

The quercetin-3 '-O-sulfate or a pharmaceutically acceptable salt thereof and the therapeutic agent may be administered in dosages as described herein (see, e.g., Compositions). Dosing ranges for therapeutic agents are known in the art. Dosing for the quercetin-3 '-O-sulfate or a pharmaceutically acceptable salt thereof may be found by routine experimentation. For quercetin-3 '-O-sulfate or a pharmaceutically acceptable salt thereof, typical daily dose ranges are, e.g. about 1-5000 mg, or about 1- 3000 mg, or about 1-2000 mg, or about 1-1000 mg, or about 1-500 mg, or about 1-100 mg, or about 10-5000 mg, or about 10-3000 mg, or about 10-2000 mg, or about 10- 1000 mg, or about 10-500 mg, or about 10-200 mg, or about 10-100 mg, or about 20- 2000 mg or about 20-1500 mg or about 20-1000 mg or about 20-500 mg, or about 20- 100 mg, or about 50-5000 mg, or about 50-4000 mg, or about 50-3000 mg, or about 50- 2000 mg, or about 50-1000 mg, or about 50-500 mg, or about 50-100 mg, about 100- 5000 mg, or about 100-4000 mg, or about 100-3000 mg, or about 100-2000 mg, or about 100-1000 mg, or about 100-500 mg. In some embodiments, the daily dose of quercetin-3 '-O-sulfate or a pharmaceutically acceptable salt thereof is about 3, 5, 10, 20, 30, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg. In some embodiments, the quercetin-3 '-O-sulfate or a pharmaceutically acceptable salt thereof is administered two to three times a day with an oral dose of about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg, or an intravenous dose of about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.. In some embodiments, the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered about one hour or about 30 minutes prior to administration of the therapeutic agent. In some embodiments, the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered such that it is in the bloodstream 30 minutes prior to administration of the therapeutic agent. This timing may be accomplished by administering the quercetin-3 '-0-sulfate or a pharmaceutically acceptable salt thereof and the therapeutic agent separately, or by administering the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and agent in the same composition that is formulated such that quercetin-3'-0 -sulfate or a pharmaceutically acceptable salt thereof reaches the bloodstream before the therapeutic agent.

Also disclosed herein are methods for regulating, preventing, and treating one or more of: cholesterol, chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), high density lipoprotein (HDL), hyperlipidemia, hypercholesterolemia, triglycerides, hypertriglyceridemia, lipid transport, glucose intolerance, hyperglycemia, diabetes mellitus, atherosclerosis, hypertension, liver diseases, pancreatitis, obesity, kidney diseases, Niemann-Pick disease, cardiovascular disease, hypoinsulinemia, insulin resistance, vascular sentosis, inflammation, or development of atherosclerotic plaques by administering an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents (e.g., lipid-lowering agents or glucose lowering agents).

Provided herein is a method of maintaining cellular physiological conditions for cell survival, comprising administering to a subject an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. Provided herein is a method of maintaining cellular physiological conditions for pancreatic islet cell survival, comprising administering to a subject an effective amount of quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof. Provided herein is a method of treating pancreatic cell stress or injury comprising administering to a subject an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, wherein at least one effect of stress or injury is improved in one or more cell types of the subject.

In one embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates insulin levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates glucose levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates triglyceride levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates body weight in the subject. In another embodiment, quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof modulates fat weight in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates adiponectin levels in the subject. In another embodiment, quercetin- 3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates cholesterol in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates high density lipoprotein levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates medium density lipoprotein levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates low density lipoprotein levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates very low density lipoprotein levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates prostaglandin levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates development of cancer in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates inflammation mediator levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates cytokine levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates foam cell levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates development of atherosclerotic streaks in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates development of atherosclerotic plaques in the subject. In yet another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates development of vascular stenosis in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates HbAlC levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates phospholipid levels in the subject. In another embodiment, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof modulates surfactant levels in the subject.

Glycated hemoglobin (HbAlC) is a form of hemoglobin used primarily to identify the average plasma glucose concentration over prolonged periods of time. It is formed in a non-enzymatic pathway by hemoglobin's normal exposure to high plasma levels of glucose. A high HbAlc represents poor glucose control. Higher levels of HbAlc are found in people with persistently elevated blood sugar, as in diabetes mellitus.

Adiponectin (also referred to as Acrp30, apMl) is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism. Adiponectin is secreted from adipose tissue into the bloodstream and is abundant in plasma relative to many hormones. Levels of the hormone are inversely correlated with body fat percentage in adults, while the association in infants and young children is more unclear. The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes, obesity, atherosclerosis and non- alcoholic fatty liver disease (NAFLD).

Somatostatin (also known as growth hormone inhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF)) is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin has two active forms produced by alternative cleavage of a single preproprotein: one of 14 amino acids, the other of 28 amino acids. Somatostatin suppresses the release of pancreatic hormones (i.e., inhibits the release of insulin and glucagon).

Glucagon helps maintain the level of glucose in the blood by binding to glucagon receptors on hepatocytes, causing the liver to release glucose - stored in the form of glycogen - through a process known as glycogeno lysis. As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by gluconeogenesis. This glucose is released into the bloodstream. Both of these mechanisms lead to glucose release by the liver, preventing the development of hypoglycemia. Glucagon also regulates the rate of glucose production through lipolysis.

Ghrelin is a hormone that signals appetite and stimulates food intake.

Ghrelin is known to exist in at least two forms: 1) n-octanoyl ghrelin in which the third serine residue is n-octanoylated and 2) des-n-octanoyl ghrelin in which the n-octanoyl group is removed. Ghrelin is the first identified peripheral hormone signaling appetite. People who were given ghrelin increased their appetite resulting in up to one third more food intake than control subjects. In addition to stimulating food intake, ghrelin levels drop once an individual starts eating. Consequently, ghrelin may act as a trigger to start food intake; ghrelin levels do not fall after eating in obese individuals which suggests that this trigger is not reset in such individuals.

Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide. This peptide belongs to a family of structurally related, small polypeptides that includes helodermin, secretin, the somatostatins, and glucagon. The biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cAMP signaling system. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the secretin/glucagon/vasoactive intestinal polypeptide (VIP) family. The physiological function of the peptide is responsible for diverse roles such as the regulating actions on hormonal synthesis and secretion in pituitary and adrenal medulla, and the differentiation and growth-promoting actions of nerve cells and germ cells. PACAP immuno-positive nerve projects into islets; the expressions of a PAC1 receptor displaying high affinity to PACAP among PACAP receptor subtypes and a VPAC2 receptor displaying nearly equal affinities to both of PACAP and VIP are observed in pancreatic beta cells; and (c) PACAP promotes the glucose-inducible insulin secretion by the isolated islet at a low level.

In the methods disclosed herein, cells can be pancreatic islet cells. Pancreatic islet cells may be damaged or subject to destruction such as, for example, by apoptosis, necrosis and/or autophagy.

Provided herein is a method of assessing cellular protective effects in pancreatic islet cells, comprising: i) selecting a patient for treatment based on one or more biomolecule levels in a sample compared to a control sample; ii) administering an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof to a subject; and iii) monitoring said one or more biomolecule levels in a subject. Biomolecules include, but are not limited to, insulin, somatostatin, glucagon, grehlin, VIP, glucose, and adiponectin. In one embodiment, insulin levels are stable and do not decrease.

Certain biomarkers (biomolecules) can be expressed at increased or decreased levels in response to administration of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof to a patient.

LIPID SYNTHESIS AND TRANSPORT

Cholesterol regulation

Cholesterol is a lipid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes where it is required to establish proper membrane permeability and fluidity. Cholesterol is the principal sterol synthesized by animals while smaller quantities are synthesized in other eukaryotes such as plants and fungi. In contrast cholesterol is almost completely absent among prokaryotes. Most cholesterol is synthesized by the body but significant quantities can also be absorbed from the diet. While minimum level of cholesterol is essential for life, excess can contribute to diseases such as atherosclerosis.

Since cholesterol is insoluble in blood, it is transported in the circulatory system within lipoproteins, complex spherical particles which have an exterior composed mainly of water-soluble proteins; fats and cholesterol are carried internally. There is a large range of lipoproteins within blood, generally called, from larger to smaller size: chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). The cholesterol within all the various lipoproteins is identical. Cholesterol is minimally soluble in water; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by lipoproteins that are water-soluble and carry cholesterol and triglycerides internally. The apolipoproteins forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied.

Cholesterol is transported towards peripheral tissues by the lipoproteins chylomicrons, very low density lipoproteins (VLDL) and low-density lipoproteins (LDL). Large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of atheromatous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol". On the other hand, high-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion. In contrast, having small numbers of large HDL particles is independently associated with atheromatous disease progression within the arteries.

Chylomicrons

Chylomicrons are the largest (1000 nm) and least dense (<0.95) of the lipoproteins. They contain only 1-2% protein, 85-88% triglycerides, ~8% phospholipids, ~3% cholesteryl esters and ~1% cholesterol. Chylomicrons contain several types of apolipoproteins including apo-AI, II & IV, apo-B48, apo-CI, II & III, apo-E and apo-H. Chylomicrons are produced for the purpose of transporting dietary triglycerides and cholesterol absorbed by intestinal epithelia. Chylomicron assembly originates in the intestinal mucosa. Excretion into the plasma is facilitated through the lymphatic system. In the plasma, chylomicrons acquire apo-CII and apo-E from HDL. Once transported to tissues, triglycerides contained in chylomicrons are hydrolyzed by apo-CII-dependent activation of lipoprotein lipase contained on the endothelial cell walls. The chylomicron remnant, including residual cholesterol, is taken up by the liver via receptor-mediated endocytosis by recognition of its apo-E component. Very Low Density Lipoproteins (VLDL)

Very low density lipoproteins are the next step down from chylomicrons in terms of size and lipid content. They are approximately 25-90 nm in size (MW 6-27 million), with a density of -0.98. They contain 5-12% protein, 50-55% triglycerides, 18-20%) phospholipids, 12-15%) cholesteryl esters and 8-10% cholesterol. VLDL also contains several types of apolipoproteins including apo-B100, apo-CI, II & III and apo- E. VLDL also obtains apo-CII and apo-E from plasma HDL. VLDL assembly in the liver involves the early association of lipids with apo-B100 mediated by microsomal triglyceride transfer protein while apo-B100 is translocated to the lumen of the ER. Lipoprotein lipase also removes triglycerides from VLDL in the same way as from chylomicrons.

Intermediate Density Lipoproteins (IDL)

Intermediate density lipoproteins are smaller than VLDL (40 nm) and more dense (~1.0). They contain the same apolipoproteins as VLDL. They are composed of 10-12% protein, 24-30%) triglycerides, 25-27%) phospholipids, 32-35%> cholesteryl esters and 8-10% cholesterol. IDLs are derived from triglyceride depletion of VLDL. IDLs can be taken up by the liver for reprocessing, or upon further triglyceride depletion, become LDL.

Low Density Lipoproteins (LDL) and Lipoprotein (a)

Low density lipoproteins are smaller than IDL (26 nm) (MW approximately 3.5 million) and more dense (-1.04). They contain the apolipoprotein apo-B100. LDL contains 20-22%> protein, 10-15%) triglycerides, 20-28%> phospholipids, 37-48% cholesteryl esters and 8-10% cholesterol. LDL and HDL transport both dietary and endogenous cholesterol in the plasma. LDL is the main transporter of cholesterol and cholesteryl esters and makes up more than half of the total lipoprotein in plasma. LDL is absorbed by the liver and other tissues via receptor mediated endocytosis. The cytoplasmic domain of the LDL receptor facilitates the formation of coated pits; receptor-rich regions of the membrane. The ligand binding domain of the receptor recognizes apo-B100 on LDL, resulting in the formation of a clathrin-coated vesicle. ATP-dependent proton pumps lower the pH inside the vesicle resulting dissociation of LDL from its receptor. After loss of the clathrin coat the vesicles fuse with lysozomes, resulting in peptide and cholesteryl ester enzymatic hydrolysis. The LDL receptor can be recycled to the cell membrane. Insulin, tri-iodothyronine and dexamethasome have shown to be involved with the regulation of LDL receptor mediated uptake.

High Density Lipoproteins

High density lipoproteins are the smallest of the lipoproteins (6-12.5 nm) (MW 175-500KD) and most dense (-1.12). HDL contains several types of apolipoproteins including apo-AI, II & IV, apo-CI, II & III, apo-D and apo-E. HDL contains approximately 55% protein, 3-15% triglycerides, 26-46%) phospholipids, 15- 30%o cholesteryl esters and 2-10% cholesterol. HDL is produced as a protein rich particle in the liver and intestine, and serves as a circulating source of Apo-CI & II and Apo-E proteins. The HDL protein particle accumulates cholesteryl esters by the esterification of cholesterol by lecithin-cholesterol acyl-transferase (LCAT). LCAT is activated by apo-AI on HDL. HDL can acquire cholesterol from cell membranes and can transfer cholesteryl esters to VLDL and LDL via transferase activity in apo-D. HDL can return to the liver where cholesterol is removed by reverse cholesterol transport, thus serving as a scavenger to free cholesterol. The liver can then excrete excess cholesterol in the form of bile acids. In a normal fasting individual, HDL concentrations range from 1.0-2.0 g/L.

Hyperlipidemia

Hyperlipidemia is an elevation of lipids in the bloodstream. These lipids include cholesterol, cholesterol esters, estersphospholipids and triglycerides. Lipid and lipoprotein abnormalities are considered as a highly modifiable risk factor for cardiovascular disease due to the influence of cholesterol, one of the most clinically relevant lipid substances, on atherosclerosis. In addition, some forms may predispose to acute pancreatitis. Hypercholesterolemia

Hyperchlesterolemia refers to an abnormally high cholesterol level. Higher concentrations of LDL and lower concentrations of functional HDL are strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke and peripheral vascular disease. Since higher blood LDL, especially higher LDL particle concentrations and smaller LDL particle size, contribute to this process more than the cholesterol content of the LDL particles, LDL particles are often termed "bad cholesterol" because they have been linked to atheroma formation. On the other hand, high concentrations of functional HDL, which can remove cholesterol from cells and atheroma, offer protection and are sometimes referred to colloquially as "good cholesterol".

Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated with atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have been identified as a mechanism by which cholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression.

Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration.

Multiple human trials utilizing HMG-CoA reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults. As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels.

The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be: < 200 mg/dL normal blood cholesterol, 200-239 mg/dL borderline-high, > 240 mg/dL high cholesterol. The American Heart Association provides a similar set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease as listed in Table 1. Table 1

The desirable LDL level is considered to be less than 100 mg/dL (2.6 mmol/L), although a newer target of < 70 mg/dL can be considered in higher risk individuals based on some of the above-mentioned trials. A ratio of total cholesterol to HDL, another useful measure, of far less than 5: 1 is thought to be healthier.

Triglyceride

Triglyceride also known as triacylglycerol, TAG or triacylglyceride is glyceride in which the glycerol is esterified with three fatty acids. Triglycerides, as major components of VLDL and chylomicrons, play an important role in metabolism as energy sources and transporters of dietary fat. In the intestine, triglycerides are split into glycerol and fatty acids via lipolysis, which are then moved into the cells lining the intestines (absorptive enterocytes). The triglycerides are rebuilt in the enterocytes from their fragments and packaged together with cholesterol and proteins to form chylomicrons. These are excreted from the cells and collected by the lymph system and transported to the large vessels near the heart before being mixed into the blood. Various tissues can capture the chylomicrons, releasing the triglycerides to be used as a source of energy. Fat and liver cells can synthesize and store triglycerides. When the body requires fatty acids as an energy source, the hormone glucagon signals the breakdown of the triglycerides by hormone-sensitive lipase to release free fatty acids. As the brain cannot utilize fatty acids as an energy source (unless converted to a ketone), the glycerol component of triglycerides can be converted into glucose, via gluconeogenesis, for brain fuel when it is broken down. Triglycerides cannot pass through cell membranes freely. Lipoprotein lipases must break down triglycerides into fatty acids and glycerol. Fatty acids can then be taken up by cells via the fatty acid transporter (FAT).

Hypertriglyceridemia

In the human body, high levels of triglycerides in the bloodstream have been linked to atherosclerosis, and, by extension, the risk of heart disease and stroke. However, the relative negative impact of raised levels of triglycerides compared to that of LDL: HDL ratios is as yet unknown. The risk can be partly accounted for by a strong inverse relationship between triglyceride level and HDL-cholesterol level. Another disease caused by high triglycerides is pancreatitis. When some fatty acids are converted to ketone bodies, overproduction can result in ketoacidosis in diabetics. The American Heart Association has set guidelines for triglyceride levels as listed in Table 2.

Table 2

Triglyceride levels as tested after fasting 8 to 12 hours.

Provided herein is a method of treating acute hypertriglyceridemia during acute lymphoblastic leukemia by administering to a patient an effective amount of quercetin-3'-0 -sulfate or a pharmaceutically acceptable salt thereof, which reduces or eliminates hypertriglyceridemia and/or one or more symptoms of hypertriglyceridemia.

Moderating the consumption of fats, alcohol and carbohydrates and partaking of aerobic exercise are considered essential to reducing triglyceride levels. Omega-3 fatty acids from fish, flax seed oil or other sources, Omega-6 fatty acids, one or more grams of niacin per day and some statins reduce triglyceride levels. In some cases, fibrates have been used as they can bring down triglycerides substantially. However they are not used as a first line measure as they can have unpleasant or dangerous side effects.

Provided herein are methods for treating or preventing hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, or a disease associated with hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia by administering quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof alone or in combination with one or more compounds that lower the level of lipid or glucose in a subject.

Glucose intolerance, hyperglycemia and hypoinsulinemia

Hyperglycemia or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood glucose level of 100+ mmol/L, but symptoms and effects may not start to become noticeable until later numbers such as 150-200+ mmol/L.

Hypoinsulinemia is a condition wherein lower than normal amounts of insulin circulate throughout the body and wherein obesity is generally not involved. This condition includes Type I diabetes.

Diabetes mellitus

Provided herein are methods that can be used to prevent or treat diabetes mellitus.

Diabetes mellitus is encompassed within insulin resistance and hypoinsulinemia and refers to a state of chronic hyperglycemia, i.e., excess sugar in the blood, consequent upon a relative or absolute lack of insulin action. There are three basic types of diabetes mellitus, Type I or insulin-dependent diabetes mellitus (IDDM), Type 2 or non-insulin-dependent diabetes mellitus (NIDDM), and Type A insulin resistance, although Type A is relatively rare. Patients with either Type I or Type 2 diabetes can become insensitive to the effects of exogenous insulin through a variety of mechanisms. Type A insulin resistance results from either mutations in the insulin receptor gene or defects in post-receptor sites of action critical for glucose metabolism. Diabetic subjects can be easily recognized by the physician, and are characterized by fasting hyperglycemia, impaired glucose tolerance, glycosylated hemoglobin, and, in some instances, ketoacidosis associated with trauma or illness. "Non-insulin dependent diabetes mellitus" or "NIDDM" refers to Type 2 diabetes. NIDDM patients have an abnormally high blood glucose concentration when fasting and delayed cellular uptake of glucose following meals or after a diagnostic test known as the glucose tolerance test. Diabetes mellitus is a syndrome of disordered metabolism, usually due to a combination of hereditary and environmental causes, resulting in hyperglycemia. Blood glucose levels are controlled by insulin made in the beta cells of the pancreas. The two most common forms of diabetes are due to either a diminished production of insulin, or diminished response by the body to insulin. Both lead to hyperglycemia, which largely causes the acute signs of diabetes: excessive urine production, resulting compensatory thirst and increased fluid intake, blurred vision, unexplained weight loss, lethargy, and changes in energy metabolism.

Chronic hyperglycemia that persists even in fasting states is most commonly caused by diabetes mellitus, and in fact chronic hyperglycemia is the defining characteristic of the disease. Type 2 diabetes mellitus is characterized by insulin resistance or reduced insulin sensitivity, combined with reduced insulin secretion. Insulin causes cellular uptake of glucose from the blood (including liver, muscle, and fat tissue cells), storing it as glycogen in the liver and muscle. When insulin is absent (or low) or when tissues fail to response to the presense of insulin, glucose is not taken up by cells, resulting in hyperglycemia.

Provided herein is a method of treating diabetes mellitus by administering to a patient, e.g. a diabetic patient, an effective amount of quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof, which reduces or eliminates hyperglycemia and/or one or more symptoms of hyperglycemia. Modulation of insulin regulation, glucose tolerance, and glucose transport can be evaluated with a variety of imaging and assessment techniques known in the art. Assessment criteria known in the art include, but are not limited to: assessment of insulin levels, assessment of blood glucose levels and glucose uptake studies by oral glucose challenge, assessment of cytokine profiles, blood-gas analysis, extent of blood-perfusion of tissues, and angiogenesis within tissues.

In one aspect, provided herein is a method of treating hyperlipidemia, the method comprising administering a therapeutically effective amount of quercetin- 3'-0-sulfate or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof reduces hyperlipidemia and/or one or more symptoms associated with hyperlipidemia in the subject. In another aspect, provided herein is a method of treating hypercholesterolemia, the method comprising administering a therapeutically effective amount of quercetin- 3'-0-sulfate or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof reduces hypercholesterolemia and/or one or more symptoms associated with hypercholesterolemia in the subject.

In another aspect, provided herein is a method of treating hypertriglyceridemia, the method comprising administering a therapeutically effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof reduces hypertriglyceridemia and/or one or more symptoms associated with hypertriglyceridemia in the subject.

In yet another aspect, provided herein is a method of treating or preventing a disease associated with hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia, the method comprising administering a therapeutically effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof prevents or alleviates at least one symptom of the disease.

Inflammatory mediator responses (e.g., PGE2, IL-1 beta, and TNF- alpha) represent a risk marker for periodontal diseases in insulin-dependent diabetes mellitus patients. Tumor necrosis factor (TNF) is a cytokine produced primarily by monocytes and macrophages. TNF is found in higher amounts within the plasma of patients with diabetes. In one embodiment, provided herein is a method of lowering levels of TNF in a diabetic patient. Also provided herein are methods for facilitating metabolic control in a subject. In one aspect, the method for facilitating metabolic control in a subject decreases the level of IL-1 beta in the subject.

The methods described herein generally involve the administration of one or more drugs for the treatment of one or more diseases. Combinations of agents can be used to treat one disease or multiple diseases or to modulate the side-effects of one or more agents in the combination. When quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof and a lipid or glucose-lowering compound as described herein are used in combination for treatment of a condition such as diabetes mellitus, any suitable ratio of the two agents, e.g., molar ratio, wt/wt ratio, wt/volume ratio, or volume/volume ratio, as described herein, may be used.

In one aspect, provided herein are methods for treating hyperlipidemia associated diseases by administering to a subject in need quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof that modulates a lipid transporter. In another aspect, provided herein are methods for treating hyperglycemia associated diseases by administering to a subject in need quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof that modulates a lipid transporter.

Cardiovascular disease refers to the class of diseases that involve the heart or blood vessels (arteries and veins). While the term technically refers to any disease that affects the cardiovascular system, it is usually used to refer to those related to atherosclerosis (arterial disease). These conditions have similar causes, mechanisms, and treatments.

Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby a principle cause of death. Atherosclerosis is a complex disease involving many cell types and molecular factors. The process, in normal circumstances a protective response to insults to the endothelium and smooth muscle cells (SMCs) of the wall of the artery, consists of the formation of fibrofatty and fibrous lesions or plaques, preceded and accompanied by inflammation. The advanced lesions of atherosclerosis may occlude the artery concerned, and result from an excessive inflammatory-fibroproliferative response to numerous different forms of insult. For example, shear stresses are thought to be responsible for the frequent occurrence of atherosclerotic plaques in regions of the circulatory system where turbulent blood flow occurs, such as branch points and irregular structures.

One observable event in the formation of an atherosclerotic plaque occurs when blood-borne monocytes adhere to the vascular endothelial layer and transmigrate through to the sub-endothelial space. Adjacent endothelial cells at the same time produce oxidized low density lipoprotein (LDL). These oxidized LDL's are then taken up in large amounts by the monocytes through scavenger receptors expressed on their surfaces. In contrast to the regulated pathway by which native LDL (nLDL) is taken up by nLDL specific receptors, the scavenger pathway of uptake is not regulated by the monocytes.

These lipid-filled monocytes are called foam cells, and are the major constituent of the fatty streak. Interactions between foam cells and the endothelial and SMCs which surround them lead to a state of chronic local inflammation which can eventually lead to smooth muscle cell proliferation and migration, and the formation of a fibrous plaque. Such plaques occlude the blood vessel concerned and thus restrict the flow of blood, resulting in ischemia.

Foam cells are cells in an atheroma derived from both macrophages and smooth muscle cells which have accumulated low density lipoproteins, LDLs, by endocytosis. The LDL has crossed the endothelial barrier and has been oxidized by reactive oxygen species produced by the endothelial cells. Foam cells can also be known as fatty like streaks and typically line the intima media of the vasculature.

Foam cells can become a health problem when they accumulate at a particular foci, thus creating a necrotic center of the atherosclerosis. If the fibrous cap that prevents the necrotic center from spilling into the lumen of a vessel ruptures, a thrombus can form which can lead to emboli occluding smaller vessels. The occlusion of small vessels results in ischemia, and contributes to stroke and myocardial infarction, two of the leading causes of cardiovascular-related death.

Vascular stenosis

Provided herein are methods that can be used to prevent or treat vascular stenosis. Vascular stenosis (and restenosis) is a pathological condition which often results from vascular trauma or damage to blood vessel walls. Vascular trauma or damage is relatively common when a patient undergoes vascular surgery or other therapeutic techniques such as angioplasty. The term "vascular stenosis" is used in a broad sense and refers to a pathological process in which the cavity of a blood vessel is narrowed and which usually results in a pathological condition characterized by impaired flow through the vessel. Following administration of a compound described herein to a patient, the patient's physiological condition can be monitored in various ways well known to the skilled practitioner. Atherosclerosis

Provided herein are methods that can be used to prevent or treat atherosclerosis. Atherosclerosis is a disease affecting arterial blood vessels. It is a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of foam cells derived from macrophage white blood cells promoted by oxidized low density lipoproteins (oxLDL) and without adequate removal of fats and cholesterol from the macrophages by high density lipoproteins (HDL). Increased activity of ABCA1 and ABCG1 are expected to increase removal of cholesterol and lipids from macrophages and prevent the development of foam cells.

Provided herein is a method of treating atherosclerosis by administering quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof to a subject. quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may also be administered in combination with other agents to treat atherosclerosis. Thus, quercetin- 3'-0-sulfate or a pharmaceutically acceptable salt thereof may be co-administered with a statin, niacin, low dose aspirin, intestinal cholesterol absorption-inhibiting supplements (ezetimibe and others, and to a much lesser extent fibrates), or a combination thereof. Hypertension

Provided herein are methods that can be used to prevent or treat hypertension by administering quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof to a subject. Hypertension, also referred to as high blood pressure, is a medical condition in which the blood pressure is chronically elevated. It normally refers to arterial hypertension. Hypertension is related to hyperglycemia and hyperlipidemia. In normotensive individuals, insulin may stimulate sympathetic activity without elevating mean arterial pressure. However, in more extreme conditions such as that of the metabolic syndrome, the increased sympathetic neural activity may over-ride the vasodilatory effects of insulin. Insulin resistance and/or hyperinsulinemia have been suggested as being responsible for the increased arterial pressure in some patients with hypertension. There are many classes of medications for treating hypertension, together called antihypertensives, which, by varying means, act by lowering blood pressure. Evidence suggests that reduction of the blood pressure by 5-6 mmHg can decrease the risk of stroke by 40%, of coronary heart disease by 15-20%, and reduces the likelihood of dementia, heart failure, and mortality from cardiovascular disease. Common drugs for treating hypertension include but are not limited to ACE inhibitors, angiotensin II receptor antagonists, alpha blockers, beta blockers, calcium channel blockers, direct renin inhibitors, and diuretics. Liver diseases

Provided herein are methods that can be used to prevent or treat liver diseases by administering quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof to a subject. Hypercholesterolemia is a common feature of primary biliary cirrhosis (PBC) and other forms of cholestatic liver disease. Primary biliary cirrhosis is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver. When these ducts are damaged, bile builds up in the liver (cholestasis) and over time damages the tissue. This can lead to scarring, fibrosis, cirrhosis, and ultimately liver failure. Hyperlipidemia with a marked increase of low-density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels is a common feature in patients with chronic cholestatic liver disease (Matteo Longo Current Treatment Options in Gastroenterology, 2007).

Pancreatitis

Provided herein are methods that can be used to prevent or treat pancreatitis. Pancreatitis is the inflammation of the pancreas. One of the causes of pancreatitis is hypertriglyceridemia (but not hypercholesterolemia) and only when triglyceride values exceed 1500 mg/dl (16 mmol/L). Development of pancreatitis in pregnant women could be a reflection of the hypertriglyceridemia because estrogen may raise blood triglyceride levels.

Provided herein is a method of treating acute hyperlipidemic pancreatitis in pregnancy by administering to a patient an effective amount of quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof, which reduces or eliminates hyperlipidemia and/or one or more symptoms of hyperlipidemia.

Obesity

Provided herein are methods that can be used to prevent or treat obesity.

Central obesity, characterized by its high waist to hip ratio, is an important risk for metabolic syndrome. Metabolic syndrome is a combination of medical disorders which often includes diabetes mellitus type 2, high blood pressure, high blood cholesterol, and triglyceride levels (Grundy SM (2004), J. Clin. Endocrinol. Metab. 89(6): 2595-600). There are two commonly prescribed medications for obesity. One is orlistat, which reduces intestinal fat absorption by inhibiting pancreatic lipase; the other is sibutramine, which is a specific inhibitor of the neurotransmitters norepinephrine, serotonin, and dopamine in the brain. Orlistat and rimonabant lead to a reduced incidence of diabetes, and all drugs have some effect on cholesterol.

Kidney diseases

Provided herein are methods that can be used to prevent or treat kidney diseases. Diabetes is the most common cause of chronic kidney disease and kidney failure, accounting for nearly 44 percent of new cases. Even when diabetes is controlled, the disease can lead to chronic kidney disease and kidney failure. Most people with diabetes do not develop chronic kidney disease that is severe enough to progress to kidney failure. Nearly 24 million people in the United States have diabetes, and nearly 180,000 people are living with kidney failure as a result of diabetes. High blood pressure, or hypertension, is a major factor in the development of kidney problems in people with diabetes.

Niemann-Pick disease

Provided herein are methods that can be used to prevent or treat Niemann-Pick disease. Niemann-Pick disease is one of a group of lysosome storage diseases that affect metabolism and that are caused by genetic mutations. The three most commonly recognized forms are Niemann-Pick Types A, B and C. Niemann-Pick Type C (NPC) patients are not able to metabolize cholesterol and other lipids properly within the cell. In Niemann Pick Type C, cholesterol and glycolipids are the materials being stored rather than sphingomyelin. These fats have varied roles in the cell. Cholesterol is normally used to either build the cell, or forms an ester. In the case of an individual with NPC, there are large amounts of cholesterol that are not used as a building material and also do not form esters. This cholesterol accumulates within the cells throughout the body, but especially in the spleen, the liver and the bone marrow. Currently, there is no known cure for NPC. There is also no standard treatment that has proven to be effective. Provided herein are methods for potential treatment of NPC.

Other disorders

Provided herein are methods that can be used to prevent or treat other disorders including but not limited to eating disorders that result in hyperlipidemia and/or hyperglycemia. A high proportion of patients suffering an acute stress such as stroke or myocardial infarction may develop hyperglycemia. In addition, hyperglycemia occurs naturally during times of infection and inflammation. When the body is stressed, endogenous catecholamines are released that serve to raise the blood glucose levels. The amount of increase varies from person to person and from inflammatory response to response.

It should be noted that although exemplary diseases are provided herein, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be used to treat or prevent any disease that is associated with hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia. For example, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be used for treatment of any suitable condition including but not limited to chronic hyperlipidemia, acute hyperlipidemia, acute hypercholesterolemia, chronic hypercholesterolemia, acute hypertriglyceridemia, chronic hypertriglyceridemia, chronic hyperglycemia, acute hyperglycemia, diabetes mellitus, non-diabetic hyperglycemia, stress-induced hyperglycemia, inflammation-induced hyperglycemia, organ transplant, an autoimmune disease, cardiovascular disease, heart attack, stroke, coronary artery disease, hypertension, liver disease, primary bile cirrhosis, pancreatitis, Niemann-Pick disease, obesity, cataracts, Wilson's disease, kidney disease and an inflammatory disease.

Cardiovascular disease

Provided herein is a method of treating cardiovascular disease in a patient by administering to the patient an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, which reduces or eliminates hyperlipidemia and/or hyperglycemia and/or one or more symptoms of hyperlipidemia or hyperglycemia. Examples of cardiovascular diseases include but are not limited to atherosclerosis, Ischemic heart disease, acute myocardial infarction, congestive heart failure and stroke.

Hyperlipidemia, Hypercholesterolemia, Hypertriglyceridemia, and Hyperglycem ia

In some embodiments, provided herein is a method of treating non- diabetic hyperglycemia by administering to a patient in need of treatment an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, which reduces or eliminates hyperglycemia and/or one or more symptoms of hyperglycemia. Certain eating disorders can produce acute non-diabetic hyperglycemia, as in the binge phase of bulimia nervosa, when the subject consumes a large amount of calories at once, frequently from foods that are high in simple and complex carbohydrates. Certain medications increase the risk of hyperglycemia, including beta blockers, thiazide diuretics, corticosteroids, niacin, pentamidine, protease inhibitors, L-asparaginase, and some antipsychotic agents.

In some embodiments, provided herein is a method of treating stress- induced hyperglycemia by administering to a patient in need of treatment an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, which reduces or eliminates hyperglycemia and/or one or more symptoms of hyperglycemia. A high proportion of patients suffering an acute stress such as stroke or myocardial infarction may develop hyperglycemia, even in the absence of a diagnosis of diabetes. Human and animal studies suggest that this is not benign, and that stress-induced hyperglycemia is associated with a high risk of mortality after both stroke and myocardial infarction.

In some embodiments, provided herein is a method of treating inflammation-induced hyperglycemia by administering to a patient in need of treatment an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, which reduces or eliminates hyperglycemia and/or one or more symptoms of hyperglycemia.

In some embodiments, provided herein is a method of preventing, decreasing and/or reversing hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia and/or one or more symptoms of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia by administering a lipid transport protein activator to a patient with a known or suspected symptom of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia. In some embodiments, the patient has tested positive for hyperglycemia (e.g. after a fasting glucose test) prior to administering the lipid transport protein activator, i.e. quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. In some embodiments, the patient, e.g. human, has tested positive for hyperlipidemia (e.g. after a fasting cholesterol test) prior to administering the lipid transport protein activator, i.e. quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has displayed one or more symptoms of hyperglycemia as described herein prior to administering the lipid transport protein activator. In some embodiments, the patient has displayed one or more symptoms of hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia as described herein prior to administering the lipid transport protein activator. In some embodiments, the patient possesses a trait (e.g. genetic trait or physical trait such as obesity) that makes the patient predisposed to hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia and/or one or more symptoms of hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia; and a lipid transport protein activator, i.e. quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered to the patient alone or in combination with a lipid- lowering compound to prevent hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and/or one more symptoms of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia. In some embodiments, the patient possesses a trait (e.g. genetic trait or physical trait such as obesity) that makes the patient predisposed to hyperglycemia and/or one or more symptoms of hyperglycemia; and a lipid transport protein activator, i.e. quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, is administered to the patient alone or in combination with a glucose-lowering compound to prevent hyperglycemia and/or one more symptoms of hyperglycemia. For example, a diabetic patient can be prescribed treatment with quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof after testing positive for hyperglycemia from a glucose blood level test such as the fasting glucose test. In another example, a patient suffering from atherosclerosis can be prescribed treatment with quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof after testing positive for hyperlipidemia from a cholesterol or triglyceride blood level test such as the fasting cholesterol or triglyceride test. Alternatively, a patient that possesses a trait (e.g. genetic trait or physical trait such as obesity) that makes the patient predisposed to hyperglycemia or hyperlipidemia and/or one or more symptoms of hyperglycemia or hyperlipidemia can be prescribed treatment with quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof to prevent hyperglycemia or hyperlipidemia and/or one more symptoms of hyperglycemia or hyperlipidemia, even when the patient is not experiencing hyperglycemia or hyperlipidemia and/or one or more symptoms of hyperglycemia or hyperlipidemia.

In some embodiments, provided herein is a method for reversing hyperglycemia or hyperlipidemia and/or one or more symptoms of hyperglycemia or hyperlipidemia in a human by administering to the human an amount of quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof sufficient to partially or completely reverse hyperglycemia or hyperlipidemia and/or one or more symptoms of hyperglycemia or hyperlipidemia in that human.

The quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof can be administered by any suitable route such as orally or by injection, e.g., intravenously or intraperitoneally, in a dose sufficient to partially or completely reverse hyperglycemia, hyperlipidemia, and/or one or more symptoms of hyperglycemia or hyperlipidemia. Such a dose in a human can be, e.g., about 0.1-100 mg, or about 0.5-50 mg, or about 1-40 mg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 mg. In general, the dose can be in the range of 0.1-3 mg/kg of body weight.

Quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be administered in a therapeutically effective dose. In some embodiments, a therapeutic concentration will be that concentration which is effective to lower the concentration of lipids, for example triglycerol and cholesterol, in a patient. In other embodiments, a therapeutic concentration will be that concentration which is effective to lower the concentration of glucose in a patient. For example, a formulation comprising between about 0.1 and about 3 mg of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof/kg of body weight, between about 0.3 mg/kg and 2 mg/kg, about 0.7 mg/kg, or about 1.5 mg/kg will constitute a therapeutically effective concentration for oral application, with routine experimentation providing adjustments to these concentrations for other routes of administration if necessary.

Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. In some embodiments, dosing may be about once a month, once every two weeks, once a week, once every other day or any other suitable interval. In some embodiments, the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary, e.g., in a diabetic patient, which may require dosing for the rest of his or her life.

Administration of the one or more agents may continue as long as necessary. In some embodiments, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered for more than about 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered for less than about 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

The lipid transport protein modulator, i.e. quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, may be administered in dosages as described herein. Dosing ranges for lipid- lowering or glucose-lowering compounds are known in the art and are contemplated herein. Individualization of dosing regimen may be utilized for optimal therapy due to inter-subject variability and pharmacokinetics. Dosing for the lipid transport modulator may be determined empirically.

For quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof, typical daily dose ranges include, for example, about 1-5000 mg, about 1-3000 mg, about 1-2000 mg, about 1-1000 mg, about 1-500 mg, about 1-100 mg, about 10-5000 mg, about 10-3000 mg, about 10-2000 mg, about 10-1000 mg, about 10-500 mg, about 10-200 mg, about 10-100 mg, about 20-2000 mg, about 20-1500 mg, about 20-1000 mg, about 20-500 mg, about 20-100 mg, about 50-5000 mg, about 50-4000 mg, about 50-3000 mg, about 50-2000 mg, about 50-1000 mg, about 50-500 mg, about 50-100 mg, about 100-5000 mg, about 100-4000 mg, about 100-3000 mg, about 100-2000 mg, about 100-1000 mg, or about 100-500 mg. In some embodiments, the daily dose of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 mg. In some embodiments, the daily dose of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 mg.

Daily doses may be administered in single or multiple doses. For instance, in some embodiments, the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered 3 times per day of an oral dose of 500 mg. In other embodiments, the quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof is administered 3 times per day of an i.v. dose of 150 mg. Daily doses of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof may be administered in the same or separate composition as a lipid-lowering compound or glucose-lowering compound. EXAMPLES

3,7-Bis(benzyloxy)-2-(4-(benzyloxy)-3-hydroxyphenyl)-5-hydroxy-4H-chromen-4-one

Quercetin dihydrate (300.0 g, 887.6 mmol, 1.00 equiv) was stirred in DMF (6 L) at 0 °C, while potassium carbonate (361.3 g, 2618.3 mmol, 2.95 equiv) were added. Benzyl bromide (311 mL, 2618.3 mmol, 2.95 equiv) was added slowly via an additional funnel. The reaction was stirred vigorously for 2 hr at 0 °C and then slowly warmed to room temperature in 2 hr. The reaction was allowed to stir at room temperature for 16 hr and poured into water (20 L). The mixture was acidified with IN hydrochloric acid until pH = 3 and extracted with ethyl acetate (3 x 8 L). The organic layer was washed with saturated brine (4 L), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash chromatography using 1 : 1 toluene/dichloromethane (16 L), dichloromethane (12 L) and 3% ethyl acetate/dichloromethane (20 L) as eluents. The resulting solid was triturated from tert-butyl methyl ether and then 1 :1 toluene/dichloromethane. The product was obtained as yellow solid (159 g, 31 % yield). Pyridinium 2-(benzyloxy)-5-(3,7-bis(benzyloxy)-5-hydroxy-4-oxo-4H-chromen-2-yl)- phenyl sulfate (lb)

3,7-Bis(benzyloxy)-2-(4-(benzyloxy)-3-hydroxyphenyl)-5-hydroxy-4H- chromen-4-one (la) (20.0 g, 35.0 mmol, 1 equiv) and sulfamic acid (6.8 g, 70.0 mmol, 2 equiv) were heated in pyridine (250 mL) in a sealed tube at 90 °C for 16 hr. The reaction mixture was cooled and concentrated under reduced pressure. The residual was added dichloromethane (100 mL), filtered and the filtrate was concentrated under reduced pressure to about 50 mL, upon which yellow precipitate started to form. The mixture was allowed to sit at room temperature for 3 hr and filtered. The yellow solid was washed with minimum amount of dichloromethane. The product was obtained as a yellow solid (15.1 g, 66 % yield).

Piperidinium 2-hydroxy-5-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenyl sulfate Lie)

Pyridinium 2-(benzyloxy)-5-(3,7-bis(benzyloxy)-5-hydroxy-4-oxo-4H- chromen-2-yl)phenyl sulfate (lb) (15.1 g, 20.6 mmol, 1 equiv) and 10% palladium on carbon (50 % wt) (3.0 g) were slurried in ethanol (850 mL). The reaction was hydrogenated for 6 hr under 50 PSI of pressure of hydrogen. The mixture was filtered through Celite, concentrated under reduced pressure and stirred in ethyl acetate (1 L) for 16 hr. The mixture was filtered and the solid was triturated with a mixture of methanol (20 mL) and ethyl acetate (1 L). The product was obtained as a yellow solid (5.5 g, 56 % yield).

Potassium Quercetin-3'-Q-Sulfate (1)

Pyridinium 2-hydroxy-5-(3,5,7-trihydroxy-4-oxo-4H-chromen-2- yl)phenyl sulfate (lc) (7.7 g) was treated with potassium hydroxide (2.4 g) in water D.I.U.F. (1 L) (pH=9). After stirring for 30 min, the mixture was acidified with 5% sulfuric acid until pH=2. Potassium acetate (200 g) in water D.I.U.F. (0.5 L) was added quickly upon which a yellow precipitate formed. The mixture was allowed to sit at room temperature for 16 hr, filtered, washed with minimum amount of water and dried in vacuum oven at 25 -30 °C for 16 hr to give the product as a yellow solid (6.8 g, 97 % yield) with a purity > 99.7 % (< 0.1 % quercetin) by LC/MS. 1H NMR (300 MHz/DMSO-d₆): δ 12.45 (s, 1H), 9.55 (br, 1H), 8.04 (d, 1H), 7.85 (dd, 1H), 6.98 (d, 1H), 6.42 (d, 1H), 6.19 (d, 1H); ¹³C NMR (300 MHz/ DMSO-d₆): δ 176.3, 164.6, 161.2, 156.6, 151.6, 146.5, 141.2, 136.4, 125.4, 123.0, 122.6, 117.6, 103.4, 98.7, 93.9; MS m/z 381.0 [M - H⁺].

Example 2

Adenosine Binding Assay

Quercetin, quercetin-3'-0-phosphate, quercetin-3'-0-sulfate and quercetin-3-O-glucuronide were tested in adenosine binding assays against the four adenosine receptor subtypes that exist in humans: A_{L S} A₂A, A_2B, and A₃.

Adenosine A^ (Human) Binding Assay

Human recombinant adenosine Ai receptors expressed in CHO cells were used in modified HEPES buffer pH 7.4. A 10 μg aliquot was incubated with 1 iiM [³H]DPCPX for 90 minutes at 25°C. Non-specific binding was estimated in the presence of 100 μΜ R(- )-PIA. Receptors were filtered and washed, the filters were then counted to determine [³H]DPCPX specifically bound. Quercetin, quercetin-3'-0-phosphate, quercetin-3'-0-sulfate and quercetin-3- O-glucuronide were screened at 30, 10, 3, 1, and 0.3 μΜ.

Results: Kd 1.4 nM

Bmax: 2700 fmol/mg protein

Specific Binding: 85%

Reference Data: Com ound ICso (nM) Ki (nM) nH

^Indicates standard reference agent used.

2-CADO = 2-Chloroadenosine

CHA = N⁶-cyclohexyladenosine

DPCPX = 8-cyclopentyl-l,3-dipropylxanthine

CGS-21680 = 2-p-(2-carboxyethyl)phenethyl

ethylcarbox-amidoadenosine

NECA = 5'-N-ethylcarboxamidoadenosine

PIA = N⁶-(2-phenylisopropyl)adenosine

Adenosine A?A (Human) Binding Assay

Human recombinant adenosine A₂A receptors expressed in human HEK-293 cells were used in modified Tris-HCl buffer pH 7.4. A 15 μg aliquot was incubated with 50 nM [³H]CGS-21680 for 90 minutes at 25°C. Non-specific binding was estimated in the presence of 50 μΜ NECA. Receptor were filtered and washed, the filters were then counted to determine [³H]CGS-21680 specifically bound. Quercetin, quercetin-3'-0-phosphate, quercetin-3'-0- sulfate and quercetin-3-O-glucuronide were screened at 30, 10, 3, 1, and 0.3 μΜ.

Results: Kd 64 nM

Bmax: 7 pmol/mg protein

Specific Binding 85% Reference Data: Compound ICso (nM) Ki (nM) nH

Alloxazine 1,100 630 0.7

2-CADO 840 470 0.8

*CGS-21680 130 79 1.0

CHA 4,400 2,500 1.1

DPCPX 71 40 1.0

NECA 130 70 0.8

R(-)-PIA 3,000 1,700 1.0

S(+)-PIA 7,700 4,300 0.9

^Indicates standard reference agent used.

Adenosine A?R (Human) Binding Assay

Procedure: Human recombinant adenosine A_2B receptors expressed in human

HEK-293 cells were used in modified Tris-HCl buffer pH 6.5. A 6 μg aliquot was incubated with 1.6 nM [³H]MRS1754 for 90 minutes at 25°C. Non-specific binding was estimated in the presence of 100 μΜ NECA. Receptors were filtered and washed, the filters were then counted to determine [³H]MRS1754 specifically bound. Quercetin, quercetin-3'-0-phosphate, quercetin-3'-0 -sulfate and quercetin-3-O-glucuronide were screened at 30, 10, 3, 1, and 0.3 μΜ.

Results: Kd 0.77 nM

Bmax: 6.2 pmol/mg protein

Specific Binding: Reference Data: Com ound ICso (nM) Ki (nM) nH

^Indicates standard reference agent

CPA = N⁶-cyclopentyladenosine

Adenosine A^ (Human) Binding Assay

Procedure: Human recombinant adenosine A₃ receptors expressed in CHO-K1 cells were used in modified HEPES buffer pH 7.4. A 2 μg aliquot was incubated with 0.5 nM [¹²⁵I]AB-MECA for 60 minutes at 25°C. Non-specific binding was estimated in the presence of 1 μΜ IB-MECA. Receptors were filtered and washed, the filters were then counted to determine [¹²⁵I]AB-MECA specifically bound. Quercetin, quercetin-3'-0-phosphate, quercetin-3'-0-sulfate and quercetin-3-O-glucuronide were screened at 30, 10, 3, 1, and 0.3 μΜ.

Results: Kd 5.9 nM

Bmax: 1800 fmol/mg protein

Specific Binding: 83%

Reference Data:

^Indicates standard reference agent used.

IB-MECA = l-Deoxy-l-[6-[[(3-iodophenyl)methyl]amino]-9H- purin-9-yl] -N-methyl-b-D- ribofuranuronamide MRS 1220 = N-[9-Chloro-2-(2-furanyl)[l,2,4]-triazolo[l,5-]quina- zolin-5-yl]benzene

Adenosine A^, GTPyS Binding Assay (Human) Procedure: Human recombinant adenosine A₃ receptors expressed in CHO-Kl cells were used. Quercetin-3'-0-sulfate and/or vehicle was preincubated with 0.02 mg/ml membranes and 1 μΜ GDP in modified HEPES pH 7.4 buffer for 20 minutes. SPA beads were then added for additional 60 minutes at 30°C. The reaction was initiated by addition of 0.3 nM [³⁵S]GTPyS for another 30 minute incubation period. Test compound-induced increase of [³⁵S]GTPyS binding by 50 percent or more (≥50%) relative to the 3 μΜ 2-Cl-IB-MECA response indicates possible A₃ receptor agonist activity. Test compound-induced inhibition of 0.1 μΜ 2- Cl-IB-MECA-induced increase of [³⁵S]GTPyS binding response by 50 percent or more (>50%) indicates receptor antagonist activity. Quercetin-3'-0-sulfate was investigated at 30, 10, 3, 1, and 0.3 μΜ.

Reference Data: Agonist EC₅₀ (nM)

*2-Cl-IB-MECA 8

Antagonist IC₅₀ (nM)

*MRS 1220 15

^Indicates standard reference agent used.

2-Cl-IB-MECA = l-[2-chloro-6-[[(3-iodophenyl)methyl]amino]- 9H-purin-9-yl]- 1 -deoxy-N-methyl-b-D-ribofuranuronamide

Binding Data for Five Binding Assays

TABLE 3

Binding data for adenosine receptor subtypes

In adenosine A₃, GTPyS binding assay (human), quercetin-3 '-O-sulfate exhibited antagonistic activity (no agonist activity) against the human A₃ receptor with an IC₅₀ = 0.461 μΜ. This assay was conducted by measuring the % inhibition of bound GTPyS, which was induced by a specific A₃ receptor agonist (2-CL-IB-MECA), in the presence of increasing concentrations of quercetin-3'-0-sulfate.

Example 3

Quercetin-3 '-O-sulfate Protects Against Tacrolimus-Induced Impairment of Glucose

Tolerance and Kidney Function

Human clinical trial can be conducted to investigate the safety, tolerability, PK, and exploratory pharmacodynamics of oral quercetin-3 '-O-sulfate (Q- Sulfate) given with or without clinical doses of tacrolimus (TAC) in normal volunteers. This can be done as a double-blind, placebo-controlled study that randomizes 40 subjects to one of the following parallel group arms: 1) Q-Sulfate 500 mg BID for 14 days with TAC BID for the first 8 days, 2) Q-Sulfate 750 mg BID for 14 days with TAC BID for the first 8 days, 3) Placebo Q-Sulfate for 14 days with TAC BID for the first 8 days (TAC alone), 4) Q-Sulfate 750 mg BID for 14 days with placebo TAC for the first 8 days. TAC is initiated at 0.1 mg/kg/day in two divided equal doses and titrated to a target trough of 10-15 ng/mL. Exploratory measures of glucose tolerance are performed by an oral glucose tolerance test (OGTT). OGTT is performed on Day -1 (study baseline), and on Days 8 and 14 one hour after the morning administration of study medication. Subjects are given 75 grams of glucose orally and had blood samples drawn at times 0 (pre-dose), 15, 30, 45, 60, and 120 minutes after glucose administration. Kidney function is measured by the estimated glomerular filtration rate (GFR) and urinary creatinine levels.

Subjects dosed with TAC alone for 8 days show impaired glucose tolerance as measured by significantly increased OGTT glucose AUC (area under the curve) on Day 8 compared to Day -1. When 500 mg Q-Sulfate is co-administered with TAC, OGTT glucose AUC is unchanged between Day -1 and Day 8. Co-administration of 750 mg Q-Sulfate with TAC partially protects against the increase in OGTT glucose AUC on Day 8.

The OGTT serum glucose concentration at 2 hours on Day -1, Day 8, and Day 14 for the treatment groups can be measured. Subjects treated with TAC alone show elevated 2 hour glucose concentrations on Day 8, which returns towards baseline on Day 14. In contrast, the 2 hour glucose concentration is unchanged in subjects treated with 500 mg Q-Sulfate and TAC, and on Day 14, the glucose concentration is lower than the Day -1 value. Co-administration of 750 mg Q-Sulfate with TAC partially protects against the increase in 2 hour glucose concentration on Day 8, and on Day 14, the glucose concentration is lower than the Day -1 value.

The OGTT serum insulin AUC on Day -1, Day 8, and Day 14 for the treatment groups can be measured. Subjects treated with TAC alone show significantly elevated OGTT insulin AUC on Day 8 compared to Day -1. When 500 mg Q-Sulfate is co-administered with TAC, OGTT insulin AUC is unchanged between Day -1 and Day 8. Co-administration of 750 mg Q-Sulfate with TAC partially protects against the increase in OGTT insulin AUC on Day 8. All treatment groups show elevated OGTT insulin AUC at Day 14 compared to Day -1.

The OGTT results indicate that TAC reduced the insulin sensitivity in normal subjects after 8 days of dosing as shown by the requirement for greater insulin production to maintain normal glucose levels. Both glucose and insulin levels remain elevated on Day 14 compared to Day -1, which is attributed to the prolonged effects of residual TAC. Subjects receiving Q-Sulfate with TAC have higher insulin and lower glucose AUC values on Day 14 compared to Day -1, suggesting that Q-Sulfate improves both insulin sensitization and beta cell insulin secretion over time. These results support the ability of Q-Sulfate to protect the insulin-producing beta cells of the pancreas from the toxic effects of TAC.

The estimated GFR on Day 1, Day 8, and Day 14 for the TAC alone treatment group can be calculated by the Hoek equation, which is based upon serum cystatin-C levels. Subjects treated with TAC alone show declining GFR on Day 8, and on Day 14, which is statistically significant from Day 1. When 500 mg Q-Sulfate is coadministered with TAC, GFR declines on Day 14 compared to Day 1. When 750 mg Q-Sulfate is co-administered with TAC, GFR declines on Day 14 compared to Day 1.

Subjects treated with TAC alone show significantly reduced creatinine excretion on Day 8 compared to Day -1. When 500 mg Q-Sulfate is co-administered with TAC, creatinine excretion is not reduced on Day 8 compared to Day -1. Subjects treated with 750 mg Q-Sulfate with TAC show a smaller reduction in creatinine excretion on Day 8 vs. Day -1 when compared to subjects treated with TAC alone. Subjects receiving TAC alone show decreased creatinine excretion on Day 14 compared to Day -1. In contrast, both doses of Q-Sulfate with TAC show increased creatinine excretion on Day 14 compared to Day -1. The results are expected to support the ability of Q-Sulfate to protect the kidney from the toxic effects of TAC.

Example 4

Quercetin-3'-0-sulfate Reduces Plasma and Liver Triglyceride in C57BL/6 Mice

Experimental Design

This study was a 2-week study conducted with male C57BL/6 mice (24 animals, 3 treatment arms, 8 rats/arm) 9-week old at the start of compound treatment. The animals were maintained (starting at 8-week old) on a 12-hr light and 12-hr dark cycle, and provided with commercial rodent chow Purina 5001 and water ad libitum. The animals were treated intraperitoneally (i.p. or IP) daily (at 8 hr after start of light cycle) for 13 days with vehicle and quercetin-3'-0-sulfate as shown below.

The stock solution of vehicle (HCO-60) was composed of 200 mg of HCO-60 per mL of 80% alcohol. Vehicle was prepared by diluting the HCO-60 stock solution 1 : 10 with saline. Quercetin-3'-0-sulfate stock solutions were prepared in HCO-60 stock solution and diluted with saline or vehicle to the appropriate dose concentration.

Tail-vein-blood samples were collected from each rat 24 hours after the last treatment (on day-4, 7, and 14) for plasma triglyceride determination. Animals were sacrificed to obtain liver for triglyceride determination on day- 14 immediately after the tail-vein blood draw.

Results

Plasma triglyceride levels: The plasma triglyceride concentrations of animals treated with vehicle or quercetin-3'-0-sulfate are shown in Figure 1. Daily treatment of quercetin-3'-0-sulfate for 13 days reduced plasma triglyceride in C57BL/6 mice.

Liver triglyceride levels: The liver triglyceride concentrations of animals treated with vehicle or quercetin-3'-0-sulfate are shown in Figure 2. Compared to vehicle treated controls (Group-1), daily treatment with 30 mg/kg (30 mpk) of quercetin-3'-0-sulfate for 13 days significantly reduced liver triglyceride of C57BL/6 mice. Example 5

Quercetin-3'-0-sulfate Protects Against Onset of Type 2 Diabetes and Attendant

Complications in Diabetic Rat Model

ZDF Rat

The inbred Zucker diabetic fatty (ZDF, fa/fa) rat (ZDF rat), derived from in-breeding Zucker rats with diabetic traits, was a commonly used animal model of Type-2 diabetes (T2D). The phenotype of ZDF rats was the result of inherited spontaneous mutation in the leptin receptor. When fed with Purina 5008, the homozygote recessive males (fa/fa) developed obesity, hyperlipidemia, fasting hyperglycemia and T2D. Hyperglycemia was apparent at about 7 weeks of age, and blood insulin levels were high between 7 and 10 weeks, but subsequently dropped as the pancreatic b-cells fail to response to glucose. Male ZDF rats fed Purina 5008 were fully diabetic by 12 weeks of age. The development from obesity through hyperglycemia to T2D in the ZDF rats closely mimicked the disease in human. Experimental Design

This study was a 4-week study conducted with male ZDF rats (24 animals, 4 treatment arms, 6 rats/arm) 6-week old at the start of compound treatment. The animals were maintained (starting at 5 -week old) on a 12-hr light and 12-hr dark cycle, and provided with commercial rodent chow Purina 5008 and water ad libitum. The animals were treated intraperitoneally (i.p.) daily (at 8 hr after start of light cycle) with the following compounds:

Pre-dose tail-vein-blood samples were collected from each rat at day 0, 7, 14, 21 and 28, and plasma glucose concentrations were determined. Body weights were also measured on the same days. Insulin and glycated hemoglobin (HbAlc) concentrations were also determined on day-28 blood. Oral glucose (2 g/kg, 5 ml/kg) tolerance test (OGTT) including fasting insulin were performed on group- 1 and group-4 animals on day-29 after 12-hr fast. Animals were sacrificed after OGTT to obtain pancreas for insulin and liver for triglyceride determination.

Results

Plasma glucose levels: The plasma glucose levels showed that quercetin-3'-0-sulfate treatment at 100 mg/kg maintained a lower plasma glucose level than vehicle treatment (Figure 3).

Insulin levels: Plasma insulin measurements (Figure 4) showed that quercetin-3'-0-sulfate treated animals maintained significantly higher plasma insulin levels under fed conditions. Untreated male ZDF rats under experimental conditions described above developed diabetes between the age of 8 and 10 weeks old (day- 14 to day-28 of this example). As shown in Figure 4, vehicle treated animals have low insulin levels corresponding to the full diabetic state. The significantly higher fed insulin levels of quercetin-3'-0-sulfate treated animals provided further evidence that quercetin-3'-0-sulfate treatment slowed down the development of diabetes in male ZDF rats.

OGTT: Plasma glucose concentrations at 15, 30, 60, and 120 minutes post oral glucose challenge (Figure 5) showed that quercetin-3'-0-sulfate treated animals were able to maintain lower plasma glucose level during OGTT. Thus, quercetin-3'-0-sulfate treatment improved oral glucose tolerance of aging male ZDF rats.

HbAlc levels: Quercetin-3'-0-sulfate (100 mg/kg) treated animals showed lower glycated hemoglobin levels (% HbAlc) at termination compared to vehicle treated animals (Figure 6)

Pancreatic Insulin: Similar to rosiglitazone treated animals, the pancreatic insulin levels of quercetin-3'-0-sulfate (lOOmg/kg) treated animals were significantly higher than that of the vehicle treated animals (Figure 7).

Liver Triglyceride: In contrast of rosiglitazone treatment, quercetin-3'- O-sulfate treated animals did not increase liver triglyceride (Figure 8).

Example 6

Quercetin-3'-0-sulfate in Combination with Metformin Improves Oral Glucose

Tolerance in Pre-diabetic Rat Model

Experimental Design:

This study was a 2-week study conducted with male ZDF rats (28 animals, 4 treatment arms, 7 rats/arm) 7-week old at the start of compound treatment. The animals were maintained (starting at 6-week old) on a 12-hr light (0600-1800) and 12-hr dark cycle, and provided with commercial rodent chow Purina 5008 and water ad libitum. The animals were treated daily with the following compounds: Group Dose #1

Treatment-twice daily dosing at 0800 and 1700 (PO)

1 PO Vehicle-water

2 Metformin 300 mg/kg

5 PO Vehicle-water

6 Metformin 300 mg/kg

Group Dose #2

Treatment-once daily dosing immediately after first dose #1 (IP)

1 IP Vehicle- 1.0M sodium bicarbonate solution plus saline

2 IP Vehicle- 1.0M sodium bicarbonate solution plus saline

5 quercetin-3'-0-sulfate 100 mg/kg

6 quercetin-3'-0-sulfate 100 mg/kg

Pre-dose tail-vein-blood samples were collected from each rat at day 0, 7, and 14, and plasma glucose concentrations were determined. Oral glucose tolerance test (OGTT) were performed on animals on day-15. After 16-hr fast, animals were dosed at 0800 with dose #1 and dose #2. Blood sample were collected 1 hour post dosing (time 0) to measure glucose levels. Animals were then dosed with glucose (2 g/kg, 10 ml/kg, PO). Blood samples were collected at 30, 60, and 120 min post glucose dose to measure glucose levels.

Results

OGTT: Plasma glucose concentrations at 0, 30, 60, and 120 minutes post oral glucose challenge (Figure 9) showed that animal treated with quercetin-3'-0- sulfate in combination with Metformin have lower plasma glucose level during OGTT, compared to animals treated with vehicles, quercetin-3'-0-sulfate alone or Metformin alone. Thus, quercetin-3'-0-sulfate in combination with Metformin treatment further improved oral glucose tolerance of pre-diabetic male ZDF rats compared with Metformin treatment alone. All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. It will be apparent to those of skill in the art that variations may be applied without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claims

CLAIMS What is claimed is:

1. A method for selectively inhibiting adenosine A3 receptor activity in an animal, comprising administering to the animal an effective amount of quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof.

2. A method for reducing or eliminating a side effect associated with, or increasing the effectiveness of, the administration of a therapeutic agent to an animal, comprising administering to the animal an effective amount of an adenosine A₃ receptor antagonist, wherein the adenosine A₃ receptor antagonist is quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

3. A method for reducing or eliminating a side effect associated with, or increasing the effectiveness of, the administration of a therapeutic agent to an animal, comprising administering to the animal an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-3, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt is in isolated and purified form.

5. The method of any one of claims 1-4, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt has a purity of greater than 98%.

6. The method of any one of claims 1-4, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt has a purity of greater than 99%.

7. The method of any one of claims 1-4, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt has a purity of greater than 99.7%.

8. The method of any one of claims 1-7, wherein the pharmaceutically acceptable salt is a sodium or potassium sulfate salt.

9. The method of any one of claims 1-8, wherein the pharmaceutically acceptable salt is a sodium sulfate salt.

10. The method of any one of claims 1-8, wherein the pharmaceutically acceptable salt is a potassium sulfate salt.

1 1. The method of any one of claims 2-10, wherein the therapeutic agent is an immunosuppressant, antiviral, antibiotic, antineoplastic, amphetamine, antihypertensive, vasodilator, barbiturate, membrane stabilizer, cardiac stabilizer, glucocorticoid, antilipedemic, antiglycemic, cannabinoid, antidipressant, antineuroleptic, antiinfective, immunomodulator or chemotherapeutic agent.

12. The method of any one of claims 2-1 1, wherein the therapeutic agent is an immunosuppressant.

13. The method of any one of claims 2-1 1, wherein the therapeutic agent is a calcineurin inhibitor.

14. The method of any one of claims 2-1 1, wherein the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, voclosporin, or hydrocortisone.

15. The method of any one of claims 2-1 1, wherein the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, or voclosporin.

16. The method of any one of claims 2-1 1, wherein the therapeutic agent is tacrolimus.

17. The method of any one of claims 2-1 1, wherein the therapeutic agent is cyclosporin.

18. The method of any one of claims 2-11 , wherein the therapeutic agent is an antilipedimic agent.

19. The method of claim 18, wherein the therapeutic agent is an HMG-

CoA inhibitor.

20. The method of claim 19, wherein the therapeutic agent is lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin.

21. The method of any one of claims 2-1 1, wherein the therapeutic agent is an antihyperglycemic agent.

22. The method of claim 21 , wherein the therapeutic agent is glyburide, glipizide, gliclazide, glimepride, a meglitinide, repaglinide, netaglinide, a biguanide, metformin, a thiazolidinedione, an a-glucosidase inhibitor, acarbose, miglitol, glucagon, somatostatin, or diazoxide.

23. The method of claim 22, wherein the therapeutic agent is metformin.

24. The method of claim 22, wherein the therapeutic agent is a thiazolidinedione.

25. The method of any one of claims 2-10, wherein the therapeutic agent is insulin.

26. The method of any one of claims 2-25, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt and the therapeutic agent are administered to the animal separately.

27. The method of any one of claims 2-25, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt and the therapeutic agent are administered to the animal simultaneously.

28. The method of any one of claims 2-25, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt is administered to the animal before or concurrently with the administration of the therapeutic agent.

29. The method of any one of claims 2-28, wherein the side effect is renal vasoconstriction, hyperglycemia, nephrotoxicity, renal function impairment, creatinine increase, proteinuria, hematuria, hypertension, renal allograft rejection, urinary tract infection, oliguria, cystitis haemorrhagic, hemolytic-uremic syndrome or micturition disorder, hepatic necrosis, hepatotoxicity, fatty liver, venooclusive liver disease, diarrhea, nausea, constipation, vomiting, dyspepsia, anorexia, or a combination thereof.

30. The method of any one of claims 2-28, wherein the side effect is hyperglycemia.

31. The method of any one of claims 2-28, wherein the side effect is calcineurin inhibitor induced hyperglycemia, new onset diabetes after transplantation, reduced kidney function, proteinuria, hematuria, hypertension or graft failure.

32. The method of any one of claims 2-28, wherein the side effect is tacrolimus induced hyperglycemia, new onset diabetes after transplantation, reduced kidney function, proteinuria, hematuria, hypertension or graft failure.

33. The method of any one of claims 2-28, wherein the side effect is calcineurin induced renal vasoconstriction.

34. The method of any one of claims 2-28, wherein the side effect is tacrolimus induced renal vasoconstriction.

35. A composition in discrete dosage form comprising quercetin-3'-0- sulfate or a pharmaceutically acceptable salt thereof.

36. The composition of claim 35, wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt is in isolated and purified form.

37. The composition of claim 35 or 36, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt has a purity of greater than 98%.

38. The composition of claim 35 or 36, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt has a purity of greater than 99%.

39. The composition of claim 35 or 36, wherein the quercetin-3'-0- sulfate or pharmaceutically acceptable salt has a purity of greater than 99.7%.

40. The composition of any one of claims 35-39, wherein the pharmaceutically acceptable salt is a sodium or potassium sulfate salt.

41. The composition of any one of claims 35-40, wherein the pharmaceutically acceptable salt is a sodium sulfate salt.

42. The composition of any one of claims 35-40, wherein the pharmaceutically acceptable salt is a potassium sulfate salt.

43. The composition of any one of claims 35-42, wherein the composition is formulated for oral administration.

44. The composition of any one of claims 35-43, wherein the composition is in the form of a tablet or capsule.

45. The composition of any one of claims 35-44, further comprising a therapeutic agent.

46. The composition of claim 45, wherein the therapeutic agent is an immunosuppressant, antiviral, antibiotic, antineoplastic, amphetamine, antihypertensive, vasodilator, barbiturate, membrane stabilizer, cardiac stabilizer, glucocorticoid, antilipedemic, antiglycemic, cannabinoid, antidepressant, antineuroleptic, antiinfective, immunomodulator or chemotherapeutic agent.

47. The composition of claim 45 or 46, wherein the therapeutic agent is an immunosuppressant.

48. The composition of claim 45 or 46, wherein the therapeutic agent is a calcineurin inhibitor.

49. The composition of claim 45 or 46, wherein the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, voclosporin, or hydrocortisone.

50. The composition of claim 45 or 46, wherein the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, or voclosporin.

51. The composition of claim 45 or 46, wherein the therapeutic agent is tacrolimus.

52. The composition of claim 45 or 46, wherein the therapeutic agent is cyclosporin.

53. The composition of claim 45 or 46, wherein the therapeutic agent is an antilipedimic agent.

54. The composition of claim 53, wherein the therapeutic agent is an HMG-CoA inhibitor.

55. The composition of claim 54, wherein the therapeutic agent is lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin.

56. The composition of claim 45 or 46, wherein the therapeutic agent is an antihyperglycemic agent.

57. The composition of claim 56, wherein the therapeutic agent is glyburide, glipizide, gliclazide, glimepride, a meglitinide, repaglinide, netaglinide, a biguanide, metformin, a thiazolidinedione, an a-glucosidase inhibitor, acarbose, miglitol, glucagon, somatostatin, or diazoxide.

58. The composition of claim 57, wherein the therapeutic agent is metformin.

59. The composition of claim 57, wherein the therapeutic agent is a thiazolidinedione.

60. The composition of claim 45, wherein the therapeutic agent is insulin.

61. A kit comprising:

(a) quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof;

(b) a therapeutic agent; and

(c) instructions for use of the quercetin-3'-0-sulfate or pharmaceutically acceptable salt, the therapeutic agent, or both.

62. The kit of claim 61 , wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt is in isolated and purified form.

63. The kit of claim 61 or 62, wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 98%.

64. The kit of claim 61 or 62, wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99%.

65. The kit of claim 61 or 62, wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99.7%.

66. The kit of any one of claims 61-65, wherein the pharmaceutically acceptable salt is a sodium or potassium sulfate salt.

67. The kit of any one of claims 61-66, wherein the pharmaceutically acceptable salt is a sodium sulfate salt.

68. The kit of any one of claims 61-66, wherein the pharmaceutically acceptable salt is a potassium sulfate salt.

69. The kit of any one of claims 61-68, wherein the therapeutic agent is an immunosuppressant, antiviral, antibiotic, antineoplastic, amphetamine, antihypertensive, vasodilator, barbiturate, membrane stabilizer, cardiac stabilizer, glucocorticoid, antilipedemic, antiglycemic, cannabinoid, antidepressant, antineuroleptic, antiinfective, immunomodulator or chemotherapeutic agent.

70. The kit of any one of claims 61-69, wherein the therapeutic agent is an immunosuppressant.

71. The kit of any one of claims 61-69, wherein the therapeutic agent is a calcineurin inhibitor.

72. The kit of claim any one of claims 61-69, wherein the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, voclosporin, or hydrocortisone.

73. The kit of claim any one of claims 61-69, wherein the therapeutic agent is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, or voclosporin.

74. The kit of claim any one of claims 61-69, wherein the therapeutic agent is tacrolimus.

75. The kit of claim any one of claims 61-69, wherein the therapeutic agent is cyclosporin.

76. The kit of any one of claims 61-69, wherein the therapeutic agent is an antilipedimic agent.

77. The kit of claim 76, wherein the therapeutic agent is an HMG-CoA inhibitor.

78. The kit of claim 77, wherein the therapeutic agent is lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin.

79. The kit of any one of claims 61-69, wherein the therapeutic agent is an antihyperglycemic agent.

80. The kit of claim 79, wherein the therapeutic agent is glyburide, glipizide, gliclazide, glimepride, a meglitinide, repaglinide, netaglinide, a biguanide, metformin, a thiazolidinedione, an a-glucosidase inhibitor, acarbose, miglitol, glucagon, somatostatin, or diazoxide.

81. The kit of claim 80, wherein the therapeutic agent is metformin.

82. The kit of claim 80, wherein the therapeutic agent is a thiazolidinedione.

83. The kit of any one of claims 61-68, wherein the therapeutic agent is insulin.

84. A method of modulating lipid, cholesterol, triglyceride, insulin or glucose levels in a subject, the method comprising administering to the subject an effective amount of quercetin-3'-0-sulfate or a pharmaceutically acceptable salt thereof.

85. The method of claim 84, wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt is in isolated and purified form.

86. The method of claim 84 or 85, wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 98%.

87. The method of claim 84 or 85, wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99%.

88. The method of claim 84 or 85, wherein the quercetin-3'-0-sulfate or pharmaceutically acceptable salt has a purity of greater than 99.7%.

89. The method of any one of claims 84-88, wherein the pharmaceutically acceptable salt is a sodium or potassium sulfate salt.

90. The method of any one of claims 84-89, wherein the pharmaceutically acceptable salt is a sodium sulfate salt.

91. The method of any one of claims 84-89, wherein the pharmaceutically acceptable salt is a potassium sulfate salt.

92. The method of any of claims 84-91, wherein the method comprises treating a disease selected from diabetes, hyperglycemia, impaired wound healing, neuropathy, insulin resistance, hyperinsulinemia, hypoinsulinemia, hypertension, hyperlipidemia, hypertriglyceridemia, hyperchlesterolemia, microvascular retinopathy, vascular stenosis, inflammation, hydronephrosis, chronic kidney disease, nonalcoholic fatty liver disease, metabolic syndrome and pancreatitis.

93. The method of claim 92, wherein the disease is diabetes.

94. The method of claim 92, wherein the disease is hyperglycemia.

95. The method of claim 92, wherein the disease is insulin resistance.

96. The method of claim 92, wherein the disease is hyperinsulinemia.

97. The method of claim 92, wherein the disease is hyperlipidemia.

98. The method of any one of claims 84-97, wherein the ratio of high density lipoproteins (HDL) concentration to low density lipoproteins (LDL) concentration in the blood of the subject is increased.

99. The method of any one of claims 84-98, further comprising administering to the subject a compound that decreases lipid levels in the subject.

100. The method of claim 99, wherein the compound that decreases lipid levels comprises clofibrate, gemfibrozil, fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, cholestyrine, colestipol, probucol, ascorbic acid, asparaginase, clofibrate, colestipol, fenofibrate, or omega-3 fatty acid.

101. The method of any one of claims 84-98, further comprising administering to the subject a compound that decreases glucose levels in the subject.

102. The method of claim 101 , wherein the compound that decreases glucose levels comprises glipizide, exenatide, incretins, sitagliptin, pioglitizone, glimepiride, rosiglitazone, metformin, exantide, vildagliptin, sulfonylurea, glucosidase inhibitor, biguanide, repaglinide, acarbose, troglitazone, or nateglinide.