WO2009158007A2

WO2009158007A2 - Methods and compositions for therapeutic treatment

Info

Publication number: WO2009158007A2
Application number: PCT/US2009/003798
Authority: WO
Inventors: Wendye Robbins; Ving Lee
Original assignee: Limerick Biopharma, Inc.
Priority date: 2008-06-27
Filing date: 2009-06-26
Publication date: 2009-12-30
Also published as: WO2009158007A3

Abstract

Methods and compositions are described for the modulation of effects of therapeutic agents. Methods and compositions are described for the modulation of efflux transporter activity to increase the efflux of therapeutic agents out of a physiological compartment and into an external environment. In particular, the methods and compositions disclosed herein provide for the increase of efflux transporter activity at blood-tissue, and blood- CSF barriers to increase the efflux of therapeutic agent from physiological compartments, including central nervous system.

Description

METHODS AND COMPOSITIONS FOR THERAPEUTIC TREATMENT

CROSS-REFERENCE

100011 This application claims the benefit of U.S. Provisional Application No. 61/076,591 , filed June 27, 2008; and U.S. Provisional Application No. 61/076,578, filed June 27. 2008; both of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[00021 Although anatomical blood barrier structures, such as the blood-brain barrier (BBB), function as a block, for example, to isolate the central nervous system from the systemic blood circulation, pharmaceutical agents often cross the barrier causing systemic side-effects rather than a desired localized action. 100031 For instance, analgesic agents, often cross the barrier causing systemic side-effects rather than a desired localized action. Therefore, there is a need in the field to find methods and modulators that block entry of unwanted agents into a physiological compartment where they cause unwanted side effects.

SUMMARY OF THE INVENTION

[OΘO4| Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

[0005| All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0006| In one aspect, the invention provides a composition comprising a therapeutic agent capable of inducing one or more symptoms of hypogonadism and a BTB transport protein modulator, wherein the therapeutic agent is present in an amount sufficient to produce a therapeutic effect, and wherein the BTB transport protein modulator is present in an amount sufficient to reduce one or more symptoms of hypogonadism induced by said therapeutic agent. In some embodiments, the invention further comprises a pharmaceutically acceptable carrier. [0007| In another aspect, the invention provides a composition comprising a therapeutic agent capable of inducing one or more symptoms of impairment in hypothalamic/pituitary/endocrine function and a BTB transport protein modulator, wherein the therapeutic agent is present in an amount sufficient to produce a therapeutic effect, and wherein the BTB transport protein modulator is present in an amount sufficient to reduce one or more symptoms of a therapeutic agent-induced impairment in hypothalamic/pituitary/endocrine function. In some embodiments, the symptom is at least partially a result of impairment of secretion of one or more hypothalamic-releasing hormones. In some embodiments, the hypothalamic-releasing hormone is selected from the group consisting of corticotropin-releasing hormone (CRH), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, and thyrotropin-releasing hormone (TRH). In some embodiments, the symptom is at least partially a result of impairment in hypothalamic response to one or more stimuli. In some embodiments, the stimulus is selected from the group consisting of light, olfactory stimuli, steroids, neurally transmitted information, autonomic inputs, blood-borne stimuli, stress, changes in temperature and an invading microorganism. In some embodiments, the symptom is at least partially a result of impairment in pituitary response to one or more hypothalamic-releasing hormones. In some embodiments, the symptom is at least partially a result of impairment of secretion of one or more pituitary hormones. In some embodiments, the symptom is at least partially a result of impairment in a response of one or more endocrine glands to one or more pituitary hormones. In some embodiments, the pituitary hormone is selected from the group consisting of ACTH, TSH, prolactin, growth hormone, endorphins, FSH, LH, oxytocin, and antidiuretic hormone (ADH).

100081 In some embodiments, the therapeutic agent is selected from the group consisting of an antihypertensive and an opiate. In some embodiments, the therapeutic agent is an opiate. In some embodiments, the opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenoφhine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenoφhine, levoφhanol, levalloφhan, β-endoφhin, leu-enkephalin, met-enkephalin, dynoφhin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the opiate is moφhine.

|0009| In some embodiments, the therapeutic agent is selected from the group consisting of non-steroidal antiinflammatory compounds, steroidal compounds, sedative hypnotic drugs, ergot alkaloids, diuretics, vasopressin, agents affecting the renal conservation of water, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, angiotensin converting enzyme inhibitors, β-adrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia, antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, and other, /?-Lactam antibiotics, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in the chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy, antifungal agents, antiviral agents including nonretroviral agents and antiretroviral agents, drugs used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants. [0010] In some embodiments, the therapeutic agent is an antiinfective agent, which is administered in combination with an agent that reduces one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the antiinfective agent, such as a BBB transport protein modulator. Non-limiting examples of antiinfective agents useful in the invention include β-lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, amikacin, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'-trichlorocarbanilide, phenoxyethanol, phenoxy propanol, phenoxyisopropanol, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline, ethambutol, hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, lineomycin, methacycline, methenamine, minocycline, neomycin, netilmicin, paromomycin, streptomycin, tobramycin, miconazole, tetracycline hydrochloride, erythromycin, zinc erythromycin, erythromycin estolate, erythromycin stearate, amikacin sulfate, doxycycline hydrochloride, capreomycin sulfate, chlorhexidine gluconate, chlorhexidine hydrochloride, chlortetracycline hydrochloride, oxytetracycline hydrochloride, clindamycin hydrochloride, ethambutol hydrochloride, metronidazole hydrochloride, pentamidine hydrochloride, gentamicin sulfate, kanamycin sulfate, lineomycin hydrochloride, methacycline hydrochloride, methenamine hippurate, methenamine mandelate, minocycline hydrochloride, neomycin sulfate, netilmicin sulfate, paromomycin sulfate, streptomycin sulfate, tobramycin sulfate, miconazole hydrochloride, amanfadine hydrochloride, amanfadine sulfate, octopirox, parachlorometa xylenol, nystatin, tolnaftate, zinc pyrithione and clotrimazole.

(00111 In some embodiments, the BTB transport protein is a BBB transport protein. In some embodiments, the BTB transport protein is an ABC transport protein. In some embodiments, the ABC transport protein is P-gP. In some embodiments, the BTB transport protein modulator is a flavonoid or flavonoid derivative. In some embodiments, the flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin. In some embodiments, the flavonoid or flavonoid derivative is quercetin or a quercetin derivative. In some embodiments, the quercetin or quercetin derivative is modified. In some embodiments, the modified quercetin or quercetin derivative is phosphorylated. In some embodiments, the flavonoid or flavonid derivative is fisetin or a fisetin derivative. In some embodiments, the fisetin or fisetin derivative is modified. In some embodiments, the modified fisetin or fisetin derivative is phosphorylated. Preferably, the flavonoid is quercetin phosphate, fisetin or fisetin phosphate.

[0012| In some embodiments, the phosphorylated quercetin is 3'-quercetin phosphate, 4'-quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof. In some embodiments, the phosphorylated quercetin is 3'-quercetin phosphate. In some embodiments, the phosphorylated quercetin is 4'-quercetin phosphate. In some embodiments, the phosphorylated quercetin is a mixture of -3 '-quercetin phosphate and 4'-quercetin phosphate. In some embodiments, the phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate. In some embodiments, the phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate. In some embodiments, the phosphorylated fisetin is 3'-fisetin phosphate, 4'- fisetin phosphate, 3-fisetin phosphate, or a combination thereof.

[00131 In some embodiments, the compositions disclosed herein further comprise an oligosaccharide. In some embodiments, the oligosaccharide is a cyclic oligosaccharide. In some embodiments, the oligosaccharide is a cyclodextrin. In some embodiments, the cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin. In some embodiments, the cyclodextrin is hydroxypropyl-β- cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof.

[0014] In some embodiments, the therapeutic agent is morphine and said flavonoid or flavonoid derivative is quercetin or fisetin. In some embodiments, the quercetin is quercetin phosphate. In some embodiments, the fisetin is fisetin phosphate. In some embodiments, the morphine and quercetin or fisetin are present in a molar ratio of about 0.001 : 1 to 10: 1. In some embodiments, the morphine is present at about 1 - 500 mg and quercetin or fisetin is present at about 10-1000 mg. In some embodiments, the morphine is present at about 10 - 200 mg and quercetin or fisetin is present at about 50-500 mg. In some embodiments, the morphine is present at about 50 mg and quercetin or fisetin is present at about 500 mg. In some embodiments, the therapeutic agent is sufentanyl and said flavonoid or flavonoid derivative is quercetin or fisetin. In some embodiments, the therapeutic agent is alfentanyl and said flavonoid or flavonoid derivative is quercetin or fisetin. In some embodiments, the therapeutic agent is remifentanyl and said flavonoid or flavonoid derivative is quercetin or fisetin. In some embodiments, the symptom of hypogonadism induced by said therapeutic agent is decreased by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50% compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal. In some embodiments, the symptom is a result of impairment of secretion of one or more hypothalamic-releasing hormones. In some embodiments, the symptom is selected from the group consisting of premature menopause, decrease of energy, fatigue, muscle mass decline, increase visceral fat, decreased positive mood factors and an increased negative mood factors, depression, decrease in fertility, decrease in libido and sexual function, increased risk for osteoporosis, increased pain sensitization, hematological abnormalities, decrease in cognitive skills, sleep disturbances, vasomotor instability, increase CAD risk, changes in secondary sex characteristic and decrease in circulating sex hormones. In some embodiments, the symptom is a decrease in circulating sex hormones. In some embodiments, the amount of said BTB transport modulator is sufficient to prevent, reduce, or eliminate said decrease in circulating sex hormones. In some embodiments, the symptom is a decrease in circulating testosterone. In some embodiments, included is a kit comprising the compositions disclosed herein and instructions for use of the composition.

[0015| In some embodiments, the symptom of a therapeutic agent-induced impairment in hypothalamic/pituitary/endocrine function is decreased at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50% compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal.

[0016| In another aspect, the invention provides methods for decreasing or preventing the appearance of one or more symptoms of hypogonadism induced by a therapeutic agent comprising administering to a subject receiving said therapeutic agent.an amount of a BTB transport protein modulator sufficient to prevent, reduce or eliminate said one or more symptoms of hypogonadism. In some embodiments, the subject is suffering from or is suspected to suffer from one or more symptoms of hypogonadism induced or capable of being induced by treatment with said therapeutic agent. In some embodiments, the BTB transport protein modulator is a BTB protein transport activator. In some embodiments, the symptom is selected from the group consisting of premature menopause, decrease of energy, fatigue, muscle mass decline, increase visceral fat, decreased positive mood factors and an increased negative mood factors, depression, decrease in fertility, decrease in libido and sexual function, increased risk for osteoporosis, increased pain sensitization, hematological abnormalities, decrease in cognitive skills, sleep disturbances, vasomotor instability, increase CAD risk, changes in secondary sex characteristic and decrease in circulating sex hormones. In some embodiments, the symptom is a decrease in circulating sex hormones. In some embodiments, the symptom is a decrease in circulating testosterone. JOOlTl In another aspect, the invention provides methods for decreasing or preventing the appearance of one or more symptoms of impairment in hypothalamic/pituitary endocrine function induced by a therapeutic agent comprising: administering to a subject receiving or who is going to receive treatment with said therapeutic agent an amount of a BTB transport protein modulator sufficient to reduce said impairment in hypothalamic function in combination with said therapeutic agent. In some embodiments, the subject has or is suspected to have impairment in a hypothalamic/pituitary/endocrine function. In some embodiments, the symptom is at least partially a result of impairment of secretion of one or more hypothalamic-releasing hormone. In some embodiments, hypothalamic-releasing hormone is selected from the group consisting of corticotropin-releasing hormone (CRH), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, and thyrotropin-releasing hormone (TRH). In some embodiments, the symptom is at least partially a result of impairment in hypothalamic response to one or more stimuli. In some embodiments, the stimuli is selected from the group consisting of light, olfactory stimuli, steroids, neurally transmitted information, autonomic inputs, blood-borne stimuli, stress, changes in temperature and an invading microorganism. In some embodiments, the symptom is at least partially a result of impairment in pituitary response to one or more hypothalamic-releasing hormone. In some embodiments, the symptom is at least partially a result of impairment of secretion of one or more pituitary hormones. In some embodiments, the symptom is at least partially a result of impairment in a response of one or more endocrine glands to one or more pituitary hormones. In some embodiments, the pituitary hormone is selected from the group consisting of ACTH, TSH, prolactin, growth hormone, endorphins, FSH, LH, Oxytocin, and antidiuretic hormone (ADH). [0018] In some embodiments, the BTB transport protein is a BBB transport protein. In some embodiments, the BTB transport protein is an ABC transport protein. In some embodiments, the ABC transport protein is P-gP. In some embodiments, the BTB transport protein modulator is a flavonoid or flavonoid derivative. In some embodiments, the flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fϊsetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin. In some embodiments, the flavonoid or flavonoid derivative is quercetin or a quercetin derivative. In some embodiments, the quercetin or quercetin derivative is modified. In some embodiments, the modified quercetin or quercetin derivative is phosphorylated. In some embodiments, the flavonoid or flavonoid derivative is fisetin or a fisetin derivative. In some embodiments, the fisetin or fisetin derivative is modified. In some embodiments, the modified fisetin or fisetin derivative is phosphorylated. Preferably, the flavonoid or flavonid derivative is quercetin phosphate, fisetin or fϊsetin phosphate.

|0019| In some embodiments, the phosphorylated quercetin is 3'-quercetin phosphate, 4'-quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof. In some embodiments, the phosphorylated quercetin is 3'-quercetin phosphate. In some embodiments, the phosphorylated quercetin is 4'-quercetin phosphate. In some embodiments, the phosphorylated quercetin is a mixture of 3 '-quercetin phosphate and 4'-quercetin phosphate. In some embodiments, the phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate. In some embodiments, the phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate. In some embodiments, the phosphorylated fisetin is 3'-fisetin phosphate, 4'- fisetin phosphate, 3 -fisetin phosphate, or a combination thereof.

[0020] In some embodiments, the composition further comprises an oligosaccharide. In some embodiments, the oligosaccharide is a cyclic oligosaccharide. In some embodiments, the oligosaccharide is a cyclodextrin. In some embodiments, the cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin. In some embodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof.

(00211 In some embodiments, the therapeutic agent is selected from the group consisting of an antihypertensive and an opiate. In some embodiments, the therapeutic agent is an opiate. In some embodiments, the opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu-enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the opiate is morphine. In some embodiments, the opiate is sufentanyl. In some embodiments, the opiate is alfentanyl. In some embodiments, the opiate is remifentanyl. In some embodiments, the administration comprises single or multiple doses of said therapeutic agent and single or multiple doses of said BTB transport protein modulator. In some embodiments, the administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form, concurrent administration in separate dosage forms, or separate administration. In some embodiments, the administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form. In some embodiments, the molar ratio of the amount of the therapeutic agent administered and the amount of BTB transport protein modulator administered is about 0.001 :1 to about 10: 1. In some embodiments, the therapeutic agent is administered in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is administered in an amount sufficient to decrease or prevent the appearance of one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary endocrine function induced by the therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50%, compared to the symptom without the BTB transport protein modulator.

100221 In another aspect of the invention, disclosed are compositions comprising a therapeutic agent capable of inducing a decrease in circulating sex hormone levels and a BTB transport protein modulator, wherein the therapeutic agent is present in an amount sufficient to produce a therapeutic effect, and wherein the BTB transport protein activator is present in an amount sufficient to prevent or reduce a therapeutic agent-induced decrease in circulating sex hormone levels. In some embodiments, the decrease in circulating sex hormone is selected from the group consisting of decrease in circulating androgens, decrease in circulating estrogens, and decrease in circulating progestagens. In some embodiments, the decrease in circulating sex hormone is decrease in circulating androgens. In some embodiments, the decrease in circulating androgens is selected from the group consisting decrease in circulating testosterone, decrease in circulating androstenedione, decrease in circulating dihydrotestosterone, decrease in circulating dehydroepiandrosterone, and decrease in circulating anabolic steroids. In some embodiments, the decrease in circulating androgens is impairment in testosterone. [ 00231 In some embodiments of the compositions disclosed herein, the compositions further comprise a pharmaceutically acceptable carrier. In some embodiments, the therapeutic agent is selected from the group consisting of an anti hypertensive and an opiate. In some embodiments, the therapeutic agent is an opiate. In some embodiments, the opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu-enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the opiate is morphine.

[0024| In some embodiments of the compositions disclosed herein, the BTB transport protein is a BBB transport protein. In some embodiments, the BTB transport protein is an ABC transport protein. In some embodiments, the ABC transport protein is a P-gP. In some embodiments, the BTB transport protein modulator is a flavonoid or flavonoid derivative. In some embodiments, the flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin. In some embodiments, the flavonoid or flavonoid derivative is quercetin or a quercetin derivative. In some embodiments, the quercetin or quercetin derivative is modified. In some embodiments, the modified quercetin or quercetin derivative is phosphorylated. In some embodiments, the phosphorylated quercetin is 3 '-quercetin phosphate, 4'-quercetin phosphate, 5,7- dideoxyquercetin phosphate, or a combination thereof. In some embodiments, the phosphorylated quercetin is 3 '-quercetin phosphate. In some embodiments, the phosphorylated quercetin is 4'-quercetin phosphate. In some embodiments, the phosphorylated quercetin is a mixture of 3'-quercetin phosphate and 4'-quercetin phosphate. In some embodiments, the phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate. In some embodiments, the phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate. In some embodiments, the flavonoid or flavonoid derivative is fisetin or a fisetin derivative. In some embodiments, the fisetin or fisetin derivative is modified. In some embodiments, the modified fisetin or fisetin derivative is phosphorylated.

[00251 In some embodiments of the compositions disclosed herein, the compositions further comprise an oligosaccharide. In some embodiments, the oligosaccharide is a cyclic oligosaccharide. In some embodiments, the oligosaccharide is a cyclodextrin. In some embodiments, the cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin. In some embodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether- 7- β-cyclodextrin, Captisol or combinations thereof. In some embodiments, the therapeutic agent is morphine and said flavonoid or flavonoid derivative is quercetin or fϊsetin.

[0026| In some embodiments of the compositions disclosed herein, the morphine and quercetin are present in a molar ratio of about 0.001 : 1 to 10: 1. In some embodiments, the morphine is present at about l - 500 mg and quercetin is present at about 10-1000 mg. In some embodiments, the morphine is present at about 10 - 200 mg and quercetin is present at about 50-500 mg. In some embodiments, the morphine is present at about 50 mg and quercetin is present at about 500 mg. In some embodiments, the therapeutic agent is sufentanyl and said flavonoid or flavonoid derivative is quercetin or fϊsetin. In some embodiments, the therapeutic agent is alfentanyl and said flavonoid or flavonoid derivative is quercetin or fϊsetin. In some embodiments, the therapeutic agent is remifentanyl and said flavonoid or flavonoid derivative is quercetin or fϊsetin. In some embodiments of the compositions disclosed herein, the impairment in sex hormone secretion induced by said therapeutic agent is decreased at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50% compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal. [0027| Also disclosed are methods of preventing or reducing a therapeutic agent-induced decrease in circulate sex hormone levels comprising providing a subject receiving treatment with said therapeutic agent with a known or suspected decrease in circulating sex hormone levels and administering to said subject an amount of a BTB transport protein modulator sufficient to prevent, reduce or eliminate said therapeutic agent-induced decrease in circulating sex hormone levels in combination with said therapeutic agent. In some embodiments, the decrease in circulating sex hormone levels is selected from the group consisting of decrease in circulating androgen levels, decrease in circulating estrogen levels, and decrease in circulating progestagen levels. In some embodiments, the decrease in circulating sex hormone levels is impairment in androgen levels. In some embodiments, the decrease in circulating androgen levels is selected from the group consisting of decrease in circulating testosterone decrease in circulating, decrease in circulating androstenedione levels, decrease in circulating dihydrotestosterone levels, decrease in circulating dehydroepiandrosterone levels, decrease in circulating anabolic steroids levels. In some embodiments, the decrease in circulating androgen levels is decrease in circulating testosterone levels. In some embodiments, the therapeutic agent is administered in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is administered in an amount sufficient to decrease an impairment in sex hormone secretion induced by the therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50%, compared to the impairment without the BTB transport protein modulator.

100281 Also disclosed herein are methods of preventing or reducing a therapeutic agent-induced decrease in circulating androgen levels comprising determining the sex of a subject receiving treatment with said therapeutic agent and administering to the subject an amount of a BTB transport protein modulator sufficient to prevent, reduce or eliminate said therapeutic agent-induced decrease in circulating androgen levels in combination with said therapeutic agent. In some embodiments, the therapeutic agent is administered in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is administered in an amount sufficient to reduce a decrease in circulating androgen levels induced by the therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50%, compared to the impairment without the BTB transport protein modulator.

BRIEF DESCRIPTION OF THE DRAWINGS

|0029] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

|0030] Figure 1 depicts blood brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier which regulates access to the brain.

|0031 ] Figure 2 depicts various transporters that regulate rate of brain permeation for compounds with varying lipophilicity.

10032 J Figure 3 provides an illustration of active transporters for both influx and efflux.

[0033) Figure 4 shows the incidence of hypogonadism in healthy males and males under opiate treatment.

(0034] Figure 5 shows that quercetin potentiates removal of morphine from rodent brain.

[0035] Figure 6 shows dose-dependent uptake of morphine in BB 19 cells.

[0036] Figure 7A shows uptake of morphine in BB 19 cells in the presence of different concentrations of quercetin-DH

[0037] Figure 7B shows uptake of morphine in BB 19 cells in the presence of different concentrations of quercetin-3G.

|0038| Figure 8A shows uptake of morphine in BB 19 cells in the presence of different concentrations of quercetin-DH

|0039| Figure 8B shows uptake of morphine in BB 19 cells in the presence of different concentrations of quercetin-3G

(0040J Figure 9A shows uptake of morphine in BB 19 cells in the presence of different concentrations of isorhamentin.

|0041] Figure 9B shows uptake of morphine in BB 19 cells in the presence of different concentrations of kaempferol.

[0042] Figure 1OA shows uptake of morphine in BB 19 cells in the presence of different concentrations of isorhamentin.

[0043] Figure 1OB shows uptake of morphine in BB19 cells in the presence of different concentrations of tamarexin.

100441 Figure 11 shows the changes of total testosterone at different time points after treatment with morphine alone or in combination with quercetin.

[0045| Figure 12 shows the changes of free testosterone at different time points after treatment with morphine alone or in combination with quercetin. [0046] Figure 13 shows the free androgen index at different time points after treatment with morphine alone or in combination with quercetin.

DETAILED DESCRIPTION OF THE INVENTION

|0047] Reference will now be made in detail to particularly preferred embodiments of the invention. Examples of the preferred embodiments are illustrated in the following Examples section.

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. AU patents and publications referred to herein are incorporated by reference.

Introduction

[0049] The invention provides compositions and methods utilizing an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by one or more substances. In some embodiments, the invention provides compositions and methods utilizing a combination of a therapeutic agent and an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. Typically, the agent capable of decreasing hypogonadism or impairment in hypothalamic/pituitary /endocrine function symptom is a modulator of a blood tissue barrier (BTB) transport protein. The methods and compositions are useful in the treatment of an animal in need of treatment, where it is desired that one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent be reduced or eliminated while one or more of the therapeutic effects of the agent are retained or enhanced. In some embodiments, the animal receiving treatments is known or is suspected to have one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments, the sex of the animal receiving the treatment is determined.

[0050J In some embodiments of the invention, the therapeutic agent is an agent capable of inducing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments of the invention, the therapeutic agent is an analgesic agent, such as an opiate or a non-opiate analgesic. In some embodiments of the invention, the therapeutic agent is a non-analgesic agent. In some embodiments, the agent is an anti hypertensive agent.

[00511 The agent causing a decrease in the symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent, e.g., a modulator of a BTB transport protein, may be an activator or an inhibitor of the protein. The modulatory effect may be dose-dependent, e.g., some modulators act as activators in one dosage range and inhibitors in another. In some embodiments, a modulator of a BTB transport protein is used in a dosage wherein it acts primarily as an activator. [0052] Typically, the use of the BTB transport protein modulator, e.g., activator, results in a decrease in one or more one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. The therapeutic effect(s) of the agent may be decreased, remain the same, or increase; however, in preferred embodiments, if the therapeutic effect is decreased, it is not decreased to the same degree as the symptom of hypogonadism orimpairment in hypothalamic/pituitary/endocrine function. It will be appreciated that a given therapeutic agent may have more than one therapeutic effect and or one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function, and it is possible that the therapeutic ratio (in this case, the ratio of change in desired effect to change in undesired effect) may vary depending on which effect is measured. However, at least one therapeutic effect of the therapeutic agent is decreased to a lesser degree than at least one symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent.

[0053| In addition, in some embodiments, one or more therapeutic effects of the agent is enhanced by use in combination with a BTB transport protein modulator, while one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is reduced or substantially eliminated. For example, in some embodiments where the therapeutic agent is an analgesic, the analgesic effect of an analgesic agent is enhanced while one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the agent is reduced or substantially eliminated. [0054] Without being bound by theory, and as an example only of a possible mechanism, it is thought that the methods and compositions of the invention operate by reducing or eliminating the concentration of the therapeutic agent from the CNS (e.g., brain), while retaining or even increasing the effective concentration of the agent in the periphery. Agents that act at least in part by peripheral mechanisms may thus retain some or all of their activity, or even display enhanced therapeutic activity, while at the same time CNS are reduced or eliminated. However, it is recognized that the mechanism of action of a particular BTB transport protein modulator in decreasing one or more symptoms as described herein may be different, or in addition to, modulation of a BTB transport protein, and that an agent that has BTB transport protein-modulating activity may nonetheless act by a different mechansim than BTB transport protein modulation. It is also possible for an agent to modulate more than one BTB tranport protein, and the overall effect will depend on the summation of all mechanisms by which an agent works.

[0055| It will be appreciated that the therapeutic effect and/or symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent may be mediated in part or in whole by one or more metabolites of the therapeutic agent, and that a BTB protein modulator that reduces or eliminates the concentration of the therapeutic agent and/or of one or active metabolites of the therapeutic agent in the physiological compartment that produce the symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function, while retaining or enhancing a peripheral concentration of the therapeutic agent and/or one or more metabolites producing a therapeutic effect, is also encompassed by the methods and compositions of the invention. In addition, a BTB transport modulator itself may be metabolized to metabolites that have differing activities in the modulation of one or more BTB transport modulators, and these metabolites are also encompassed by the compositions and methods of the invention.

[0056] Hence, in some embodiments the invention provides compositions that include a therapeutic agent and a BTB transport protein modulator, where the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is present in an amount sufficient to decrease symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent when compared to the symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function without the BTB transport protein modulator, when the composition is administered to an animal. The decrease in the symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the agent can be measurable. The BTB transport protein modulator is a BTB transport protein activator in some embodiments. In some embodiments the BTB transport protein modulator is a modulator of ATP binding cassette (ABC) transport proteins. In some embodiments the BTB transport protein modulator is a modulator of P-glycoprotein (P-gP).

|0057| In some embodiments, compositions of the invention include one or more therapeutic agent as well as one or more than one BTB transport protein modulators. One or more of the therapeutic agents may induce one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function which are desired to be decreased.

|0058| Compositions of the invention may be prepared in any suitable form for administration to an animal. In some embodiments, the invention provides pharmaceutical compositions.

[0059) In some embodiments, the invention provides compositions suitable for oral administration. In some embodiments, compositions are suitable for transdermal administration. In some embodiments, compositions are suitable for injection by any standard route of injection, e.g., intravenous, subcutaneous, intramuscular, or intraperitoneal. Compositions suitable for other routes of administration are also encompassed by the invention, as described herein.

[0060] BTB transport protein modulators of use in the invention include any suitable BTB transport modulators. In some embodiments, the BTB transport protein modulator is one or more pyrone analogs. In some embodiments, the BTB transport protein modulator is one or more polyphenols. In some embodiments, the BTB transport protein modulator is one or more flavonoids. In some embodiments, the BTB transport protein modulator is quercetin or a quercetin derivative. In some embodiments, the BTB transport protein modulator is fisetin or a fisetin derivative.

[00611 Therapeutic agents of use in the invention include any agent capable of inducing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function where it is desired to reduce or eliminate, while retaining or enhancing a therapeutic effect of the agent. In some instances a symptom may be desirable in some cases and undesirable in others. It is within the invention to titrate the combination of dosage of therapeutic agent and of BTB transport protein modulator in such a way as to obtain a ratio of therapeutic effect to hypogonadism or impairment in hypothalamic/pituitary/endocrine function symptom that is considered optimal. Thus, in some embodiments, one or more symptoms of hypogonadism induced by the therapeutic agent is reduced but not eliminated. In some embodiments of the invention, the therapeutic agent is an agent capable of inducing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In other embodiments, one or more symptoms of hypogonadism induced by the therapeutic agent are substantially eliminated. In some embodiments of the invention, the therapeutic agent is an analgesic agent, such as an opiate or a non-opiate analgesic. In some embodiments of the invention, the therapeutic agent is a non-analgesic agent. In some embodiments, the agent is an anti hypertensive agent. 100621 In some embodiments the invention provides methods of treatment. In certain embodiments, the invention provides a method of treating a condition by administering to an animal suffering from the condition an effective amount of a therapeutic agent and an amount of a BTB transport protein modulator, e.g., activator, sufficient to reduce or eliminate a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments the BTB transport protein modulator is a BTB transport protein activator. In some embodiments, the therapeutic agent is an analgesic agent, e.g., an opiate. In certain embodiments the invention provides methods of treatment of pain, e.g., chronic pain, by administration of an analgesic, e.g., an opiate, without the development of one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function, by co-administering a modulator of a BTB transport protein in combination with the analgesic, thereby preventing or delaying development of one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. 10063 ] In some embodiments the invention provides methods of decreasing one or more symptoms of hypogonadismor impairment in hypothalamic/pituitary/endocrine function of an agent in an animal, e.g. a human, that has received an amount of the agent sufficient to produce a hypogonadism or an impairment in hypothalamic/pituitary/endocrine function symptom by administering to the animal, e.g., human, an amount of a BTB transport protein modulator sufficient to reduce or eliminate the impairment in hypothalamic/pituitary/endocrine function symptom. In some embodiments of the invention, the therapeutic agent is an agent capable of inducing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments of the invention, the therapeutic agent is an analgesic agent, such as an opiate or a non-opiate analgesic. In some embodiments of the invention, the therapeutic agent is a non-analgesic agent. In some embodiments, the agent is an anti hypertensive agent. In some embodiments, the animal receiving treatments is known or is suspected to have one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments, the sex of the animal receiving the treatment is determined.

Blood-Tissue Barrier

[00641 In some embodiments, the invention provides methods and compositions that modulate a blood tissue barrier (BTB) transport protein. BTB transport proteins play a role in the maintenance of barrier to foreign molecules and/or removal of substances from spaces (e.g. cells). The barrier can be a boundary between blood and a physiological compartment such as a cell, an organ, or a tissue. The barrier can be a cell membrane or a layer of cells. One example of such barrier is the blood brain barrier.

A. Blood Brain Barrier

[0065| The access to the brain is controlled by at least two barriers, i.e., blood brain barrier (BBB) and blood- cerebrospinal fluid (CSF) barrier (see FIG. 1). As used herein, the term "blood brain-barrier" can encompass the blood-brain and blood-CSF barriers, unless otherwise indicated. The methods and compositions described herein are suitable for modulating the access of drugs into the brain. In some embodiments, the methods and compositions involve the modification of the blood brain barrier and/or blood-CSF barrier to prevent the entry of drugs into the central nervous system (CNS), e.g., by promoting efflux of the drugs from the CNS. In some embodiments, the compositions and methods of the invention utilize a modulator of a blood brain-barrier transport protein. In some embodiments, the compositions and methods of the invention utilize an activator of a blood brain-barrier transport protein.

[00661 The blood brain barrier is formed by tight intercellular junctions of brain capillary endothelial cells. The junctions are sealed by zonulae occludentes and tight junctions. The capillaries are covered by a continuous basal membrane enclosing pericytes, an intermittent cell layer, and the outer basal membrane is contacted by astrocytes. The electrical resistance across the endothelium is high, about 1500 to about 2000 'Ω/cm². [00671 The blood brain barrier regulates the transfer of substances between circulating blood and brain by facilitated transport and/or facilitated efflux. The interface on both luminal and abluminal surfaces contain physical and metabolic transporter components. [0068] The exchange of substances between circulating blood and brain can be determined by evaluating octanol/H₂0 partition coefficient, facilitated transport, and/or facilitated efflux. The methods of measuring blood brain barrier integrity can be used to identify suitable central nervous system modulators for use in the methods and compositions described herein.

|0069| Various transporters exist to regulate rate of brain permeation for compounds with varying lipophilicity (see FIG. 2). Generally, hydrophilic nutrients, such as glucose and amino acids, are allowed entry into the physiological compartments of the methods and compositions disclosed herein. Conversely, compounds with low lipophilicity are pumped away from the physiological compartments by, for example, xenobiotic efflux transporters. These transporters are preferably modulated by the methods and compositions described herein to prevent entry of compounds and drugs into the central nervous system.

[0070J The blood CSF barrier is formed by the tight junctions of the epithelium of the choroid plexus and arachnoid membrane surrounding the brain and spinal cord. It is involved in micronutrient extraction, clearance of metabolic waste, and transport of drugs.

[00711 Mechanisms and routes of compounds into and out of brain include - paracellular aqueous pathway for water soluble agents, transcellular lipophilic pathway for lipid soluble agents, transport proteins for glucose, amino acids, purines, etc., specific receptor mediated endocytosis for insulin, transferrin, etc., adsorptive endocytosis for albumin, other plasma proteins, etc., and transporters (e.g., blood-brain barrier transport proteins) such as P-glycoprotein (P-gP), multi-drug resistance proteins (MRP), organic anion transporter (OAT) efflux pumps, gamma-am inobutyric acid (GABA) transporters and other transporters that modulate transport of drugs and other xenobiotics. Methods and compositions of the invention may involve modulation of one or more of these transporters. Preferably, the central nervous system modulators affect one or more of these mechanisms and routes to extrude drugs from the central nervous system.

[0072J The methods and compositions described herein also modulate other CNS barriers, such as neuronal transport barriers, as well as other CNS barriers.

|0073| In some embodiments, the blood brain barrier is modulated with a nitric oxide synthase (NOS) inhibitor. Preferably, the NOS inhibitor is a NOS-3 inhibitor. Non-limiting examples of NOS-3 inhibitors include analogs of L-arginine, such as N^G-Monomethyl-L-Arginine (L-NMMA), L-N-Methyl Arginine (L- NMA), N^G-Nitro-L-Arginine Methyl Ester (L-NAME), 7-nitroindazole (7-NI). See WO 00/23102, herein incorporated by reference in its entirety.

B. Blood-Tissue Barrier Transporters

[0074| In some embodiments, the invention provides methods and compositions that modulate ATP Binding Cassette (ABC) transport proteins. ABC transport proteins are a superfamily of membrane transporters with similar structural features. These transport proteins are widely distributed in prokaryotic and eukaryotic cells. They are critical in the maintenance of barrier to foreign molecules and removal of waste from privileged spaces, and may be overexpressed in certain glial tumors conferring drug resistance to cytotoxic drugs. 48 members of the superfamily are described. There are 7 major subfamilies, which include ABC A-G. Subfamilies C, B, and G play a role in transport activity at blood brain barrier and blood-CSF barrier. ABC A substrates include lipids and cholesterol; ABC B transporters include P-glycoprotein (P-gP) and other multi drug resistance proteins (MRPs); ABC C contains MRP proteins; ABC E is expressed in ovary, testis and spleen; and ABC G contains breast cancer resistance protein (BCRP). |0075| Other examples of blood-CSF barrier transporters that can be modulated by methods and compositions of the invention include organic anion transport systems (OAT), P-gP, and the GABA transporters - GAT-I and GAT2/BGT- 1. Substrate compounds for OATs include opiate peptides, including enkephalin and deltorphin II, anionic compounds, indomethacin, salicylic acid and cimetidine. OATs are inhibited by baclofen, tagamet, indomethacin, etc. and transport HVA (dopamine metabolite) and metabolites of norepinephrine, epinephrine, 5- HT3, and histamine.

|0076| GABA transporters are Na and Cl dependent, and are specific for GABA, taurine, β alanine, betaine, and nipecotic acid. GAT2 transporters are localized to abluminal and luminal surfaces of capillary endothelial cells. GAT-I is localized to the outside of neurons and glia. GABA-transporter substrates include lorazepam, midazolam, diazepam, klonazepam and baclofen. Probenicid inhibits luminal membrane GABA transporters from capillary endothelial cells. GAT-I is inhibited by Tiagabine.

[0077] In some embodiments, the invention provides methods and compositions that modulate P-gP, e.g., that activate P-gP. P-gP, also known as ABCBl , forms a protective barrier to pump away by excreting compounds into bile, urine, and intestinal lumen. Three isoforms have been identified in rodents (mdrla, mdrl b, mdr2) and two in humans (MDRl and MDR2). It is expressed in epithelium of the brain choroid plexus (which forms the blood-cerebrospinal fluid barrier), as well as on the luminal surface of blood capillaries of the brain (blood-brain barrier) and other tissues known to have blood-tissue barriers, such as the placenta, the ovaries, and the testes. |0078| In the brain, P-gP is expressed in multiple cell types within brain parenchyma including astrocytes and microglia and in luminal plasma membrane of capillary endothelium where it acts as a barrier to entry and efflux pump activity. P-gP transports a wide range of substrates out of cerebral endothelial cells into vascular lumen. P-gP is also expressed in the apical membrane of the choroid plexus and may transport substances into CSF. |0079| P-gP substrates include molecules that tend to be lipophilic, planar molecules or uncharged or positively charged molecules. Non-limiting examples include organic cations, weak organic bases, organic anions and other uncharged compounds, including polypeptides and peptide derivatives, aldosterone, anthracyclines, colchicine, dexamethasone, digoxin, diltiazem, HIV protease inhibitors, loperamide, MTX, morphine, ondansetron, phenytoin and β-blockers. Inhibitors of P-gP include quinidine, verapamil, rifampin, PSC 833 (see Schinkel, J. Clin Invest., 1996, herein incorporated by reference in its entirety), carbamazepine, and amitryptiline.

[0080| Brain penetration of a number of recognized compounds has been shown to be dependent on P-gP transport activity. Substrates of P-gP include opioids (morphine, meperidine, pentazocine, methadone, and fentanyl), tricyclic antidepressants (including amitriptyline and nortriptyline), glucocorticoids (prednisone, prednisolone, Cortisol, aldosterone, and dexamethasone), antiepileptic drugs (phenytoin, topiramate, and valproic acid), non-sedating antihistamines (cetirizine, loratadine) and antibiotic and antiretroviral agents. In some instances (e.g., loperamide), P-gP appears to completely restrict access to the CNS. In other circumstances (e.g., morphine), CNS penetration appears to be only partially restricted by PgP in the natural state. [00811 Multi-drug resistance protein (MRP) substrates include acetaminophen glucoronide, protease inhibitors, methotrexate and ampicillin. Inhibitors of MRP include buthionine sulphoximine, an inhibitor of glutathione biosynthesis. 100821 Further information on transporters that can be modulated in embodiments of the methods and compositions of the invention are provided in Table 1 below. Fig. 3 also provides an illustration of active transporters for both influx and efflux.

Table 1 - Active Transporters in the Blood-Brain Barrier.

C. Placental Barriers

[0083] Access to the fetus from the maternal circulation is controlled by the placenta, a physical barrier that separates the blood supply of the mother and fetus. The major function of the placenta is to transfer nutrients and oxygen from the mother to the fetus and to assist in the removal of waste products from the fetus to the mother. The placenta, therefore, provides a link between the maternal and fetal circulations while simultaneously acting as a barrier to protect the fetus from foreign substances in the maternal blood. Thus, some embodiments of the methods and compositions described herein are for the modulation of access of drugs, chemicals and other substances through the placenta. In some embodiments, the methods and compositions involve the modification of the placental barrier to prevent the entry of drugs through the placental barrier and into the fetal environment, e.g., by efflux of drugs across the placenta.

[0084] Modulation of the placental barrier to prevent entry of drugs or other foreign substances to the fetal environment is important because of the sensitivity of the fetus to such substances. Studies have shown that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the fetus via passive diffusion, potentially harming the fetus during its growth and developmental stages. See, e.g., Syme, M. R. et al., Clin. Pharmacokinet. 43:487-514 (2004), herein incorporated by reference in its entirety. In addition, the fetus may be additionally harmed by drugs that are actively pumped across the placenta by various transporters located on both the fetal and maternal side of the trophoblast layer. Facilitated diffusion also appears to be a minor transfer mechanism for some drugs. Modulation of the entry pathways through the placenta, therefore, is important to preventing fetal exposure to drugs and other substances present in the maternal circulation.

Placental Development and Anatomy

[0085| One of the functions of the placenta, in addition to its barrier-purpose, is to connect the fetus to the uterine wall near the fundus uteri, and more frequently on the posterior than on the anterior wall of the uterus. The placenta during fetal development is formed through the interweaving of both fetal and maternal portions, which allows the close proximity localization of the maternal and fetal circulation systems. [0086] The fetal portion of the placenta consists of the villi of the chorion frondosum. These structures branch repeatedly, and increase in size throughout the fetal developmental stages. The chorion frondosum villi are suspended in the intervillous space where they are bathed in maternal blood. The circulation within the villi are conveyed to the space by the uterine arteries and carried away by the uterine veins. A branch of an umbilical artery enters each villus and ends in a capillary plexus from which the blood is drained by a tributary of the umbilical vein. The vessels of the villus are surrounded by a thin layer of mesoderm consisting of gelatinous connective tissue, which is covered by two strata of ectodermal cells derived from the trophoblast: the deeper stratum. The next layer of tissue consists of the mesodermic tissue, which represents the cytotrophoblast or layer of Langhans. The superficial layer, which is in contact with the maternal blood, is the syncytiotrophoblast. After the fifth month, the two strata of cells are replaced by a single layer of flattened cells. |0087| The maternal portion of the placenta is formed by the decidua placentalis containing the intervillous space. As mentioned above, this space is produced by the enlargement and intercommunication of the spaces in the trophoblastic network. The changes involve the disappearance of the greater portion of the stratum compactum, but the deeper part of this layer persists and is condensed to form what is known as the basal plate. Between the basal plate and the uterine muscular fibers are the stratum spongiosum and the boundary layer. Through the stratum spongiosum, boundary layer and the basal plate, the uterine arteries and veins pass to and from the intervillous space. The endothelial lining of the uterine vessels ceases at the point where they terminate in the intervillous space, which is lined by the syncytiotrophoblast. Portions of the stratum compactum persist and are condensed to form a series of septa, which extend from the basal plate through the thickness of the placenta and subdivide it into the lobules or cotyledons seen on the uterine surface of the detached placenta. The cotyledons function as a vascular unit within the placenta.

|0088] The fetal and maternal blood currents traverse the placenta, the former passing through the blood vessels of the placental villi and the latter through the intervillous space. The two circulations do not intermingle, being separated from each other by the delicate walls of the villi. Nevertheless, the fetal blood is able to absorb, through the walls of the villi, oxygen and nutritive materials from the maternal blood, and give up to the latter its waste products. The purified blood is carried back to the fetus by the umbilical vein. The placenta, therefore, not only establishes a mechanical connection between the mother and the fetus, but also provides nutrition, respiration, and excretion services for the fetus.

|0089| During embryonic and early fetal development, the maternal blood does not communicate with the fetal circulation through the placenta. Maternal blood does not perfuse the placenta during the embryonic period and the feto-placental-maternal circulation does not become established until around the tenth week of pregnancy. Hence, access of drugs and other chemicals present in the maternal blood during the first 10 weeks of gestation occurs via diffusion through extracellular fluid. Maternal blood access to the placental circulation only occurs after development and establishment of the feto-placental-maternal circulation.

D. Placental Transport Mechanisms

|0090| Transplacental exchanges are known to involve passive transfer, active transport, facilitated diffusion, phagocytosis and pinocytosis. See, e.g., Pacifici GM, et al., Clin. Pharmacokinet. 28:235-69 (1995), herein incorporated by reference. Studies, however, have shown that phagocytotic and pinocytotic mechanisms are too slow to have any significant influence on drug or chemical transfer from the maternal circulation to the fetus. Syme et al. (2004). Therefore, one embodiment of the methods and compositions disclosed herein is to modulate passive transfer, facilitated diffusion and active transport of drugs, chemicals and other substances across the placental barrier.

Passive Transfer

[00911 One embodiment is the modulation of passive transfer of drugs, chemicals and other substances across the placental barrier. Passive transfer represents the permeation of a molecule through a physical barrier, such as a cell membrane, down its concentration gradient. Passive diffusion does not require the input of energy, is not saturable and is not subject to competitive inhibition. When drugs cross the placenta by passive diffusion, the amount that crosses in any given time is dependent on the concentration of the drug in the maternal circulation, its physicochemical properties and the properties of the placenta that determine how readily the drug will pass. [0092] Passive diffusion is favored for low-molecular weight and highly lipid-soluble drugs that are predominantly un-ionized. The placenta resembles a lipid bilayer membrane, so only the non-protein bound portion of a drug, barring any applicable active-transport mechanisms, is free to diffuse across it.

Facilitated Diffusion

[0093| Another embodiment of the methods and compositions disclosed herein is the modulation of facilitated diffusion mechanisms in the placental barrier. Facilitated diffusion requires the presence of a carrier substance within the placenta. Moreover, the transport of the system becomes saturated at high concentrations relative to the Michaelis-Menten constant (K_m) of the transporter. However, transport by this mechanism does not require the input of energy, as opposed to active transport of substances. Facilitated diffusion usually equalizes the concentration of drugs, chemicals, or substances between the maternal and fetal circulations. It may be that for many substances, such as carbohydrates, facilitated diffusion provides a means to increase transport rates when the functional and metabolic needs of the fetus would not be met by passive diffusion alone. Folkart GR, et al. Am. J. Obstet. Gynecol., 80:221-223 (1960), herein incorporated by reference.

|0094| Studies have shown that only a few drugs use facilitated diffusion mechanisms to traverse the placental barrier. Ganciclovir has been demonstrated to be taken up into maternal-facing syncytiotrophoblast vesicles by a carrier-dependent system. Henderson GI et al., Am. J. Med. Sci. 306: 151-156 (1993). However, transport of Ganciclovir probably involves a combination of passive and facilitated diffusion mechanisms, the rate-limiting transfer step being passive diffusion. Syme et al. (2004). Placental carrier-mediated transport systems have also been found in maternal-facing syncytiotrophoblast membrane vesicles for cephalosporin, cephalexin and glucocorticoids. Kudo Y, et al., Biochim. Biophys. Acta 731 :415-420 (1989); Fant ME, et al., Biochim. Biophys. Acta 731 :415-420 (1983), incorporated by reference herein. In light of the relatively few drugs that use this mechanism, it has been suggested that structurally related endogenous compounds, such as hormones and nucleosides, will most likely be the primary species to benefit from this transport system. Syme et al. (2004).

Active Transporters

|0095| Another embodiment of the methods and compositions disclosed herein is use of modulators in manipulating active transport of drugs, chemicals and other substances across the placental barrier. Active transport across the placental barrier, as opposed to facilitated diffusion or passive transport, requires energy, usually in the form of adenosine triphosphate (ATP) or through energy stored in the transmembrane electrochemical gradient provided by ^"Na⁺, Cl^* or H⁺. Because of the input of energy, active transport systems may work against a concentration gradient, however, saturation of the transporters can occur.

|0096| Extensive studies have been conducted regarding placental transport systems of nutrients, such as amino acids, vitamins and glucose. See Hahn T, et al., Early Pregnancy 2:168-182 (1996); Moe AJ, Am. J.

Physiol. 268.C1321-1331 (1995); Bissonnette JM, Mead Johnson Symp. Perinat. Dev. Med., 18:21-23 (1981), all incorporated herein by reference. Active transport of drugs occurs through the same transport systems, most likely due to structurally similarities between the transported drugs and endogenous substrates. Syme et al.

(2004).

[00971 Active drug transporters are located either in the maternal-facing brush border (apical) membrane or the fetal-facing basolateral (basal) membrane where they pump drugs into or out of the synctiotrophoblast. Table 2 summarizes the active transporters that have been identified in the placenta.

Table 2: Active transporters in Placenta.

P-Glycoproteins (P-gP)

[0098| Another embodiment of the methods and compositions disclosed herein is the modulation of the placental P-gP transporter. The multidrug resistant gene (MDRl) product, P-glycoprotein, is a member of the ATP-binding cassette (ABC) transporter family. In the placenta, P-gP is expressed in the trophoblast cells of the brush-border membrane, but not the basal membrane. Cordon-Cardo C. et al., J. Histochem. Cytochem. 38: 1277-87 (1990); Sugawara I, et al., Cancer Res. 48: 1926-1929 (1988), herein incorporated by reference in its entirety. Studies have demonstrated that placental P-gP regulates the transfer of cyclosporine, vincristine, vinblastine and digoxin into trophoblast cells. Ushigome F, et al., Eur. J. Pharmacol. 408: 1-10 (2000); Pavek P, et al., J. Pharm. Sci. 10: 1583-1592 (2001 ), herein incorporated by reference. However, the transfers of the drugs were predominantly in the fetal-to-maternal transfer direction, thereby reducing fetal exposure to the drugs. Ushigame et al. (2000).

[0099] Studies in the mdrla (P-gP) knockout (-/-) mouse demonstrate the importance of the P-gP transporter in reducing fetal exposure to drugs and other chemicals or substances. For example, Lankas et al. (Reprod. Toxicol. 12:457-463 (1998), herein incorporated by reference) has shown that administration of an isomer of the pesticide avermectin was associated with a 100% incidence of fetal cleft palate in the mdrla knockout mice. In contrast, heterozygous (+/-) mice were less sensitive and homozygous (+/+) mice insensitive at the same doses tested on the knockout mice. In addition, the degree of chemical exposure was inversely related to the expression of P-gP, which was determined by fetal genotyping. Other studies in mdrla knockout mice have confirmed the major fetoprotective role that the P-gP transporter plays. Smit JW, et al., J. Clin. Invest. 104: 1441-1447 (1999).

Multidrug Resistance Associated Protein (MRP) Family

(00100] Another embodiment of the methods and compositions disclosed herein is the modulation of placental MRP transporters. The MRP family consists of seven members, designated MRP l to MRP7. For review, see Borst P, et al., J. Natl. Cancer Inst. 92: 1295-1302 (2000), herein incorporated by reference. In human placenta, at least three members of the MRP family have been identified: MRPl, MRP2 and MRP3. Sugawara I, et al., Cancer Lett. 1 12:23-31 (1997); St-Pierre V, et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 279:R1495- 1503 (2000); Flens MJ et al., Am. J. Pathol. 148:1237-1247 (1996), herein incorporated by reference. MRP 1 and MRP 3 were found to be localized primarily in the fetal endothelial cells of the placenta microcapillary. Hipfner DR, et al., Biochim. Biophys. Acta 1461 :359-376 (1999). MRP2, MRP3, and to a lesser extent MRPl , are also expressed in the apical membrane of the synctiotrophoblast. Sugawara et al. (1997); Flens et al. (1996) and St.-Pierre et al. (2000).

1001011 MRP -related placental proteins transport a variety of substrates primarily in the direction of the fetal-to- maternal transfer. Accordingly, researchers have suggested that MRP-transporters could exert a feto-protective role by the removal of metabolic end products from the fetus to the mother. St.-Pierre et al. (2000); Cui Y, et al., MoI. Pharmacol. 55:929-937 (1999), herein incorporated by reference.

Breast Cancer Resistant Protein (BCRP)

|00102| Another embodiment of the methods and compositions disclosed herein is the modulation of placental BCRP transporters. BCRP, an ATP-driven transporter, is highly expressed in the placenta. Allikmets R., et al., Cancer Res. 58:5337-5339 (1998), herein incorporated by reference. BCRP is responsible for rendering tumor cells resistant to chemotherapy agents, such as topotecan, mitoxantrone, doxorubicin and daunorubicin. Allen JD, et al., Cancer Res. 59:4237-4241 (1999). BCRP has also been shown to restrict the passage of topotecan and mitoxantrone to the fetus in mice. Jonker JW et al., J. Natl. Cancer Inst. 92:1651-1656 (2000), herein incoφorated by reference.

Monoamine Transporters

[00103| Yet another embodiment is the modulation of monoamine transporters in placenta. Studies have identified the placental monoamine transporters as serotonin transporter (SERT), norepinephrine transporter (NET) and the extraneuronal monoamine transporter (OCT3). Ramamoorthy S, et al., Placenta 14:449-461 (1993); Ramamoorthy S., et al., Biochem. 32: 1346-1353 (1993); Kekuda R., et al, J. Biol. Chem. 273: 15971- 15979 (1998), all herein incorporated by reference. SERT and NET derive energy from the transmembrane Na⁺ and Cl^" electrochemical gradient, and are primarily localized in the brush-border membrane of the placental trophoblast. Both SERT and NET transport serotonin, dopamine and norepinephrine from the maternal circulation to the fetus. Drug substrates of the SERT and NET transporters include amphetamines, although cocaine and non-tricyclic antidepressants bind to the SERT and NET transporters with high affinity without being transferred across the membrane.

[00104] OCT3 is localized to the basal membrane, where it transports serotonin, dopamine, norepinephrine and histamine via a Na⁺ and Cl^" independent system. Ganapathy V et al., J. Pharmacol. Exp. Ther. 294:413-420 (2000); Kekuda et al. (1998). Amphetamines, imipramine and desipramine may be actively transported by placental OCT3.

Organic Cation Transporters

[00105| One additional embodiment of the present invention is the modulation of placental Organic Cation Transporters. Placental Na+-driven organic cation transporter 2 (OCTN2) has been identified and localized to the basal membrane of the synctiotrophoblast. Wu X et al., J. Pharmacol. Exp. Ther. 290: 1482-1492 (1999), herein incorporated by reference. Placental OCTN2 transports carnitine across the placenta in the direction of the maternal-to-fetal transfer. Ohashi R., et al., J. Pharmacol. Exp. Ther. 291 :778-784 (1999), herein incorporated by reference. Studies have identified metamphetamine, quinidine, verapamil, pyrilamine, desipramine, dimethylamiloride, cimetidine, and procainimide as drug substrates for OCTN2. Wu X, et al., Biochem. Biophys. Res. Commun. 246:589-595 (1998); Wu X, et al., Biochim. Biophys. Acta 1466:315-327 (2000), herein incorporated by reference.

Monocarboxylate Transporters and the Dicarboxylate Transporters

[00106| Another embodiment of the methods and compositions disclosed herein is the modulation of monocarboxylate (MCT) and dicarboxylate (NaDC3 transporters. Both MCT (e.g. lactate transport) and NaDC3 (e.g. succinate transport), which utilize electrochemical gradients for transport, are localized to the brush border membrane of the placenta, with MCT being expressed in the basal membrane to a lesser extent. Price NT, et al., Biochem. J. 329:321-328 (1998); Ganapathy V, et al., Biochem J. 249: 179-184 (1988); Balkovetz DF, et al., 263: 13823-13830 (1988), all incorporated by reference herein. Valproic acid, a teratogenic substance, may be a substrate for MCT transfer, and compete with lactate for transport across the placental barrier. Nakamura H. et al., Pharm. Res. 19: 154-161 (2002), herein incorporated by reference.

Transporter Modulators (e.g., Activators or Inhibitors)

[00107] The invention provides compositions and methods for reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent. In some embodiments, the compositions and embodiments described herein modulate the efflux of a therapeutic agent out of physiological compartments, including across the blood brain barrier and/or a tissue and/or an organ and/or a cell via a BTB or fetal transport protein, e.g., the P-gP transporter. In some embodiments, such modulators activate and/or increase the efflux by the BTB or fetal transport protein, e.g., P-gP transporters on the blood brain barrier and/or tissue.

[00108| Modulators may be any suitable modulator. In some embodiments, modulators useful in the invention are pyrone analogs, including polyphenols, such as flavonoids. Suitable modulators include catechins from green tea, including (-) epicatechin. See Wang, E, et al., Biochem. Biophys. Res. Comm. 297:412-418 (2002); Zhou, S., et al., Drug Metabol. Rev. 36:57-104 (2004), both of which are herein incorporated by reference in its entirety. Other suitable modulators, e.g., P-gP modulators for use herein include flavonols, including, but not limited to, kaempferol, quercetin, fisetin and galangin.

[00109| In other embodiments, P-gP transporter modulators may include small molecules, including 2-p-Tolyl- 5,6,7,8-tetrahydrobenzo[d]imidazo[2,l -b]thiazole; l-Carbazol-9-yl-3-(3,5-dimethylpyrazol-l-yl)-propan-2-ol; 2- (4-Chloro-3,5-dimethylphenoxy)-/V-(2-phenyl-2H-benzotriazol-5-yl)-acetamide; 7V-[2-(4-Chloro-phenyl)- acetylJ-Λ^-^J-dimethyl-quinazolin^-yO-guanidine; l-Benzyl-7,8-dimethoxy-3-phenyl-³H-pyrazolo[3,4- c]isoquinoline; /V-(3-Benzooxazol-2-yl-4-hydroxyphenyl)-2-p-tolyIoxyacetamide; 8-Allyl-2-phenyl-⁸H-l,3a,8- triazacyclopenta[a]indene; 3-(4-Chloro-benzyl)-5-(2-methoxyphenyl)-[l ,2,4]oxadiazole; 2-Phenethylsulfanyl- 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-ylamine; (5, 12, 13-Triaza-indeno[ 1 ,2-b]anthracen- 13-yl)- acetic acid ethyl ester; 2,2'-(l-phenyl-Η-l ,2,4-triazole-3,5-diyl)bis-phenol; and 2-(2-Chloro-phenyl)-5-(5- methylthiophen-2-yl)-[l ,3,4]oxadiazole. See Kondratov, et al., Proc. Natl. Acad. Sci. 98: 14078-14083 (2001), herein incorporated by reference in its entirety.

[00110| In one embodiment, a P-gP substrate is used to inhibit transport across the blood brain barrier and/or tissue and/or an organ and/or a cell. Multi Drug Resistance Proteins consist of a family of plasma membrane proteins encoded by the MDR (multidrug resistance) gene.

[001 1 11 In some embodiments, the invention utilizes a modulator of a BTB transport protein. In some embodiments, the invention utilizes a modulator of a BTB transport protein that is an ABC transport protein. In some embodiments, the invention utilizes a BTB transport protein activator. In some embodiments, the BTB transport protein modulator is a modulator of P-gP, e.g., an activator of P-gP. A. Pyrone Analogs |00112| One class of compounds useful in the compositions and methods of the invention are pyrone analogs. As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. 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. [00113| "Acyl" refers to a -(C=O)- radical which is attached to two other moieties through the carbon atom. Those groups may be chosen from alkyl, alkenyl, alkynyl, aryl, heterocyclic, heteroaliphatic, heteroaryl, and the like. Unless stated otherwise specifically in the specification, an acyl group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R³, -N(R^a)₂, -C(O)R³, -C(O)OR³, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(0)R³, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)₁OR³ (where t is 1 or 2),-S(O)_tN(R^a)₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R³ is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[00114] "Acyloxy" refers to a R(C=O)O- radical wherein R is alkyl, aryl, heteroaryl or heterocyclyl. Unless stated otherwise specifically in the specification, an acyloxy group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR³, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R³, -C(O)OR³, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R³)C(0)R^a, -N(R³)S(O)_tR^a (where t is 1 or 2), -S(0)_t0R³ (where t is 1 or 2) -S(O)_tN(R^a)₂ (where t is 1 or 2) , -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[00115] "Alkylaryl" refers to an (alkyl)aryl- radical, where alkyl and aryl are as defined herein. [00116] "Aralkyl" refers to an (aryl)alkyl — radical where aryl and alkyl are as defined herein. [00117] "Alkoxy" refers to a (alkyl)O-radical, where alkyl is as described herein and contains 1 to 10 carbons (e.g., Ci-Cio alkyl). Whenever it appears herein, a numerical range such as " 1 to 10" refers to each integer in the given range; e.g., " 1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C_rC₄ alkoxy group. An alkoxy moiety is optionally substituted by one or more of the substituents described as suitable substituents for an alkyl radical.

(00118] "Alkyl" refers to a straight or branched hydrocarbon chain radical, having from one to ten carbon atoms (e.g., C₁-Ci₀ alkyl). Whenever it appears herein, a numerical range such as " 1 to 10" refers to each integer in the given range; e.g., " 1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like. The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, I -methylethyl (/so-propyl), «-butyl, /7-pentyl, 1 ,1 -dimethylethyl (/-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR", -SR", -OC(O)-R³, -N(R^a)₂, -C(O)R³, -C(O)OR³, -C(O)N(R^a)₂, -N(R^a)C(0)0R^a, -N(R^a)C(O)R^a, -N(R³)S(O)_tR³ (where t is 1 or 2), -S(O)_tOR^a (where t is 1 or 2),-S(O),N(R³)₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alky], fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[00119| "Alkenyl" refers to a straight or branched hydrocarbon chain radical group, containing at least one double bond, and having from two to ten carbon atoms (ie. C₂-C₁₀ alkenyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1 -enyl, pent-1-enyl, penta-l ,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R³, -N(R^a)₂, -C(O)R³, -C(O)OR³, -C(0)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R³, -N(R³)S(O)_tR³ (where t is 1 or 2), -S(O)₁OR" (where t is 1 or 2),-S(O)_tN(R^a)₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R³ is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[00120] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group, containing at least one triple bond, having from two to ten carbon atoms (ie. C₂-C,_o alkynyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR³, -SR", -OC(O)-R³, -N(R³)₂, -C(O)R³, -C(O)OR³, -C(O)N(R³)₂, -N(R³)C(0)0R³, -N(R³)C(O)R³, -N(R³)S(O),R^a (where t is 1 or 2), -S(O)₁OR³ (where t is 1 or 2),-S(O),N(R^a)₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. |001211 "Amine" refers to a -N(R^a)₂ radical group, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R³, -N(R^a)₂, -C(O)R^a, -C(O)OR³, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O),OR^a (where t is 1 or 2),-S(O)_tN(R^a)₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[00122| An "amide" refers to a chemical moiety with formula -C(O)NR^aR^b or -NR^aC(0)R^b, where R^aor R^b is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclic (bonded through a ring carbon). An amide may be an amino acid or a peptide molecule attached to a compound of Formula (I), thereby forming a prodrug. Any amine or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

(00123| "Aromatic" or "aryl" refers to an aromatic radical with six to fourteen ring carbon atoms (e.g., C₆-C)₄ aromatic or C₆-C₁₄ aryl). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groupslt has at least one ring having a conjugated pi electron system.. Whenever it appears herein, a numerical range such as "6 to 14" refers to each integer in the given range; e.g., "6 to 14 ring atoms" means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently: hydroxyl, carboxaldehyde, amine, C₁-Ci₀ alkyl, C₂-C₁₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-Ci₀ aliphatic acyl, C₆-C₁₀ aromatic acyl, C₆- C_|0 aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, alkyl, phosphonate, aryl, heteroaryl, heterocyclic, C₃- Cocycloalkyl, -CN -OR^a, -SR^a, -OC(O)-R³, -N(R^a)₂, -C(O)R³, -C(O)OR³, -C(O)N(R^a)₂, -N(R^a)C(O)OR³, -N(R^a)C(0)R³, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(O)₁OR³ (where t is J or 2),-S(O),N(R^a)₂ (where t is 1 or 2), - PO₃XY (where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z (where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. [00124] "Carboxaldehyde" refers to a -(C=O)H radical. [00125| "Carboxyl" refers to a -(C=O)OH radical.

|00126] "Carbohydrate" as used herein, includes, but not limited to, monosaccharides, disaccharides, oligosaccharides, or polysaccharides. Monosaccharide for example includes, but not limited to, aldotrioses such as glyceraldehyde, ketotrioses such as dihydroxyacetone, aldotetroses such as erythrose and threose, ketotetroses such as erythrulose, aldopentoses such as arabinose, lyxose, ribose and xylose, ketopentoses such as ribulose and xylulose, aldohexoses such as allose, altrose, galactose, glucose, gulose, idose, mannose and talose, ketohexoses such as fructose, psicose, sorbose and tagatose, heptoses such as maπnoheptulose, sedoheptulose, octoses such as octolose, 2-keto-3-deoxy-manno-octonate, nonoses such as sialoseallose. Disaccharides for example includes, but not limited to, glucorhamnose, trehalose, sucrose, lactose, maltose, galactosucrose, TV-acetyllactosamine, cellobiose, gentiobiose, isomaltose, melibiose, primeverose, hesperodinose, and rutinose. Oligosaccharides for example includes, but not limited to, raflfϊnose, nystose, panose, cellotriose, maltotriose, maltotetraose, xylobiose, galactotetraose, isopanose, cyclodextrin (α-CD) or cyclomaltohexaose, β-cyclodextrin (β -CD) or cyclomaltoheptaose and γ-cyclodextrin (γ-CD) or cyclomaltooctaose. Polysaccharide for example includes, but not limited to, xylan, mannan, galactan, glucan, arabinan, pustulan, gellan, guaran, xanthan, and hyaluronan. Some examples include, but not limited to, starch, glycogen, cellulose, inulin, chitin, amylose and amylopectin.

A compound of Formula I having a carbohydrate moiety can be referred to as the pyrone analog glycoside or the pyrone analog saccharide. As used herein, "carbohydrate" further encompasses the glucuronic as well as the glycosidic derivative of compounds of Formula I. Where the phosphonated pyrone analog has no carbohydrate moiety, it can be referred to as the aglycone. Further, where a phenolic hydroxy is derivatized with any of the carbohydrates described above, the carbohydrate moiety is referred to as a glycosyl residue. Unless stated otherwise specifically in the specification, a carbohydrate group is optionally substituted by one or more substituents which are independently: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, - SR³, -OC(O)-R³, -N(R^a)₂, -C(O)R", -C(O)OR³, -C(0)N(R^a)₂, -N(R³)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O),OR^a (where t is 1 or 2),-S(O)_tN(R^a)₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. |00127| "Cyano" refers to a -CN moiety.

(00128| "Cycloalkyl" or "carbocyclyl" refers to a monocyclic or polycyclic non-aromatic radical that contains 3 to 10 ring carbon atoms (ie. C₃-Ci₀ cycloalkyl). It may be saturated or unsaturated. Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 10 carbon atoms" means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which are independently: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR", -SR^a, -OC(O)-R⁸, -N(R^a)₂, -C(O)R³, -C(O)OR^a, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)S(O),R^a (where t is 1 or 2), -S(O)₁OR" (where t is 1 or 2),-S(O)_tN(R^a)₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

|00129| "Ester" refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclic (bonded through a ring carbon). Any hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N. Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which are independently : halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, -SR", -OC(O)-R", -N(R^a)₂, -C(O)R", -C(O)OR³, -C(O)N(R³)₂, -N(R")C(O)OR^a, -N(R^a)C(0)R", -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)₁OR³ (where t is 1 or 2),-S(O),N(R")₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[00130] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group. 100131 ) Group "-PO₄XY" refers to -OPO₃XY, and group "-PO₄Z" refers to -OPO₃Z, Group "-OCH₂PO₄XY" refers to - OCH₂OPO₃XY, and group "-OCH₂PO₄Z" refers to - OCH₂OPO₃Z, |00132] "Halo", "halide", or, alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" are included in haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

|00133| The terms "heteroalkyl" "heteroalkenyl" and "heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.

[00134| "Heteroaryl" or, alternatively, "heteroaromatic" refers to a 5- to 18-membered aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic fused ring system. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; e.g., "5 to 18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. An "N-containing heteroaromatic" or "N-containing heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1 ,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, benzo[b][l ,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofiirazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l ,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, όJ-dihydro-SH-benzo^Jlcycloheptaπ^-clpyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,

5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9, lO-hexahydrocyclooctatdJpyridinyl_jisothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1 ,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9, 10, 1 Oa-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 1 //-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently: hydroxyl, carboxaldehyde, amine, C₁-Ci₀ alkyl, C₂-C₁₀ alkynyl, C₂-C₁₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-C₁₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆- C_|O alkylaryl acyl, alkoxy, alkyl, phosphonate, aryl, heteroaryl, heterocyclic, C₃-Ci₀cycloalkyl, -CN, -OR^a, -SR", -OC(O)-R³, -N(R^a)₂, -C(O)R³, -C(O)OR\ -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)₁OR³ (where t is 1 or 2),-S(O),N(R^a)₂ (where t is 1 or 2), -PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO₃Z ( where Z is calcium, magnesium or iron) where each R³ is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[00135| "Heterocyclyl" or "heterocyclic" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as "3 to 18" refers to each integer in the given range; e.g., "3 to 18 ring atoms" means that the heteroaryl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C₅-C₁₀ heterocyclyl. In some embodiments, it is a C₄-Ci₀ heterocyclyl. In some embodiments, it is a C₃-C₍₀ heterocyclyl. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated.

The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxoρiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomoφholinyl, thiamoφholinyl, 1-oxo-thiomoφholinyl, and 1,1-dioxo-thiomorpholinyl.

Unless stated otherwise specifically in the specification, a heterocylyl moiety is optionally substituted by one or more substituents which are indedependently: hydroxyl, carboxaldehyde, amine, Ci-Ci_O alkyl, C₂-Ci₀ alkynyl,

C₂-C)₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C₁-Ci₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-Ci_O aralkyl acyl, C₆-C₁₀alkylaryl acyl, alkoxy, alkyl, phosphonate, aryl, heteroaryl, heterocyclic, C₃-

C₁₀cycloalkyl, -CN, -OR^a, -SR^a, -OC(O)-R³, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a,

-N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)₁OR³ (where t is 1 or 2),-S(O),N(R^a)₂ (where t is 1 or 2), -

PO₃XY ( where X and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or-

PO₃Z ( where Z is calcium, magnesium or iron) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

|00136] "Imino" refers to the =N-H radical.

100137] "Isocyanato" refers to a -N=C=O radical.

[00138| "Isothiocyanato" refers to a -N=C=S radical.

[00139] "Mercapto" refers to a (alkyl)S- or (H)S- radical.

|00140] "Moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

|001411 "Nitro" refers to the -NO₂ radical.

[00142| "Oxa" refers to the -O- radical.

1001431 "Oxo" refers to the =O radical.

[00144| "Sulfinyl" refers to a -S(=O) — R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclic (bonded through a ring carbon)

100145] "Sulfonyl" refers to a -S(=O)₂-R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclic (bonded through a ring carbon).

[00146| "Sulfonamidyl" refers to a -S(=O)₂-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclic

(bonded through a ring carbon).

|00147] "Sulfoxyl" refers to a -S(=O)₂OH radical.

|00148] "Sulfonate" refers to a -S(=O)₂-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclic (bonded through a ring carbon).

[00149| "Thiocyanato" refers to a -C=N=S radical.

[00150| "Thioxo" refers to the =S radical.

[001511 "Substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, heteroaryl, heterocyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, phosphonate, silyl, sulfinyl, suifonyl, sulfonamidyl, sulfoxyl, sulfonate, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The subsituents themselves may be substituted, for example, a cycloakyl substituent may have a halide substituted at one or more ring carbons, and the like.The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above.

[00152] In this application, 3'-quercetin phosphate is also named as quercetin-3'-O-phosphate. 4'-Quercetin phosphate is also named as quercetin-4'-O-phosphate. 3'-Fisetin phosphate is also named as fϊsetin-3'-0- phosphate. 4'-Fisetin phosphate is also named as fisetin-4'-O-phosphate. 3-Fisetin phosphate is also named as fisetin-3-O-phosphate. The term "quercetin phosphate" is used interchangeably with "phosphorylated quercetin". The term "fisetin phosphate" is used interchangeably with "phosphorylated fisetin"

[00153] The compounds presented herein may possess one or more chiral centers and each center may exist in the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns. |00154] The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds having the same type of activity. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[00155] Pyrone analogs of Formula I and their pharmaceutically/veterinarily acceptable salt or esters are provided in this invention,

Formula I

[001561 wherein X is O, S, or NR'. wherein R' is hydrogen, C_rC₁₀alkyl, C₂-C₁₀ alkynyl, C₂-Ci₀ alkenyl, C_rCio aliphatic acyl, C₆-C₁₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-C₁₀ alkylaryl acyl, aryl, C₃-C]₀ heterocyc IyI, heteroaryl, or C₃-C₁₀ cycloalkyl;

[00157] R|, and R₂ are independently hydrogen, hydroxy!, C₁-Ci₀ alkyl, C₂-C₁₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C_rCi₀ aliphatic acyl, C₆-C₁₀ aromatic acyl, C₆-Ci₀aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, amine, aryl, C₄-C₁₀ heterocyclyl, heteroaryl, C₃-Ci₀ cycloalkyl, -OPO₃WY, -

OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z;

[00158] R₃ and R₄ are independently hydrogen, hydroxyl, Ci-C₁₀ alkyl, C₂-C,_o alkynyl, C₂-C ,₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C _rCi₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C₁₀aralkyl acyl, C₆- Cio alkylaryl acyl, alkoxy, amine, aryl, C₄-Ci₀ heterocyclyl, heteroaryl, C₃-Ci₀cycloalkyl, -OPO₃WY, - OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z;

(00l59| or R₃ and R₄ are taken together to form a C₅-Ci₀ heterocyclyl, C₅-C₁₀cycloalkyl, aryl, or heteroaryl; and W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation.

|00160| In some embodiments, X is O. [00161 | In other embodiments, X is S. [00162) In yet other embodiments, X is NR'.

(00163| In some embodiments, R' is hydrogen. In some embodiments, R' is unsubstituted C₁-Ci₀ alkyl. In some embodiments, R' is substituted C_I-C_I0 alkyl. In some embodiments, R' is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R' is substituted C₂-C₁₀ alkynyl. In some embodiments, R' is unsubstituted C₂-C₁₀ alkenyl. In some embodiments, R' is substituted C₂-Ci₀ alkenyl. In some embodiments, R' is unsubstituted C₁-C₁₀ aliphatic acyl. In some embodiments, R' is substituted C₁-C₁₀ aliphatic acyl. In some embodiments, R' is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R' is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R' is unsubstituted C₆-C]₀ aralkyl acyl. In some embodiments, R' is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R' is unsubstituted C₆-Ci₀ alky laryl acyl. In some embodiments, R' is substituted C₆-Ci₀ alky laryl acyl. In some embodiments, R' is unsubstituted aryl. In some embodiments, R' is substituted aryl. In some embodiments, R' is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R' is substituted C₃-C]₀ heterocyclyl. In some embodiments, R' is unsubstituted heteroaryl. In some embodiments, R' is substituted heteroaryl. In some embodiments, R' is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R' is substituted C₃-C₁₀ cycloalkyl.

[00164] In some embodiments, R| is hydrogen. In some embodiments, R₁ is optionally substituted Ci-C]₀ alkyl. hydroxyl. In some embodiments, Ri is unsubstituted C₁-C₁₀ alkyl. In some embodiments, R₁ is substituted C₁- C]₀ alkyl. In some embodiments, R_t is unsubstituted C₁-C]₀ alkyl. In some other embodiments, Ri is substituted C₁-C₁₀ alkyl. In some embodiments, R₁ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₁ is substituted C₂-C₁₀ alkynyl. In some embodiments, Ri is unsubstituted C₂-C]₀ alkenyl. In some embodiments, R₁ is substituted C₂-C]₀ alkenyl. In some embodiments, R₁ is carboxyl. In some embodiments, R] is unsubstituted carbohydrate. In some embodiments, Ri is substituted carbohydrate. In some embodiments, R₁ is unsubstituted ester. In some embodiments, Ri is substituted ester. In some embodiments, R₁ is unsubstituted acyloxy. In some embodiments, R₁ is substituted acyloxy. In some embodiments, R] is nitro. In some embodiments, Ri is halogen. In some embodiments, R₁ is unsubstituted C₁-C₁₀ aliphatic acyl. In some embodiments, R₁ is substituted Ci-C]₀ aliphatic acyl. In some embodiments, Ri is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, Ri is substituted C₆-C]₀ aromatic acyl. In some embodiments, Ri is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₁ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₁ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₁ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₁ is unsubstituted alkoxy. In some embodiments, R₁ is substituted alkoxy. In some embodiments, R₁ is unsubstituted amine. In some embodiments, R) is substituted amine. In some embodiments, Ri is unsubstituted aryl. In some embodiments, R, is substituted aryl. In some embodiments, R] is unsubstituted C₄-Ci₀ heterocyclyl. In some embodiments, R₁ is substituted C₄-C₁₀ heterocyclyl. In some embodiments, R| is unsubstituted heteroaryl. In some embodiments, R₁ is substituted heteroaryl. In some embodiments, Ri is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, Ri is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R_t is -OPO₃WY. In some embodiments, R₁ is -OCH₂PO₄WY. In some embodiments, Ri is -OCH₂PO₄Z. In some embodiments, Ri is - OPO₃Z.

|00165] In some embodiments, when R| is aryl, it is monocyclic. In some embodiments, when Ri is aryl, it is bicyclic. In some embodiments, when R| is heteroaryl, it is monocyclic. In some embodiments, when R₁ is heteroaryl, it is bicyclic.

[00166| In some embodiments, R₂ is hydrogen. In some embodiments, R₂ is hydroxyl. In some embodiments, R₂ is optionally substituted C₁-Ci₀ alkyl. In some embodiments, R₂ is unsubstituted C₁-Ci₀ alkyl. In some embodiments, R₂ is substituted C₁-Ci₀ alkyl. In some embodiments, R₂ is unsubstituted C₁-Ci₀ alkyl. In some other embodiments, R₂ is substituted C₁-Ci₀ alkyl. In some embodiments, R₂ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₂ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₂ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₂ is substituted C₂-Ci₀ alkenyl. In some embodiments, R₂ is carboxyl. In some embodiments, R₂ is unsubstituted carbohydrate. In some embodiments, R₂ is substituted carbohydrate. In some embodiments, R₂ is unsubstituted ester. In some embodiments, R₂ is substituted ester. In some embodiments, R₂ is unsubstituted acyloxy. In some embodiments, R₂ is substituted acyloxy. In some embodiments, R₂ is nitro. In some embodiments, R₂ is halogen. In some embodiments, R₂ is unsubstituted C₁-C₁₀ aliphatic acyl. In some embodiments, R₂ is substituted C₁-Ci₀ aliphatic acyl. In some embodiments, R₂ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₂ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₂ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₂ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₂ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₂ is substituted C₆-C₁₀ alky Iaryl acyl. In some embodiments, R₂ is unsubstituted alkoxy. In some embodiments, R₂ is substituted alkoxy. In some embodiments, R₂ is unsubstituted amine. In some embodiments, R₂ is substituted amine. In some embodiments, R₂ is unsubstituted aryl. In some embodiments, R₂ is substituted aryl. In some embodiments, R₂ is unsubstituted C₄-C]₀ heterocyclyl. In some embodiments, R₂ is substituted C₄-Ci₀ heterocyclyl. In some embodiments, R₂ is unsubstituted heteroaryl. In some embodiments, R₂ is substituted heteroaryl. In some embodiments, R₂ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₂ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂ is -OPO₃WY. In some embodiments, R₂ is -OCH₂PO₄WY. In some embodiments, R₂ is - OCH₂PO₄Z. In some embodiments, R₂ is -OPO₃Z.

|00167] In some embodiments, R₃ is hydrogen. In some embodiments, R₃ is optionally substituted Ci-C₁₀alkyl. hydroxyl. In some embodiments, R₃ is unsubstituted C]-C₁₀ alkyl. In some embodiments, R₃ is substituted C_r Ci₀ alkyl. In some embodiments, R₃ is unsubstituted Ci-C₁₀ alkyl. In some other embodiments, R₃ is substituted C₁-C₁₀ alkyl. In some embodiments, R₃ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₃ is substituted C₂-C₁₀ alkynyl. In some embodiments, R₃ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₃ is substituted C₂-C,₀ alkenyl. In some embodiments, R₃ is carboxyl. In some embodiments, R₃ is unsubstituted carbohydrate. In some embodiments, R₃ is substituted carbohydrate. In some embodiments, R₃ is unsubstituted ester. In some embodiments, R₃ is substituted ester. In some embodiments, R₃ is unsubstituted acyloxy. In some embodiments, R₃ is substituted acyloxy. In some embodiments, R₃ is nitro. In some embodiments, R₃ is halogen. In some embodiments, R₃ is unsubstituted C]-Ci₀ aliphatic acyl. In some embodiments, R₃ is substituted Ci-Ci₀ aliphatic acyl. In some embodiments, R₃ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₃ is substituted C₆-C,₀ aromatic acyl. In some embodiments, R₃ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₃ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₃ is unsubstituted C₆-C₎₀ alky laryl acyl. In some embodiments, R₃ is substituted C₆-C]₀ alkylaryl acyl. In some embodiments, R₃ is unsubstituted alkoxy. In some embodiments, R₃ is substituted alkoxy. In some embodiments, R₃ is unsubstituted amine. In some embodiments, R₃ is substituted amine. In some embodiments, R₃ is unsubstituted aryl. In some embodiments, R₃ is substituted aryl. In some embodiments, R₃ is unsubstituted C₄-Ci₀ heterocyclyl. In some embodiments, R₃ is substituted C₄-Ci₀ heterocyclyl. In some embodiments, R₃ is unsubstituted heteroaryl. In some embodiments, R₃ is substituted heteroaryl. In some embodiments, R₃ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₃ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₃ is -OPO₃WY. In some embodiments, R₃ is -OCH₂PO₄WY. In some embodiments, R₃ is -OCH₂PO₄Z. In some embodiments, R₃ is - OPO₃Z.

[00168| In some embodiments, R₄ is hydrogen. In some embodiments, R₄ is optionally substituted Ci-Ci₀ alkyl. hydroxyl. In some embodiments, R₄ is unsubstituted Ci-Ci₀ alkyl. In some embodiments, R₄ is substituted C_r Ci₀ alkyl. In some embodiments, R₄ is unsubstituted C|-C|₀ alkyl. In some other embodiments, R₄ is substituted Ci-C₁₀ alkyl. In some embodiments, R₄ is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R₄ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₄ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₄ is substituted C₂-C₁₀ alkenyl. In some embodiments, R₄ is carboxyl. In some embodiments, R₄ is unsubstituted carbohydrate. In some embodiments, R₄ is substituted carbohydrate. In some embodiments, R₄ is unsubstituted ester. In some embodiments, R₄ is substituted ester. In some embodiments, R₄ is unsubstituted acyloxy. In some embodiments, R₄ is substituted acyloxy. In some embodiments, R₄ is nitro. In some embodiments, R₄ is halogen. In some embodiments, R₄ is unsubstituted Ci-C₁₀ aliphatic acyl. In some embodiments, R₄ is substituted C|-Cιo aliphatic acyl. In some embodiments, R₄ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₄ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₄ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₄ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₄ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₄ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₄ is unsubstituted alkoxy. In some embodiments, R₄ is substituted alkoxy. In some embodiments, R₄ is unsubstituted amine. In some embodiments, R₄ is substituted amine. In some embodiments, R₄ is unsubstituted aryl. In some embodiments, R₄ is substituted aryl. In some embodiments, R₄ is unsubstituted C₄-C₁₀ heterocyclyl. In some embodiments, R₄ is substituted C₄-C)₀ heterocyclyl. In some embodiments, R₄ is unsubstituted heteroaryl. In some embodiments, R₄ is substituted heteroaryl. In some embodiments, R₄ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₄ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₄ is -OPO₃WY. In some embodiments, R₄ is -OCH₂PO₄WY. In some embodiments, R₄ is -OCH₂PO₄Z. In some embodiments, R₄ is - OPO₃Z.

|00169] In some embodiments, R₃ and R₄ are taken together to form an unsubstituted C₅-Ci₀ heterocyclyl. In other embodiments, R₃ and R₄ are taken together to form a substituted C₅-C₁₀ heterocyclyl. In some embodiments, R₃ and R₄ are taken together to form an unsubstituted C₅-C₁₀cycloalkyl. In some embodiments, R₃ and R₄ are taken together to form a substituted C₃-Ci₀cycloalkyl. In some embodiments, R₃ and R₄ are taken together to form an unsubstituted aryl. In some embodiments, R₃ and R₄ are taken together to form a substituted aryl. In some embodiments, R₃ and R₄ are taken together to form an unsubstituted heteroaryl. In some embodiments, R₃ and R₄ are taken together to form a substituted heteroaryl. [00170| In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium. In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments,

Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.

[00171 ] In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.

|00172] The 2,3 bond may be saturated or unsaturated in the compounds of Formula I.

[00173] In some embodiments of the invention, the pyrone analog of Formula I is of Formula II:

Formula II

[00174] wherein X, Ri, R₂, W, Y, and Z are defined as in Formula I;

[001751 X₁, X₂, X₃, and X₄ are independently CR₅, O, S, or N;

[00176| each instance of R₅ is independently hydrogen, hydroxyl, carboxaldehyde, amino, C,-Ci_O alkyl, C₂-Ci₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C_rC₁₀ aliphatic acyl, C₆-C₁₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, amine, aryl, C₃-C₁₀ heterocyclyl, heteroaryl, C₃-

Co cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z.

(00177] In some embodiments, X₁ is CR₅.

[00178] In other embodiments, X₁ is O.

[00179] In yet other embodiments, X₁ is S.

|00180| In further embodiments, X₁ is N.

(00181 ] In some embodiments, X₂ is CR₅.

[00182] In other embodiments, X₂ is O.

[00183] In yet other embodiments, X₂ is S.

|00184] In further embodiments, X₂ is N.

[00185] In some embodiments, X₃ is CR₅.

|00186] In other embodiments, X₃ is O.

[00187] In yet other embodiments, X₃ is S.

|00188] In further embodiments, X₃ is N. [00189| In other embodiments, X₄ is CR₅. (00190| In some embodiments, X₄ is O. [001911 In yet other embodiments, X₄ is S. [001921 In some embodiments, X₄ is N. [00193| In some embodiments, Xi, X₂, X₃, and X₄ are CR₅. 100194) In some embodiments, Xi and X₃ are CR₅ and X₂ and X₄ are N. |00195| In some embodiments, X₂ and X₄ are CR₅ and X, and X₃ are N. [001961 In some embodiments, X₂ and X₃ are CR₅ and X) and X₄ are N. [001971 In various embodiments, R, is one of the following formulae:

[00198| wherein Ri₆ is hydrogen, C_rCi_Oalkyl, C₂-Ci₀ alkynyl, C₂-C₁₀ alkenyl, carbohydrate, Ci-C₁₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, aryl, C₃-Ci₀ heterocyclyl, heteroaryl, C₃-C₁₀ cycloalkyl, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z;

|00199| R)₇ is hydrogen, hydroxy, carboxaldehyde, amine, C|-Ci_Oalkyl, C₂-Ci₀ alkynyl, C₂-Ci_O alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-C,₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆-C _I0 alkylaryl acyl, alkoxy, aryl, C₃-Ci₀ heterocyclyl, heteroaryl, or C₃-C₁₀ cycloalkyl, -OPO₃WY, - OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z; each instance Of Ri₈ and R₂, is independently hydrogen, hydroxyl, carboxaldehyde, amine, C|-C₁₀ alkyl, C₂-Ci₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-Ci₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-Ci₀ alky laryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C₃-C,_o heterocyclic, C₃-Ci₀ cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, - OCH₂PO₄Z or -OPO₃Z;

1002001 Ri₉ is hydrogen, C,-C₁₀ alkyl, C₂-C₁₀ alkynyl, C₂-Ci₀ alkenyl, carbohydrate, Ci-Ci₀ aliphatic acyl, C₆-C₁₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, aryl, C₃-Ci₀ heterocyclyl, heteroaryl, optionally substituted C₃-C₁₀ cycloalkyl, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z; |00201 ] s is an integer of O, 1, 2, or 3; and |00202] n is an integer of O, 1 , 2, 3, or 4.

[00203] In some embodiments, Ri₆ is hydrogen. In some embodiments, R_!6 is unsubstituted CpCi₀ alkyl. In some embodiments, R₎₆ is substituted Ci-C₁₀ alkyl. In some embodiments, R₁₆ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, Ri₆ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₁₆ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₁₆ is substituted C₂-C₁₀ alkenyl. In some embodiments, Ri₆ is unsubstituted carbohydrate. In some embodiments, Ri₆ is substituted carbohydrate. In some embodiments, Ri₆ is unsubstituted Ci-Ci₀ aliphatic acyl. In some embodiments, Ri₆ is substituted C_rCi₀ aliphatic acyl. In some embodiments, R₎₆ is unsubstituted C₆-C₎₀ aromatic acyl. In some embodiments, R_]6 is substituted C₆-Cj₀ aromatic acyl. In some embodiments, R₁₆ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R,₆ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R)₆ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₁₆ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₎₆ is unsubstituted aryl. In some embodiments, R₁₆ is substituted aryl. In some embodiments, R₎₆ is unsubstituted C₃-C₁₀ heterocyclyl. In some embodiments, R|₆ is substituted C₃-C₁₀ heterocyclyl. In some embodiments, R₁₆ is unsubstituted heteroaryl. In some embodiments, R,₆ is substituted heteroaryl. In some embodiments, R,₆ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₎₆ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₁₆ is -PO₃WY. In some embodiments, Ri₆ is - CH₂PO₄WY. In some embodiments, Ri₆ is -CH₂PO₄Z. In some embodiments, R₎₆ is -PO₃Z. |00204) In some embodiments, R_i7 is hydrogen. In some embodiments, R_n is hydroxy. In some embodiments, R₁₇ is carboxaldehyde. In some embodiments, R_n is unsubstituted amine. In some embodiments, R₁₇ is substituted amine. In some embodiments, R₁₇ is unsubstituted C₁-C₁₀ alkyl. In some embodiments, Ri₇ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R_n is substituted C₂-C ₎₀ alkynyl. In some embodiments, R_n is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R|₇ is substituted C₂-C₁₀ alkenyl. In some embodiments, R₁₇ is carboxyl. In some embodiments, R₎₇ is unsubstituted carbohydrate. In some embodiments, R,₇ is substituted carbohydrate. In some embodiments, R_n is unsubstituted ester. In some embodiments, R_n is substituted ester. In some embodiments, R₎₇ is unsubstituted acyloxy. In some embodiments, R₁₇ is substituted acyloxy. In some embodiments, R_t7 is nitro. In some embodiments, R₁₇ is halogen. In some embodiments, R₁₇ is unsubstituted C_rC₁₀ aliphatic acyl. In some embodiments, R₎₇ is substituted C₁-Ci₀ aliphatic acyl. In some embodiments, R₁₇ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₁₇ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₁₇ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R_n is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₁₇ is unsubstituted C₆-Ci₀ alkylaryl acyl. n some embodiments, R_t7 is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₁₇ is unsubstituted alkoxy. In some embodiments, R_n is substituted alkoxy. In some embodiments, R₎₇ is unsubstituted aryl. In some embodiments, R,₇ is substituted aryl. In some embodiments, R_n is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₁₇ is substituted C₃-C]₀ heterocyclyl. In some embodiments, R,₇ is unsubstituted heteroaryl. In some embodiments, R_n is substituted heteroaryl. In some embodiments, R₁₇ is unsubstituted C₃-C)₀ cycloalkyl. In some embodiments, Ri₇ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R_n is -OPO₃WY. In some embodiments, R,₇ is -OCH₂PO₄WY. In some embodiments, R_n is -OCH₂PO₄Z. In some embodiments, R_n is - OPO₃Z.

[00205) In some embodiments, R,₈ is hydrogen. In some embodiments, Ri₈ is hydroxy. In some embodiments, Ri₈ is carboxaldehyde. In some embodiments, R]₈ is unsubstituted amine. In some embodiments, Rj₈ is substituted amine. In some embodiments, R₁₈ is unsubstituted Ci-C]₀ alkyl. In some embodiments, R_]8 is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R]₈ is substituted C₂-Ci₀ alkynyl. In some embodiments, R]₈ is unsubstituted C₂-C₁₀ alkenyl. In some embodiments, R₁₈ is substituted C₂-C₁₀ alkenyl. In some embodiments, R₁₈ is carboxyl. In some embodiments, R]₈ is unsubstituted carbohydrate. In some embodiments, R,₈ is substituted carbohydrate. In some embodiments, R₁₈ is substituted carbohydrate. In some embodiments, R₁₈ is unsubstituted ester. In some embodiments, R₁₈ is substituted ester. In some embodiments, R₁₈ is unsubstituted acyloxy. In some embodiments, Rj₈ is substituted acyloxy. In some embodiments, R₎₈ is nitro. In some embodiments, R₁₈ is halogen. In some embodiments, R]₈ is unsubstituted Ci-C₁₀ aliphatic acyl. In some embodiments, R,₈ is substituted C₁-C)₀ aliphatic acyl. In some embodiments, R]₈ is unsubstituted C₆-C₎₀ aromatic acyl. In some embodiments, R₁₈ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, Ri₈ is unsubstituted C₆-C]₀ aralkyl acyl. In some embodiments, R₁₈ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₁₈ is unsubstituted C₆-C₁₀ alky laryl acyl. In some embodiments, R₁₈ is substituted C₆-C]₀ alkylaryl acyl. In some embodiments, Ri₈ is unsubstituted alkoxy. In some embodiments, R]₈ is substituted alkoxy. In some embodiments, R₁₈ is unsubstituted aryl. In some embodiments, R₁₈ is substituted aryl. In some embodiments, R₁₈ is unsubstituted C₃-C₁₀ heterocyclyl. In some embodiments, R₁₈ is substituted C₃-C₁₀ heterocyclyl. In some embodiments, Ri₈ is unsubstituted heteroaryl. In some embodiments, Ri₈ is substituted heteroaryl. In some embodiments, R₁₈ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₁₈ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R]₈ is -OPO₃WY. In some embodiments, R]₈ is - OCH₂PO₄WY. In some embodiments, R₁₈ is -OCH₂PO₄Z. In some embodiments, R₁₈ is -OPO₃Z. [00206J In some embodiments, R₁₉ is hydrogen. In some embodiments, R₁₉ is unsubstituted Ci-C|_O alkyl. In some embodiments, R_i9 is substituted Ci-Ci₀ alkyl. In some embodiments, Ri₉ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₁₉ is substituted C₂-C]₀ alkynyl. In some embodiments, R₁₉ is unsubstituted C₂-C₁₀ alkenyl. In some embodiments, R₁₉ is substituted C₂-C]₀ alkenyl. In some embodiments, R₁₉ is unsubstituted carbohydrate. In some embodiments, Ri₉ is substituted carbohydrate. In some embodiments, R,₉ is unsubstituted C]-Ci₀ aliphatic acyl. In some embodiments, R_]9 is substituted Ci-C₁₀ aliphatic acyl. In some embodiments, R₁₉ is unsubstituted C₆-C]₀ aromatic acyl. In some embodiments, R]₉ is substituted C₆-C]₀ aromatic acyl. In some embodiments, R₁₉ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₎₉ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₁₉ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₁₉ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₁₉ is unsubstituted aryl. In some embodiments, R]₉ is substituted aryl. In some embodiments, R₎₉ is unsubstituted C₃-C]₀ heterocyclyl. In some embodiments, R]₉ is substituted C₃-C₁₀ heterocyclyl. In some embodiments, Ri₉ is unsubstituted heteroaryl. In some embodiments, R,₉ is substituted heteroaryl. In some embodiments, R₎₉ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R]₉ is substituted C₃-Ci₀cycloalkyl. In some embodiments, R₁₉ is -PO₃WY. In some embodiments, R₁₉ is - CH₂PO₄WY. In some embodiments, Ri₉ is -CH₂PO₄Z. In some embodiments, Ri₉ is -PO₃Z. (00207| In some embodiments, R₂₁ is hydrogen. In some embodiments, R₂₁ is hydroxy. In some embodiments, R₂i is carboxaldehyde. In some embodiments, R₂₎ is unsubstituted amine. In some embodiments, R₂, is substituted amine. In some embodiments, R₂i is unsubstituted C_rCi_Oalkyl. In some embodiments, R₂, is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₂] is substituted C₂-Ci₀ alkynyl. In some embodiments, R₂, is unsubstituted C₂-Ci_O alkenyl. In some embodiments, R₂, is substituted C₂-Ci_O alkenyl. In some embodiments, R₂, is carboxyl. In some embodiments, R₂i is unsubstituted carbohydrate. In some embodiments, R₂, is substituted carbohydrate. In some embodiments, R₂, is unsubstituted ester. In some embodiments, R₂i is substituted ester. In some embodiments, R₂i is unsubstituted acyloxy. In some embodiments, R_2] is substituted acyloxy. In some embodiments, R₂₁ is nitro. In some embodiments, R₂₎ is halogen. In some embodiments, R₂i is unsubstituted C_rC₁₀ aliphatic acyl. In some embodiments, R₂i is substituted C₁-Ci₀ aliphatic acyl. In some embodiments, R₂i is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂₁ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂i is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₂₁ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₂₁ is unsubstituted C₆-Ci₀ alky laryl acyl. In some embodiments, R₂₁ is substituted C₆-C]₀ alkylaryl acyl. In some embodiments, R₂₁ is unsubstituted alkoxy. In some embodiments, R₂i is substituted alkoxy. In some embodiments, R₂, is unsubstituted aryl. In some embodiments, R₂| is substituted aryl. In some embodiments, R₂ι is unsubstituted C₃-C₁₀ heterocyclyl. In some embodiments, R₂₎ is substituted C₃-Ci_O heterocyclyl. 1° some embodiments, R₂i is unsubstituted heteroaryl. In some embodiments, R₂₁ is substituted heteroaryl. In some embodiments, R₂i is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₁ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₂₁ is -OPO₃WY. In some embodiments, R₂) is -OCH₂PO₄WY. In some embodiments, R₂i is -OCH₂PO₄Z. In some embodiments, R₂₁ is - OPO₃Z.

|002081 In some embodiments, s is an integer of O. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.

|00209] In some embodiments, n is an integer of O. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.

[00210| In various embodiments, W and Y are independently potassium, sodium, or lithium. [00211 | In various embodiments, Z is calcium, magnesium or iron.

(00212| In various embodiments of the invention, the pyrone analog is of Formulae III, IV, V, or VI as illustrated in Scheme I.

Scheme I. Exemplary subclasses of Formula II

[00213| In some embodiments of the invention where the Xi, X₂, X₃, and X₄ of the compounds of Formula Il are CR₅ the compound is of Formula III:

Formula III

|00214| wherein X, Ri, R₂, W, Y, and Z are defined as in Formula I and Formula II;

[00215| R₆, R₇, R₈, and R₉ are independently hydrogen, hydroxyl, carboxaldehyde, amino, Ci-Ci₀ alkyl, C₂-Ci₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-Ci₀ aliphatic acyl, C₆-C]₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, amine, aryl, C₃-Ci₀ heterocyclyl, heteroaryl, C₃- Co cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z.

[00216| In some embodiments, R₆ is hydrogen. In some embodiments, R₆ is hydroxyl. In some embodiments, R₆ is carboxaldehyde. In some embodiments, R₆ is unsubstituted amine. In some embodiments, R₆ is substituted amine. In some embodiments, R₆ is unsubstituted Ci-Ci₀ alkyl. In some embodiments, R₆ is substituted C_rCio alkyl. In some embodiments, R₆ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₆ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₆ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₆ is substituted C₂- Ci₀ alkenyl. In some embodiments, R₆ is carboxyl. In some embodiments, R₆ is unsubstituted carbohydrate. In some embodiments, R₆ is substituted carbohydrate. In some embodiments, R₆ is unsubstituted ester. In some embodiments, R₆ is substituted ester. In some embodiments, R₆ is unsubstituted acyloxy. In some embodiments, R₆ is substituted acyloxy. In some embodiments, R₆ is nitro. In some embodiments, R₆ is halogen. In some embodiments, R₆ is unsubstituted Ci-Ci₀ aliphatic acyl. In some embodiments, R₆ is substituted C,-Ci₀ aliphatic acyl. In some embodiments, R₆ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₆ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₆ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₆ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₆ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₆ is substituted C₆-C)₀ alkylaryl acyl. In some embodiments, R₆ is unsubstituted alkoxy. In some embodiments, R₆ is substituted alkoxy. In some embodiments, R₆ is unsubstituted aryl. In some embodiments, R₆ is substituted aryl. In some embodiments, R₆ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₆ is substituted C₃-C₁₀ heterocyclyl. In some embodiments, R₆ is unsubstituted heteroaryl, In some embodiments, R₆ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₆ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₆ is -OPO₃WY. In some embodiments, R₆ is -OCH₂PO₄WY. In some embodiments, R₆ is - OCH₂PO₄Z. In some embodiments, R₆ is -OPO₃Z.

[00217] In some embodiments, R₇ is hydrogen. In some embodiments, R₇ is hydroxyl. In some embodiments, R₇ is carboxaldehyde. In some embodiments, R₇ is unsubstituted amine. In some embodiments, R₇ is substituted amine. In some embodiments, R₇ is unsubstituted C₁-C₁₀ alkyl. In some embodiments, R₇ is substituted C₁-C₁₀ alkyl. In some embodiments, R₇ is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R₇ is substituted C₂-C₁₀ alkynyl. In some embodiments, R₇ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₇ is substituted C₂- C|_O alkenyl. In some embodiments, R₇ is carboxyl. In some embodiments, R₇ is unsubstituted carbohydrate. In some embodiments, R₇ is substituted carbohydrate. In some embodiments, R₇ is unsubstituted ester. In some embodiments, R₇ is substituted ester. In some embodiments, R₇ is unsubstituted acyloxy. In some embodiments, R₇ is substituted acyloxy. In some embodiments, R₇ is nitro. In some embodiments, R₇ is halogen. In some embodiments, R₇ is unsubstituted C₁-C₁₀ aliphatic acyl. In some embodiments, R₇ is substituted C₁-C₁₀ aliphatic acyl. In some embodiments, R₇ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₇ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₇ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₇ is substituted C₆-C]₀ aralkyl acyl. In some embodiments, R₇ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₇ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₇is unsubstituted alkoxy. In some embodiments, R₇ is substituted alkoxy. In some embodiments, R₇ is unsubstituted aryl. In some embodiments, R₇ is substituted aryl. In some embodiments, R₇ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₇ is substituted C₃-C₁₀ heterocyclyl. In some embodiments, R₇ is unsubstituted heteroaryl, In some embodiments, R₇ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₇ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₇ is -OPO₃WY. In some embodiments, R₇ is -OCH₂PO₄WY. In some embodiments, R₇ is - OCH₂PO₄Z. In some embodiments, R₇ is -OPO₃Z.

[002t8| In some embodiments, R₈ is hydrogen. In some embodiments, R₈ is hydroxyl. In some embodiments, R₈ is carboxaldehyde. In some embodiments, R₈ is unsubstituted amine. In some embodiments, R₈ is substituted amine. In some embodiments, R₈ is unsubstituted Ci-Ci₀ alkyl. In some embodiments, R₈ is substituted C₁-C₁₀ alkyl. In some embodiments, R₈ is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R₈ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₈ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₈ is substituted C₂- C₁₀ alkenyl. In some embodiments, R₈ is carboxyl. In some embodiments, R₈ is unsubstituted carbohydrate. In some embodiments, R₈ is substituted carbohydrate. In some embodiments, R₈ is unsubstituted ester. In some embodiments, R₈ is substituted ester. In some embodiments, R₈ is unsubstituted acyloxy. In some embodiments, R₈ is substituted acyloxy. In some embodiments, R₈ is nitro. In some embodiments, R₈ is halogen. In some embodiments, R₈ is unsubstituted C,-C|₀ aliphatic acyl. In some embodiments, R₈ is substituted C₁-Ci₀ aliphatic acyl. In some embodiments, Rgis unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₈ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₈ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₈ is substituted C₆-Cioaralkyl acyl. In some embodiments, R₈ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₈ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₈ is unsubstituted alkoxy. In some embodiments, R₈ is substituted alkoxy. In some embodiments, R₈ is unsubstituted aryl. In some embodiments, R₈ is substituted aryl. In some embodiments, R₈ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₈ is substituted C₃-Ci₀ heterocyclyl. Jn some embodiments, R₈ is unsubstituted heteroaryl, In some embodiments, R₈ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₈ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₈ is -OPO₃WY. In some embodiments, R₈ is -OCH₂PO₄WY. In some embodiments, R₈ is - OCH₂PO₄Z. In some embodiments, R₈ is -OPO₃Z.

[00219| In some embodiments, R₉ is hydrogen. In some embodiments, R₉ is hydroxyl. In some embodiments, R₉ is carboxaldehyde. In some embodiments, R₉ is unsubstituted amine. In some embodiments, R₉ is substituted amine. In some embodiments, R₉ is unsubstituted Ci-C_)Oalkyl. In some embodiments, R₉ is substituted Ci-Ci₀ alkyl. In some embodiments, R₉ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₉ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₉ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₉ is substituted C₂- Ci_O alkenyl. In some embodiments, R₉ is carboxyl. In some embodiments, R₉ is unsubstituted carbohydrate. In some embodiments, R₉ is substituted carbohydrate. In some embodiments, R₉ is unsubstituted ester. In some embodiments, R₉ is substituted ester. In some embodiments, R₉ is unsubstituted acyloxy. In some embodiments, R₉ is substituted acyloxy. In some embodiments, R₉ is nitro. In some embodiments, R₉ is halogen. In some embodiments, R₉ is unsubstituted C_rC|₀ aliphatic acyl. In some embodiments, R₉ is substituted C_rCi₀ aliphatic acyl. In some embodiments, R₉ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₉ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₉ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₉ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₉ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₉ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₉ is unsubstituted alkoxy. In some embodiments, R₉ is substituted alkoxy. In some embodiments, R₉ is unsubstituted aryl. In some embodiments, R₉ is substituted aryl. In some embodiments, R₉ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₉ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, R₉ is unsubstituted heteroaryl, In some embodiments, R₉ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₉ is substituted C₃-C)₀ cycloalkyl. In some embodiments, R₉ is -OPO₃WY. In some embodiments, R₉ is -OCH₂PO₄WY. In some embodiments, R₉ is - OCH₂PO₄Z. In some embodiments, R₉ is -OPO₃Z. [00220] In various embodiments of the invention, the pyrone analog of Formula III is of Formula VII:

Formula VII

[002211 wherein R₂, R,₆, R_n R,₈, and s are as defined in Formula II and R₆, R₇, R₈, and R₉ are as defined in Formula IM. |002221 In other embodiments of the invention, the pyrone analog of Formula III is a compound of Formula VIII:

Formula VIII

[00223| wherein R₂, R₁₆, Ris, Ri₉, and s are as defined in Formula II and R₆, R₇, R₈, and R₉ are as defined in

Formula III.

J00224J In some embodiments of the invention, the pyrone analog of Formula II is of Formula IX:

Formula IX

|00225] wherein R₂, Ri₆, Ris,

and s are as defined in Formula II; and

|00226| R₆, R₇, Rg, and R₉ are independently hydrogen, carboxaldehyde, amino, Ci-Ci₀ alkyl, C₂-Ci₀alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C_rC|₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, amine, aryl, C₃-C₁₀ heterocyclyl, heteroaryl, C₃- Cocycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z.

|00227) In some embodiments, R₆ is hydrogen. In some embodiments, R₆ is carboxaldehyde. In some embodiments, R₆ is unsubstituted amine. In some embodiments, R₆ is substituted amine. In some embodiments, R₆ is unsubstituted C_rCioalkyl. In some embodiments, R₆ is substituted Ci-Ci_O alkyl. In some embodiments, R₆ is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R₆ is substituted C₂-C₁₀ alkynyl. In some embodiments, R₆ is unsubstituted C₂-C₁₀ alkenyl. In some embodiments, R₆ is substituted C₂-Ci₀ alkenyl. In some embodiments, R₆ is carboxyl. In some embodiments, R₆ is unsubstituted carbohydrate. In some embodiments, R₆ is substituted carbohydrate. In some embodiments, R₆ is unsubstituted ester. In some embodiments, R₆ is substituted ester. In some embodiments, R₆ is unsubstituted acyloxy. In some embodiments, R₆ is substituted acyloxy. In some embodiments, R₆ is nitro. In some embodiments, R₆ is halogen. In some embodiments, R₆ is unsubstituted Ci-Ci₀ aliphatic acyl. In some embodiments, R₆ is substituted C _rCi₀ aliphatic acyl. In some embodiments, R₆ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₆ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₆ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₆ is substituted C₆- Cio aralkyl acyl. In some embodiments, R₆ is unsubstituted C₆-Ci₀ alky lary I acyl. In some embodiments, R₆ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₆ is unsubstituted alkoxy. In some embodiments, R₆ is substituted alkoxy. In some embodiments, R₆ is unsubstituted aryl. In some embodiments, R₆ is substituted aryl. In some embodiments, R₆ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₆ is substituted C₃-C₁0 heterocyclyl. In some embodiments, R₆ is unsubstituted heteroaryl, In some embodiments, R₆ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₆ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₆ is - OPO₃WY. In some embodiments, R₆ is -OCH₂PO₄WY. In some embodiments, R₆ is -OCH₂PO₄Z. In some embodiments, R₆ is -OPO₃Z.

|00228] In some embodiments, R₇ is hydrogen. In some embodiments, R₇ is carboxaldehyde. In some embodiments, R₇ is unsubstituted amine. In some embodiments, R₇ is substituted amine. In some embodiments, R₇ is unsubstituted C₁-Ci₀ alkyl. In some embodiments, R₇ is substituted Ci-C₁₀ alkyl. In some embodiments, R₇ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₇ is substituted C₂-C₁₀ alkynyl. In some embodiments, R₇ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₇ is substituted C₂-C₁₀ alkenyl. In some embodiments, R₇ is carboxyl. In some embodiments, R₇ is unsubstituted carbohydrate. In some embodiments, R₇ is substituted carbohydrate. In some embodiments, R₇ is unsubstituted ester. In some embodiments, R₇ is substituted ester. In some embodiments, R₇ is unsubstituted acyloxy. In some embodiments, R₇ is substituted acyloxy. In some embodiments, R₇ is nitro. In some embodiments, R₇ is halogen. In some embodiments, R₇ is unsubstituted C,-C₁₀ aliphatic acyl. In some embodiments, R₇ is substituted C_I-C_J0 aliphatic acyl. In some embodiments, R₇ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₇ is substituted C₆-C_]0 aromatic acyl. In some embodiments, R₇ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₇ is substituted C₆- C|_Oaralkyl acyl. In some embodiments, R₇ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₇ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₇is unsubstituted alkoxy. In some embodiments, R₇ is substituted alkoxy. In some embodiments, R₇ is unsubstituted aryl. In some embodiments, R₇ is substituted aryl. In some embodiments, R₇ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₇ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, R₇ is unsubstituted heteroaryl, In some embodiments, R₇ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₇ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₇ is - OPO₃WY. In some embodiments, R₇ is -OCH₂PO₄WY. In some embodiments, R₇ is -OCH₂PO₄Z. In some embodiments, R₇ is -OPO₃Z.

|00229] In some embodiments, R₈ is hydrogen. In some embodiments, R₈ is hydroxy!. In some embodiments, R₈ is carboxaldehyde. In some embodiments, R₈ is unsubstituted amine. In some embodiments, R₈ is substituted amine. In some embodiments, R₈ is unsubstituted Ci-Ci₀ alkyl. In some embodiments, R₈ is substituted C₁-Ci₀ alkyl. In some embodiments, R₈ is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R₈ is substituted C₂-Ci₀ alkynyl. n some embodiments, R₈ is unsubstituted C₂-C₁₀ alkenyl. In some embodiments, R₈ is substituted C₂- C₁₀ alkenyl. In some embodiments, R₈ is carboxyl. In some embodiments, R₈ is unsubstituted carbohydrate. In some embodiments, R₈ is substituted carbohydrate. In some embodiments, R₈ is unsubstituted ester. In some embodiments, R₈ is substituted ester. In some embodiments, R₈ is unsubstituted acyloxy. In some embodiments, R₈ is substituted acyloxy. In some embodiments, R₈ is nitro. In some embodiments, R₈ is halogen. In some embodiments, R₈ is unsubstituted C_rCi₀ aliphatic acyl. In some embodiments, R₈ is substituted C_rC₁₀ aliphatic acyl. In some embodiments, R₈is unsubstituted C₆-C)₀ aromatic acyl. In some embodiments, R₈ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₈ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₈ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₈ is unsubstituted C₆-C ₁₀ alkylaryl acyl. In some embodiments, R₈ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₈ is unsubstituted alkoxy. In some embodiments, R₈ is substituted alkoxy. In some embodiments, R₈ is unsubstituted aryl. In some embodiments, R₈ is substituted aryl. In some embodiments, R₈ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, Rs is substituted C₃-C₁₀ heterocyclyl. In some embodiments, R₈ is unsubstituted heteroaryl, In some embodiments, R₈ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₈ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₈ is -OPO₃WY. In some embodiments, R₈ is -OCH₂PO₄WY. In some embodiments, R₈ is - OCH₂PO₄Z. In some embodiments, R₈ is -OPO₃Z.

[00230] In some embodiments, R₉ is hydrogen. In some embodiments, R₉ is carboxaldehyde. In some embodiments, R₉ is unsubstituted amine. In some embodiments, R₉ is substituted amine. In some embodiments, R₉ is unsubstituted C₁-Ci₀ alkyl. In some embodiments, R₉ is substituted Ci-Ci₀ alkyl. In some embodiments, R₉ is unsubstituted C₂-Ci₀alkynyl. In some embodiments, R₉ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₉ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₉ is substituted C₂-C]₀ alkenyl. In some embodiments, R₉ is carboxyl. In some embodiments, R₉ is unsubstituted carbohydrate. In some embodiments, R₉ is substituted carbohydrate. In some embodiments, R₉ is unsubstituted ester. In some embodiments, R₉ is substituted ester. In some embodiments, R₉ is unsubstituted acyloxy. In some embodiments, R₉ is substituted acyloxy. In some embodiments, R₉ is nitro. In some embodiments, R₉ is halogen. In some embodiments, R₉ is unsubstituted C|-C_)Oaliphatic acyl. In some embodiments, R₉ is substituted C,-C|₀ aliphatic acyl. In some embodiments, R₉ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₉ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₉ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₉ is substituted C₆- Ci_O aralkyl acyl. In some embodiments, R₉ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₉ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₉ is unsubstituted alkoxy. In some embodiments, R₉ is substituted alkoxy. In some embodiments, R₉ is unsubstituted aryl. In some embodiments, R₉ is substituted aryl. In some embodiments, R₉ is unsubstituted C₃-C₁₀ heterocyclyl. In some embodiments, R₉ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, R₉ is unsubstituted heteroaryl, In some embodiments, R₉ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₉ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₉ is - OPO₃WY. In some embodiments, R₉ is -OCH₂PO₄WY. In some embodiments, R₉ is -OCH₂PO₄Z. In some embodiments, R₉ is -OPO₃Z. |00231 ] In some embodiments of the invention, the pyrone analog of Formula III is of Formula X:

Formula X

1002321 wherein R₂, Ri₆, Ri_8, and R₁₉ are as defined in Formula II and R₇ and R₉ are as defined in Formula IH. 1002331 In other embodiments of the invention, the pyrone analog of Formula III is of Formula XI:

Formula XI

[00234] wherein R₂, Ri₆, R_JS, and R₁₉ are as defined in Formula II and R₆, R7, and R₉ are as defined in Formula III.

1002351 In some embodiments of the invention, compounds of the following Formulae VIII-A, VIII-B, and VIII-C, are useful in the methods of the invention, where each instance of R_e and Rj is independently hydrogen, -OPO₃WY, -OPO₃Z, -OCH₂OPOWY, Or-OCH₂OPO₃Z, where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun and Z is calcium, magnesium or iron .

Formula VIII-A Formula VIII-B Formula VIII-C

[00236] In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R₀ and Rj are hydrogen. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R_e is -OPO₃WY and Rj is hydrogen. In some embodiments of the invention, for a compound of Formulae VIII- A, VIII-B, or VIII-C, R₄; is -OPO₃WY and R₀ is -OPO₃WY. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R₀ is a mixture of hydrogen and -OPO₃WY and R_d is - OPO₃WY. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, Rς is hydrogen and R₀ is a mixture of hydrogen and -OPO₃Z. In some embodiments of the invention, for a compound of Formulae VIU-A, VIII-B, or VIII-C, R₀ is -OPO₃Z and Rj is hydrogen. In some embodiments of the invention, for a compound of Formulae VIII-A, VlII-B, or VIII-C, R₀ is -OPO₃Z and Rj is -OPO₃Z. In some embodiments of the invention, for a compound of Formulae VHI-A, VIII-B, or VIII-C, R₀ is a mixture of hydrogen and -OPO₃Z and R_d is -OPO₃Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R₀ is hydrogen and R₄ is a mixture of hydrogen and -OPO₃Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R_c is -CH₂OPO₃Z and Rj is hydrogen. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R₀ is -CH₂OPO₃Z and R₀ is -CH₂OPO₃Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R₀ is a mixture of hydrogen and -CH₂OPO₃Z and Rj is -CH₂OPO₃Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R₀ is hydrogen and Rj is a mixture of hydrogen and -CH₂OPO₃Z. |00237| In other embodiments of the invention, the pyrone analog of Formula III is of Formula XII:

Formula XlI

|00238| wherein R₂, Ri₆, Rιs_, and R,₉ are as defined in Formula II and R₆, R_8, and R₉ are as defined in Formula

III.

(00239J In other embodiments of the invention, the pyrone analog of Formula III is of Formula XIII:

Formula XIII

[00240| wherein X, R_18, and R,₉ are as defined in Formula II and R₆, R₇ and R₉ are as defined in Formula III. |002411 In some embodiments, the pyrone analog of Formula III is of Formula XI V:

Formula XIV

1002421 In some embodiments, the pyrone analog of Formula III is of Formula XV:

Formula XV

1002431 wherein Ri_8, R₁₉, and n are as defined in Formula II.

|00244| In some embodiments, the pyrone analog of Formula III is of Formula XVI:

Formula XVI

1002451 wherein Ri_8, R₁9, R₂ι, and n are as defined in Formula II;

|00246| R_2O is hydrogen, C_rCi_Oalkyl, C₂-C|_O alkynyl, C₂-Ci₀ alkenyl, carbohydrate, Ci-C₁₀ aliphatic acyl, C₆-C_w aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, aryl, C₃-C₁₀ heterocyclyl, heteroaryl, optionally substituted C₃-C₁₀ cycloalkyl, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z; and

1002471 W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation.

[00248] In some embodiments, R₂₀ is hydrogen. In some embodiments, R₂₀ is unsubstituted Ci-C₁₀ alkyl. In some embodiments, R₂₀ is substituted C_rCio alkyl. In some embodiments, R₂₀ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₂₀ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₂₀ is unsubstituted C₂-Cj₀ alkenyl. In some embodiments, R₂₀ is substituted C₂-C₁₀ alkenyl. In some embodiments, R₂₀ is unsubstituted carbohydrate. In some embodiments, R₂₀ is substituted carbohydrate. In some embodiments, R₂₀ is unsubstituted Ci-Cio aliphatic acyl. In some embodiments, R₂₀ is substituted C_rC₁₀aliphatic acyl. In some embodiments, R₂₀ is unsubstituted Ce-C_1O aromatic acyl. In some embodiments, R₂₀ is substituted Ce-C₁₀ aromatic acyl. In some embodiments, R₂₀ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₂₀ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₂₀ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₂₀ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₂₀ is unsubstituted aryl. In some embodiments, R₂₀ is substituted aryl. In some embodiments, R₂₀ is unsubstituted C₃-C₁₀ heterocyclyl. In some embodiments, R₂₀ is substituted C₃-Ci₀ heterocyclyl. ^m some embodiments, R₂₀ is unsubstituted heteroaryl. In some embodiments, R₂₀ is substituted heteroaryl. In some embodiments, R₂₀ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₀ is substituted C₃-C)₀ cycloalkyl. In some embodiments, R₂₀ is -PO₃WY. In some embodiments, R₂₀ is - CH₂PO₄WY. In some embodiments, R₂₀ is -CH₂PO₄Z. In some embodiments, R₂₀ is -PO₃Z. [00249| In some embodiments, the pyrone analog of Formula III is of Formula XVII:

Formula XVII

|00250] wherein Ri₈ is as defined in Formula II; and

[00251 | R_2O is hydrogen, C₁-Ci₀ alkyl, C₂-C₁₀ alkynyl, C₂-Ci₀ alkenyl, carbohydrate, C,-C₁₀ aliphatic acyl, C₆-C₁₀ aromatic acyl, C₆-Ci₀aralkyl acyl, C₆-C₁₀ alkylaryl acyl, aryl, C₃-C₁₀ heterocyclyl, heteroaryl, optionally substituted C₃-C,₀cycloalkyl, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z.

|002521 In some embodiments, R₂₀ is hydrogen. In some embodiments, R₂₀ is unsubstituted Ci-C)₀ alkyl. In some embodiments, R₂₀ is substituted Ci-C₁₀ alkyl. In some embodiments, R₂₀ is unsubstituted C₂-C io alkynyl. In some embodiments, R₂₀ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₂₀ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₂₀ is substituted C₂-Ci_O alkenyl. In some embodiments, R₂₀ is unsubstituted carbohydrate. In some embodiments, R₂₀ is substituted carbohydrate. In some embodiments, R₂₀ is unsubstituted Ci-Ci₀ aliphatic acyl. In some embodiments, R₂₀ is substituted C₁-C₁₀ aliphatic acyl. In some embodiments, R₂₀ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂₀ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₂₀ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₂₀ is substituted C₆-C)₀ aralkyl acyl. In some embodiments, R₂₀ is unsubstituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₂₀ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₂₀ is unsubstituted aryl. In some embodiments, R₂₀ is substituted aryl. In some embodiments, R₂₀ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₂₀ is substituted C₃-C₁₀ heterocyclyl. In some embodiments, R₂₀ is unsubstituted heteroaryl. In some embodiments, R₂₀ is substituted heteroaryl. In some embodiments, R₂₀ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₂₀ is substituted C₃-C)₀ cycloalkyl. In some embodiments, R₂₀ is -PO₃WY. In some embodiments, R₂₀ is - CH₂PO₄WY. In some embodiments, R₂₀ is -CH₂PO₄Z. In some embodiments, R₂₀ is -PO₃Z. [00253| In some embodiments, the pyrone analog of Formula III is of Formula XVIII:

Formula XVIII

|00254] wherein R₁₈ and R)₉ are as defined in Formula II; |00255| wherein each instance of R₂2 is independently hydrogen, hydroxyl, carboxaldehyde, amine, Ci-Ci₀ alkyl, C₂-Ci₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C_rC|₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-Ci₀ alky lary I acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C₃-Ci₀ heterocyclic, C₃-Ci₀cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z; and [00256| t is an integer of 0, 1, 2, 3, or 4

[00257| In some embodiments, R₂₂ is hydrogen. In some embodiments, R₂₂ is hydroxy. In some embodiments, R₂₂ is carboxaldehyde. In some embodiments, R₂₂ is unsubstituted amine. In some embodiments, R₂₂ is substituted amine. In some embodiments, R₂₂ is unsubstituted C₁-Ci₀ alkyl. In some embodiments, R₂₂ is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R₂₂ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₂₂ is unsubstituted C₂-C₁₀ alkenyl. In some embodiments, R₂₂ is substituted C₂-Ci₀ alkenyl. In some embodiments, R₂₂ is carboxyl. In some embodiments, R₂₂ is unsubstituted carbohydrate. In some embodiments, R₂₂ is substituted carbohydrate. In some embodiments, R₂₂ is unsubstituted ester. In some embodiments, R₂₂ is substituted ester. In some embodiments, R₂₂ is unsubstituted acyloxy. In some embodiments, R₂₂ is substituted acyloxy. In some embodiments, R₂₂ is nitro. In some embodiments, R₂₂ is halogen. In some embodiments, R₂₂ is unsubstituted C_rCi₀ aliphatic acyl. In some embodiments, R₂₂ is substituted C₁-Ci₀ aliphatic acyl. In some embodiments, R₂₂ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₂₂ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₂₂ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₂₂ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₂₂ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₂₂ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₂₂ is unsubstituted alkoxy. In some embodiments, R₂₂ is substituted alkoxy. In some embodiments, R₂₂ is unsubstituted aryl. In some embodiments, R₂₂ is substituted aryl. In some embodiments, Ris is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₂₂ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, R₂₂ is unsubstituted heteroaryl. In some embodiments, R₂₂ is substituted heteroaryl. In some embodiments, R₂₂ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₂ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₂ is -OPO₃WY. In some embodiments, R₂₂ is -OCH₂PO₄WY. In some embodiments, R₂₂ is -OCH₂PO₄Z. In some embodiments, R₂₂ is - OPO₃Z.

[00258] In some embodiments, t is an integer of O. In some embodiments, t is an integer of 1. In some embodiments, t is an integer of 2. In some embodiments, t is an integer of 3. In some embodiments, t is an integer of 4. [00259| In some embodiments, the pyrone analog of Formula III is of Formula XIX:

Formula XIX

|00260| wherein R|₈ and R_]9 are as defined in Formula II; (00261 ] wherein each instance Of R₂₂ is independently hydrogen, hydroxyl, carboxaldehyde, amine, C_rC|₀ alkyl, C₂-C₁₀ alkynyl, C₂-C₁₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C₁-Ci₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆-Ci₀ alky laryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl,

C₃-C₁₀ heterocyclic, C₃-Ci₀ cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z Or -OPO₃Z; and

|002621 m is an integer of 0, 1, or 2.

|00263] In some embodiments, m is an integer of 0. In some embodiments, m is an integer of 1. In some embodiments, m is an integer of 2.

|00264] In some embodiments, the pyrone analog of Formula III is of Formula XX:

Formula XX

[00265] wherein Ri₈ and Ri₉ are as defined in Formula II;

|00266] wherein each instance Of R₂₂ is independently hydrogen, hydroxyl, carboxaldehyde, amine, Ci-Ci₀ alkyl, C₂-C₁₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-Ci₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-C₁₀ alky laryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C₃-C₁₀ heterocyclic, C₃-C₁₀ cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z; and [00267] p is an integer of 0, 1 , 2 or 3. f00268j In some embodiments, R₂₂ is hydrogen. In some embodiments, R₂₂ is hydroxy. In some embodiments, R₂₂ is carboxaldehyde. In some embodiments, R₂₂ is unsubstituted amine. In some embodiments, R₂₂ is substituted amine. In some embodiments, R₂₂ is unsubstituted C₁-C₁₀ alkyl. In some embodiments, R₂₂ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₂₂ is substituted C₂-C₁₀ alkynyl. In some embodiments, R₂₂ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₂₂ is substituted C₂-C)₀ alkenyl. In some embodiments, R₂₂ is carboxyl. In some embodiments, R₂₂ is unsubstituted carbohydrate. In some embodiments, R₂₂ is substituted carbohydrate. In some embodiments, R₂₂ is unsubstituted ester. In some embodiments, R₂₂ is substituted ester. In some embodiments, R₂₂ is unsubstituted acyloxy. In some embodiments, R₂₂ is substituted acyloxy. In some embodiments, R₂₂ is nitro. In some embodiments, R₂₂ is halogen. In some embodiments, R₂₂ is unsubstituted C₁-Ci₀ aliphatic acyl. In some embodiments, R₂₂ is substituted C_rC₁₀ aliphatic acyl. In some embodiments, R₂₂ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₂₂ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂₂ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₂₂ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₂₂ is unsubstituted C₆-C)₀ alkylaryl acyl. In some embodiments, R₂₂ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₂₂ is unsubstituted alkoxy. In some embodiments, R₂₂ is substituted alkoxy. In some embodiments, R₂₂ is unsubstituted aryl. In some embodiments, R₂₂ is substituted aryl. In some embodiments, Ri₈ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R₂₂ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, R₂₂ is unsubstituted heteroaryl. In some embodiments, R₂₂ is substituted heteroaryl. In some embodiments, R₂₂ is unsubstituted C₃-Ci₀ cycloalkyl.

In some embodiments, R₂₂ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₂ is -OPO₃WY. In some embodiments, R₂₂ is -OCH₂PO₄WY. In some embodiments, R₂₂ is -OCH₂PO₄Z. In some embodiments, R₂₂ is -

OPO₃Z.

[00269| In some embodiments, p is an integer of O. In some embodiments, p is an integer of 1. In some embodiments, p is an integer of 2. .In some embodiments, p is an integer of 3.

[00270] In some embodiments, the pyrone analog of Formula III is of Formula XXI:

Formula XXI

[00271 ] wherein Ri₈ and R₂₁ as defined in Formula II; and

|00272] R₂₀ is hydrogen, Ci-Ci_O alkyl, C₂-C)₀ alkynyl, C₂-Ci₀ alkenyl, carbohydrate, Ci-Ci₀ aliphatic acyl, C₆- C₁₀ aromatic acyl, C₆-Ci₀aralkyl acyl, C₆-Ci₀ alkylaryl acyl, aryl, C₃-Ci₀heterocyclyl, heteroaryl, optionally substituted C₃-C,₀cycloalkyl, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z.

|00273| In some embodiments, R₂₀ is hydrogen. In some embodiments, R₂₀ is unsubstituted Ci-Ci₀ alkyl. In some embodiments, R₂₀ is substituted Ci-Ci₀ alkyl. In some embodiments, R₂₀ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₂₀ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₂₀ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₂₀ is substituted C₂-C₁₀ alkenyl. In some embodiments, R₂₀ is unsubstituted carbohydrate. In some embodiments, R₂₀ is substituted carbohydrate. In some embodiments, R₂₀ is unsubstituted Ci-Ci₀ aliphatic acyl. In some embodiments, R₂₀ is substituted C, -C]₀ aliphatic acyl. In some embodiments, R₂₀ is unsubstituted C₆-C)₀ aromatic acyl. In some embodiments, R₂₀ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂₀ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₂₀ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₂₀ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₂₀ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₂₀ is unsubstituted aryl. In some embodiments, R₂₀ is substituted aryl. In some embodiments, R₂₀ is unsubstituted C₃-C]₀ heterocyclyl. In some embodiments, R₂₀ is substituted C₃-Ci₀ heterocyclyl. I" some embodiments, R₂₀ is unsubstituted heteroaryl. In some embodiments, R₂₀ is substituted heteroaryl. In some embodiments, R₂₀ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₀ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₀ is -PO₃WY. In some embodiments, R₂₀ is - CH₂PO₄WY. In some embodiments, R₂₀ is -CH₂PO₄Z. In some embodiments, R₂₀ is -PO₃Z. [00274] In some embodiments, the pyrone analog of Formula III is of Formula XXII:

Formula XXII

|00275] wherein Ri₈ and R₂, are as defined in Formula II;

100276] wherein X₅ is a Ci to C₄ group, optionally interrupted by O, S, NR₂₃, or NR₂₃R₂₃ as valency permits, forming a ring which is aromatic or nonaromatic;

[00277] each instance OfR₂₃ is independently hydrogen, C₁-Ci₀ alkyl, C₂-C₁₀ alkynyl, C₂-C₁₀ alkenyl, carbohydrate, acyloxy, C_rCi₀ aliphatic acyl, C₆-C₁₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, aryl, heteroaryl, C₅-Ci₀ heterocyclyl, C₃-C₀ cycloalkyl, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z. [00278] In some embodiments, R₂₃ is hydrogen. In some embodiments, R₂₃ is unsubstituted CpCio alkyl. In some embodiments, R₂₃ is substituted C_rC₁₀ alkyl. In some embodiments, R₂₃ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₂₃ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₂₃ is unsubstituted C₂-C₁₀ alkenyl. fn some embodiments, R₂₃ is substituted C₂-Ci₀ alkenyl. In some embodiments, R₂₃ is unsubstituted acyloxy. In some embodiments, R₂₃ is substituted acyloxy. In some embodiments, R₂₃ is unsubstituted carbohydrate. In some embodiments, R₂₃ is substituted carbohydrate. In some embodiments, R₂₃ is unsubstituted acyloxy. In some embodiments, R₂₃ is substituted acyloxy. In some embodiments, R₂₃ is unsubstituted Ci-C₁₀ aliphatic acyl. In some embodiments, R₂₃ is substituted C₁-C₁₀ aliphatic acyl. In some embodiments, R₂₃ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂₃ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂₃ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₂₃ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₂₃ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₂₃ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₂₃ is unsubstituted alkoxy. In some embodiments, R₂₃ is substituted alkoxy. In some embodiments, R₂₃ is unsubstituted aryl. In some embodiments, R₂₃ is substituted aryl. In some embodiments, R₂₃ is unsubstituted C₃-C₁₀heterocyclyl. In some embodiments, R₂₃ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, R₂₃ is unsubstituted heteroaryl. In some embodiments, R₂₃ is substituted heteroaryl. In some embodiments, R₂₃ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₃ is substituted C₃-C)₀ cycloalkyl.

|00279| In some embodiments, the pyrone analog of Formula III is of Formula XXIII:

Formula XXIII |00280] Wherein R₂₀ is hydrogen, C_rCi_O alkyl, C₂-Ci₀ alkynyl, C₂-Ci₀ alkenyl, carbohydrate, C,-C|₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, aryl, C₃-C₁₀ heterocyclyl, heteroaryl, optionally substituted C₃-C₁₀ cycloalkyl, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z; [002811 Het is a 3 to 10 membered optionally substituted monocyclic or bicyclic heteroaromatic or heteroalicyclic ring system containing 1, 2, 3, 4, or 5 heteroatoms selected from the group of O, S, and N, with the proviso that no two adjacent ring atoms are O or S, wherein the ring system is unsaturated, partially unsaturated or saturated, wherein any number of the ring atoms have substituents as valency permits which are hydrogen, hydroxyl, carboxyaldehyde, alkylcarboxaldehyde, imino, C_rC|_O alkyl, C | -C]₀ alkynyl, C_rC|₀ alkenyl, carboxyl, carbohydrate, acyloxy, nitro, halogen, C₁-Ci₀ aliphatic acyl, C₅-C₁₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆-C₁₀ alkylaryl acyl, alkoxy, amine, aryl, heteroaryl, C₅-Ci₀ heterocyclyl, C₅-Ci₀ cycloalkyl, -OPO₃WY, - OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z; and

|00282] W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation.

|00283] In some embodiments, R₂₀ is hydrogen. In some embodiments, R₂₀ is unsubstituted C_rC|oalkyl. In some embodiments, R₂₀ is substituted C_rC₁₀ alkyl. In some embodiments, R₂₀ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R₂₀ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₂₀ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₂₀ is substituted C₂-C₎₀ alkenyl. In some embodiments, R₂₀ is unsubstituted carbohydrate. In some embodiments, R₂₀ is substituted carbohydrate. In some embodiments, R₂₀ is unsubstituted C₁-C₁₀ aliphatic acyl. In some embodiments, R₂₀ is substituted C₁-Ci₀ aliphatic acyl. In some embodiments, R₂₀ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂₀ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₂₀ is unsubstituted C₆-C₁₀aralkyl acyl. In some embodiments, R₂₀ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₂₀ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₂₀ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₂₀ is unsubstituted aryl. In some embodiments, R₂₀ is substituted aryl. In some embodiments, R₂₀ is unsubstituted C₃-C₁₀ heterocyclyl. In some embodiments, R₂₀ is substituted C₃-C₁₀ heterocyclyl. In some embodiments, R₂₀ is unsubstituted heteroaryl. In some embodiments, R₂₀ is substituted heteroaryl. In some embodiments, R₂₀ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R₂₀ is substituted C₃-C₁₀ cycloalkyl. In some embodiments, R₂₀ is -PO₃WY. In some embodiments, R₂₀ is - CH₂PO₄WY. In some embodiments, R₂₀ is -CH₂PO₄Z. In some embodiments, R₂₀ is -PO₃Z. |00284| In some embodiments, Het is one of the following formulae:

1002851 wherein each instance Of Ri₈ is independently hydrogen, hydroxyl, carboxaldehyde, amine, Ci-Ci₀ alkyl, C₂-Ci₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, CrCi₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C₎₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C₃-C₁₀ heterocyclic, C₃-C₁₀ cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z; [00286| s is an integer of 0, 1 , 2, or 3; and [00287| n is an integer of 0, 1, 2, 3, or 4.

[00288| In some embodiments, Ri₈ is hydrogen. In some embodiments, Ri₈ is hydroxy. In some embodiments, Ri₈ is carboxaldehyde. In some embodiments, R₁₈ is unsubstituted amine. In some embodiments, R₁₈ is substituted amine. In some embodiments, R_ig is unsubstituted C_rC|_O alkyl. In some embodiments, Ri₈ is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R₁₈ is substituted C₂-C₁₀ alkynyl. In some embodiments, R,₈ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R₁₈ is substituted C₂-Ci₀ alkenyl. In some embodiments, R₁₈ is carboxyl. In some embodiments, Ri₈ is unsubstituted carbohydrate. In some embodiments, R₁₈ is substituted carbohydrate. In some embodiments, R₁₈ is substituted carbohydrate. In some embodiments, Ri₈ is unsubstituted ester. In some embodiments, R₎₈ is substituted ester. In some embodiments, R₁₈ is unsubstituted acyloxy. In some embodiments, Ri₈ is substituted acyloxy. In some embodiments, R_]8 is nitro. In some embodiments, R₁₈ is halogen. In some embodiments, R₁₈ is unsubstituted CpC₁₀ aliphatic acyl. In some embodiments, R₁₈ is substituted C₁-Ci₀ aliphatic acyl. In some embodiments, R₁₈ is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, Ri₈ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, Ri₈ is unsubstituted C₆-C)₀ aralkyl acyl. In some embodiments, R₎₈ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R|_g is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₎₈ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, Ri₈ is unsubstituted alkoxy. In some embodiments, Ri₈ is substituted alkoxy. In some embodiments, R₁₈ is unsubstituted aryl. In some embodiments, R,₈ is substituted aryl. In some embodiments, R)₈ is unsubstituted C₃-C,₀ heterocyclyl. In some embodiments, Ri₈ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, Ri₈ is unsubstituted heteroaryl. In some embodiments, Ri₈ is substituted heteroaryl. In some embodiments, R)₈ is unsubstituted C₃-Ci₀ cycloalkyl. • In some embodiments, R_]8 is substituted C₃-C₁₀ cycloalkyl. In some embodiments, Ri₈ is -OPO₃WY. In some embodiments, Ri₈ is - OCH₂PO₄WY. In some embodiments, R_]8 is -OCH₂PO₄Z. In some embodiments, R₁₈ is -OPO₃Z. [00289] In some embodiments, n is an integer of O. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.

[00290] In some embodiments, s is an integer of O. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3. |00291 ) In some embodiments of the invention, the pyrone analog of Formula II is of Formula IV:

Formula IV

[00292| wherein X, X₂, X₄, R', Ri, R₂, W, Y, and Z are as defined for Formula II; and |00293] Rio and Rn are independently hydrogen, hydroxyl, carboxaldehyde, amino, Ci-C|_O alkyl, C₂-Ci₀ alkynyl, C₂-Ci₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C_rCi₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C₁₀ aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, amine, aryl, C₃-Ci₀ heterocyclyl, heteroaryl, C₃- Co cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z Or -OPO₃Z.

[00294| In some embodiments, R|₀ is hydrogen. In some embodiments, Ri₀ is hydroxyl. In some embodiments, Riois carboxaldehyde. In some embodiments, R|₀ is unsubstituted amine. In some embodiments, R₁₀ is substituted amine. In some embodiments, R₎₀ is unsubstituted C_rCi_O alkyl. In some embodiments, R,_o is substituted C|-C|_Oalkyl. In some embodiments, R,_o is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R|₀ is substituted C₂-C₁₀ alkynyl. In some embodiments, Ri₀ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, Rio is substituted C₂-Ci₀ alkenyl. In some embodiments, R₁₀ is carboxyl. In some embodiments, R)₀ is unsubstituted carbohydrate. In some embodiments, Ri₀ is substituted carbohydrate. In some embodiments, R₎₀ is unsubstituted ester. In some embodiments, Ri₀ is substituted ester. In some embodiments, Ri₀ is unsubstituted acyloxy. In some embodiments, Ri₀ is substituted acyloxy. In some embodiments, R]₀ is nitro. In some embodiments, Ri₀ is halogen. In some embodiments, Ri₀ is unsubstituted C_rC₁₀ aliphatic acyl. In some embodiments, R₁₀ is substituted C_rC|₀ aliphatic acyl. In some embodiments, R_]0 is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, R|₀ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R₁₀ is unsubstituted C₆-C,₀ aralkyl acyl. In some embodiments, R₁₀ is substituted C₆-C]₀ aralkyl acyl. In some embodiments, R₁₀ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₁₀ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R|_O is unsubstituted alkoxy. In some embodiments, R₁₀ is substituted alkoxy. In some embodiments, R|₀ is unsubstituted aryl. In some embodiments, R|₀ is substituted aryl. In some embodiments, R₁₀ is unsubstituted C₃-C₁₀ heterocyclyl. In some embodiments, R|₀ is substituted C₃-C₁₀ heterocyclyl. In some embodiments, R|₀ is unsubstituted heteroaryl, In some embodiments, R₎₀ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R|₀ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₁₀ is - OPO₃WY. In some embodiments, Ri₀ is -OCH₂PO₄WY. In some embodiments, R₁₀ is -OCH₂PO₄Z. In some embodiments, R₁₀ is -OPO₃Z.

|00295| In some embodiments, Rn is hydrogen. In some embodiments, R_{1 1} is hydroxyl. In some embodiments, R_n is carboxaldehyde. In some embodiments, R_{1 1} is unsubstituted amine. In some embodiments, R₁ , is substituted amine. In some embodiments, R_n is unsubstituted C₁-Ci₀ alkyl. In some embodiments, Rn is substituted C_rC₁₀alkyl. In some embodiments, R_{1 1} is unsubstituted C₂-C)₀ alkynyl. In some embodiments, Rn is substituted C₂-Ci₀ alkynyl. In some embodiments, Rn is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, Rn is substituted C₂-Ci₀ alkenyl. In some embodiments, R, , is carboxyl. In some embodiments, Rn is unsubstituted carbohydrate. In some embodiments, Rn is substituted carbohydrate. In some embodiments, R_{t l} is unsubstituted ester. In some embodiments, Rn is substituted ester. In some embodiments, R_n is unsubstituted acyloxy. In some embodiments, Rn is substituted acyloxy. In some embodiments, R_n is nitro. In some embodiments, Rn is halogen. In some embodiments, R_u is unsubstituted Ci-C)₀ aliphatic acyl. In some embodiments, R, , is substituted C_rC₁₀ aliphatic acyl. In some embodiments, R_n is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, Rn is substituted C₆-Ci₀ aromatic acyl. In some embodiments, Rn is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R, i is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R_n is unsubstituted C₆-Ci₀ alky laryl acyl. In some embodiments, R_n is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, Rn is unsubstituted alkoxy. In some embodiments, Rn is substituted alkoxy. In some embodiments, R₁₁ is unsubstituted aryl. In some embodiments, Rn is substituted aryl. In some embodiments, Rn is unsubstituted C₃-C₁₀ heterocyclyl. In some embodiments, R_{1 1} is substituted C₃-C₁₀ heterocyclyl. In some embodiments, R_n is unsubstituted heteroaryl, In some embodiments, Rn is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, Rn is substituted C₃-C₁₀ cycloalkyl. In some embodiments, Rn is - OPO₃WY. In some embodiments, R_{1 1} is -OCH₂PO₄WY. In some embodiments, R₁ , is -OCH₂PO₄Z. In some embodiments, R_{1 1} is -OPO₃Z.

|00296| In some embodiments of the invention, the pyrone analog of Formula IV is of Formula XXIV or Formula XXV:

Formula XXIV Formula XXV

[002971 wherein R_t8, R₁₉, and n are as defined in Formula II.

[00298] In some embodiments of the invention, the pyrone analog of Formula IV is of Formula XXVI or

Formula XXVII:

Formula XXVI Formula XXVII

|00299| wherein R₂, R₅, W, Y, and Z are as defined for Formula II and R₁₀ and R_n are as defined for Formula

IV;

|00300| R,₆ is hydrogen, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z; [00301] wherein each instance Of R]₈ is independently hydrogen, hydroxyl, carboxaldehyde, amine, C₁-Ci₀ alkyl, C₂-Ci₀ alkynyl, C₂-C|_O alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C_rC|_Oaliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆-C)₀ alky lary I acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl,

C₃-Ci₀ heterocyclic, C₃-C,₀cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z; and

|00302] n is an integer of 0, 1 , 2, 3, or 4.

(00303| In some embodiments of the invention, the pyrone analog of Formula IV is of Formula XXVIII:

Formula XXVHI

[00304] wherein R₂, W, Y, and Z are as defined for Formula II and Ri₀ and R_M are as defined for Formula IV;

|00305| R₁₆ is hydrogen, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z;

|00306| wherein each instance Of Ri₈ is independently hydrogen, hydroxyl, carboxaldehyde, amine, Ci-Ci₀ alkyl, C₂-Ci₀ alkynyl, C₂-C,_o alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-C)₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C)₀ aralkyl acyl, C₆-C)₀ alky laryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl,

C₃-Ci₀ heterocyclic, C₃-C₁₀ cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z; and

[00307| n is an integer of 0, 1 , 2, 3, or 4.

[00308] In some embodiments of the invention, the pyrone analog of Formula II is of Formula V:

Formula V

|00309| wherein X, X,, X₄, R', R,, R₂, W, Y, and Z are as defined for Formula II; and

|00310] R)₂ and R)₃ are independently hydrogen, hydroxyl, carboxaldehyde, amino, C,-Ci₀ alkyl, C₂-C)₀ alkynyl, C₂-C)₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C)-C)₀ aliphatic acyl, C₆-C)₀ aromatic acyl, C₆-Ci₀ aralkyl acyl, C₆-C)₀ alkylaryl acyl, alkoxy, amine, aryl, C₃-C₁₀ heterocyclyl, heteroaryl, C₃-

C₁₀ cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z.

[00311 ) In some embodiments, R)₂ is hydrogen. In some embodiments, Ri₂ is hydroxyl. In some embodiments,

Ri₂ is carboxaldehyde. In some embodiments, R₎₂ is unsubstituted amine. In some embodiments, R,₂ is substituted amine. In some embodiments, R)₂ is unsubstituted C)-Ci₀ alkyl. In some embodiments, R,₂ is substituted C)-C₎₀ alkyl. In some embodiments, R,₂ is unsubstituted C₂-C)₀ alkynyl. In some embodiments, R)₂ is substituted C₂-Ci₀ alkynyl. In some embodiments, R₎₂ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, R)₂ is substituted C₂-Ci₀ alkenyl. 'ⁿ some embodiments, R_n is carboxyl. In some embodiments, R_]2 is unsubstituted carbohydrate. In some embodiments, R,₂ is substituted carbohydrate. In some embodiments, R,₂ is unsubstituted ester. In some embodiments, R₁₂ is substituted ester. In some embodiments, R₎₂ is unsubstituted acyloxy. In some embodiments, R₎₂ is substituted acyloxy. In some embodiments, R|₂ is nitro. In some embodiments, R,₂ is halogen. In some embodiments, R|₂ is unsubstituted Ci-Ci₀ aliphatic acyl. In some embodiments, R₁₂ is substituted C₁-C₁₀ aliphatic acyl. In some embodiments, R₁₂ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₁₂ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, Ri₂ is unsubstituted C₆-Ci₀ aralkyl acyl. In some embodiments, R|₂ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₁₂ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₎₂ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, Ri₂ is unsubstituted alkoxy. In some embodiments, Ri₂ is substituted alkoxy. In some embodiments, R₎₂ is unsubstituted aryl. In some embodiments, R_n is substituted aryl. In some embodiments, R_n is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R,₂ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, Ri₂ is unsubstituted heteroaryl, In some embodiments, R,₂ is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R_[2 is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₎₂ is - OPO₃WY. In some embodiments, R,₂ is -OCH₂PO₄WY. In some embodiments, R,₂ is -OCH₂PO₄Z. In some embodiments, R₁₂ is -OPO₃Z.

|00312] In some embodiments, R₎₃ is hydrogen. In some embodiments, R_i3 is hydroxyl. In some embodiments, Ri₃ is carboxaldehyde. In some embodiments, R_n is unsubstituted amine. In some embodiments, R_n is substituted amine. In some embodiments, R,₃ is unsubstituted Ci-C|_O alkyl. In some embodiments, R_n is substituted Ci-C₁₀ alkyl. In some embodiments, R₁₃ is unsubstituted C₂-C₁₀ alkynyl. In some embodiments, R₁₃ is substituted C₂-Ci₀ alkynyl. In some embodiments, Ri₃ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, Ri₃ is substituted C₂-Ci₀ alkenyl. In some embodiments, R_n is carboxyl. In some embodiments, R_n is unsubstituted carbohydrate. In some embodiments, R_n is substituted carbohydrate. In some embodiments, R₁₃ is unsubstituted ester. In some embodiments, R₁₃ is substituted ester. In some embodiments, R₁₃ is unsubstituted acyloxy. In some embodiments, R₁₃ is substituted acyloxy. In some embodiments, R₁₃ is nitro. In some embodiments, R,₃ is halogen. In some embodiments, Ri₃ is unsubstituted Ci-Ci₀ aliphatic acyl. In some embodiments, Ri₃ is substituted Ci-C]₀ aliphatic acyl. In some embodiments, R_n is unsubstituted C₆-Ci₀ aromatic acyl. In some embodiments, Ri₃ is substituted C₆-Ci₀ aromatic acyl. In some embodiments, R_n is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₁₃ is substituted C₆-C₁₀ aralkyl acyl. In some embodiments, R_n is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R_n is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R_n is unsubstituted alkoxy. In some embodiments, Ri₃ is substituted alkoxy. In some embodiments, R_n is unsubstituted aryl. In some embodiments, R,₃ is substituted aryl. In some embodiments, R₁₃ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R,₃ is substituted C₃-Ci₀ heterocyclyl. In some embodiments, Ri₃ is unsubstituted heteroaryl, In some embodiments, R_n is unsubstituted C₃-Ci₀ cycloalkyl. In some embodiments, R_n is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R₎₃ is - OPO₃WY. In some embodiments, R,₃ is -OCH₂PO₄WY. In some embodiments, R_n is -OCH₂PO₄Z. In some embodiments, R₁₃ is -OPO₃Z.

|00313] In some embodiments of the invention, the pyrone analog of Formula V is of Formula XXIX or Formula XXX:

Formula XXIX Formula XXX

|00314| wherein R₂, R₅, Ris , n, W, Y, and Z are as defined for Formula II and R₎₂ and R₎₃ are as defined for

Formula V; and

[00315| R₁₆ is hydrogen, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z.

(00316] In some embodiments of the invention, the pyrone analog of Formula V is of Formula XXXl:

Formula XXXI

[00317] wherein R₂, Ri₈ , n, W, Y, and Z are as defined for Formula II and Ri₂ and R,₃ are as defined for

Formula V; and

[00318] Ris is hydrogen, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z.

[00319] In some embodiments of the invention, the pyrone analog of Formula II is of Formula VI:

Formula VI

[00320] wherein X, X,, X₃, R', R,, R₂, W, Y, and Z are as defined for Formula II; and [00321] Ri₄ and Ri₅ are independently hydrogen, hydroxyl, carboxaldehyde, amino, C₁-Ci₀ alkyl, C₂-Ci₀ alkynyl, C₂-C₁₀ alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, CpCi₀ aliphatic acyl, C₆-Ci₀ aromatic acyl, C₆-C|_O aralkyl acyl, C₆-Ci₀ alkylaryl acyl, alkoxy, amine, aryl, C₃-C₁₀ heterocyclyl, heteroaryl, C₃- Co cycloalkyl, -OPO₃WY, -OCH₂PO₄WY, -OCH₂PO₄Z or -OPO₃Z. 1003221 In some embodiments, R_M is hydrogen. In some embodiments, R_M is hydroxyl. In some embodiments, R_uis carboxaldehyde. In some embodiments, R₁₄ is unsubstituted amine. In some embodiments, R₁₄ is substituted amine. In some embodiments, R₎₄ is unsubstituted C_rCi_Oalkyl. In some embodiments, R₎₄ is substituted C_rC|_O alkyl. In some embodiments, R₁₄ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, R_H is substituted C₂-C₁₀ alkynyl. In some embodiments, R₎₄ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, Rι₄ is substituted C₂-Ci₀ alkenyl. ^m some embodiments, R|₄ is carboxyl. In some embodiments, R_M is unsubstituted carbohydrate. In some embodiments, R₎₄ is substituted carbohydrate. In some embodiments, Ri₄ is unsubstituted ester. In some embodiments, R|₄ is substituted ester. In some embodiments, R|₄ is unsubstituted acyloxy. In some embodiments, R₁₄ is substituted acyloxy. In some embodiments, R₁₄ is nitro. In some embodiments, R₁₄ is halogen. In some embodiments, R|₄ is unsubstituted C_rC|₀ aliphatic acyl. In some embodiments, R₁₄ is substituted C _rCι₀ aliphatic acyl. In some embodiments, R₁₄ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, R₎₄ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₎₄ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₁₄ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R_]4 is unsubstituted C₆-Ci₀ alky laryl acyl. In some embodiments, R,₄ is substituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₁₄ is unsubstituted alkoxy. In some embodiments, R₁₄ is substituted alkoxy. In some embodiments, R₁₄ is unsubstituted aryl. In some embodiments, R₁₄ is substituted aryl. In some embodiments, R₁₄ is unsubstituted C₃-C)₀ heterocyclyl. In some embodiments, R₁₄ is substituted C₃-C_J0 heterocyclyl. In some embodiments, Ri₄ is unsubstituted heteroaryl, In some embodiments, R,₄ is unsubstituted C₃-C₁₀ cycloalkyl. In some embodiments, R₁₄ is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R|₄ is - OPO₃WY. In some embodiments, R,₄ is -OCH₂PO₄WY. In some embodiments, R,₄ is -OCH₂PO₄Z. In some embodiments, R,₄ is -OPO₃Z.

|00323) In some embodiments, R₁₅ is hydrogen. In some embodiments, R₎₅ is hydroxyl. In some embodiments, Ri₅ is carboxaldehyde. In some embodiments, Ri₅ is unsubstituted amine. In some embodiments, R₁₅ is substituted amine. In some embodiments, R,₅ is unsubstituted C,-C₁₀ alkyl. In some embodiments, R₁₅ is substituted Ci-C_t0 alkyl. 1° some embodiments, R₎₅ is unsubstituted C₂-Ci₀ alkynyl. In some embodiments, Ri₅ is substituted C₂-Ci₀ alkynyl. In some embodiments, Ri₅ is unsubstituted C₂-Ci₀ alkenyl. In some embodiments, Ri₅ is substituted C₂-C ,₀ alkenyl. In some embodiments, Ri₅ is carboxyl. In some embodiments, Ri₅ is unsubstituted carbohydrate. In some embodiments, R|₅ is substituted carbohydrate. In some embodiments, Ri₅ is unsubstituted ester. In some embodiments, R₎₅ is substituted ester. In some embodiments, R₁₅ is unsubstituted acyloxy. In some embodiments, R₁₅ is substituted acyloxy. In some embodiments, R₁₃ is nitro. In some embodiments, R]₃ is halogen. In some embodiments, R₎₃ is unsubstituted Ci-Ci₀ aliphatic acyl. In some embodiments, R₁₅ is substituted C|-C₎₀ aliphatic acyl. In some embodiments, R₁₅ is unsubstituted C₆-C₁₀ aromatic acyl. In some embodiments, Ri₅ is substituted C₆-C₁₀ aromatic acyl. In some embodiments, R₁₅ is unsubstituted C₆-C₁₀ aralkyl acyl. In some embodiments, R₁₅ is substituted C₆-Ci₀ aralkyl acyl. In some embodiments, R₁₅ is unsubstituted C₆-Ci₀ alkylaryl acyl. In some embodiments, R₁₅ is substituted C₆-C₁₀ alkylaryl acyl. In some embodiments, R₎₅ is unsubstituted alkoxy. In some embodiments, R₁₅ is substituted alkoxy. In some embodiments, Ri₅ is unsubstituted aryl. In some embodiments, R₁₅ is substituted aryl. In some embodiments, R|₅ is unsubstituted C₃-Ci₀ heterocyclyl. In some embodiments, R|₅ is substituted C₃-C₁₀ heterocyclyl. Jn some embodiments, Ri₅ is unsubstituted heteroaryl, In some embodiments, R,₅ is unsubstituted C₃-Ci₀ cycloalkyl. 'ⁿ some embodiments, R_!5 is substituted C₃-Ci₀ cycloalkyl. In some embodiments, R_]5 is - OPO₃WY. In some embodiments, R₁₅ is -OCH₂PO₄WY. In some embodiments, R,₅ is -OCH₂PO₄Z. In some embodiments, R,₅ is -OPO₃Z.

(00324) In some embodiments of the invention, the pyrone analog of Formula VI is of Formula XXXII or Formula XXXIII:

Formula XXXH Formula XXXIII

|00325] wherein R₂, R₅, Ris, n,W, Y, and Z are as defined for Formula II and R₁₄ and R₁₅ are as defined for Formula V; and

|00326| Ri₆ is hydrogen, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z. |00327| In some embodiments of the invention, the pyrone analog of Formula VI is of Formula XXXIV:

Formula XXXIV

[00328] wherein R₂, Ri₈, n,W, Y, and Z are as defined for Formula II and R)₄ and R₁₅ are as defined for Formula V; and

R₁₆ is hydrogen, -PO₃WY, -CH₂PO₄WY, -CH₂PO₄Z or -PO₃Z.

B. Polyphenols

|003291 One class of compounds useful in the compositions and methods of the invention is polyphenols. Many polyphenols are modulators of BTB transport proteins; however, any suitable polyphenol that produces a decrease of one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, no matter what the mechanism, may be used in the compositions and methods of the invention.

|00330] A particularly useful class of polyphenols is the flavonoids. Flavonoids, the most abundant polyphenols in the diet, can be classified into subgroups based on differences in their chemical structures. The basic flavonoid structure is shown below (formula XXXV):

Formula XXXV wherein the 2,3 bond may be saturated or unsaturated, and wherein each R can be independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted amine, substituted or unsubstituted thiol, substituted or unsubstituted C₁-Ci₀ alkyl, substituted or unsubstituted C₁-Ci₀ alkynyl, substituted or unsubstituted Ci-C₁₀ alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₅-Ci₀ cycloalkyl, substituted or unsubstituted C₅-Ci₀ heterocycloalkyl, substituted or unsubstituted C)-Ci₀ aliphatic acyl, substituted or unsubstituted C₁-Ci₀ aromatic acyl, trialkyl silyl, substituted or unsubstituted ether, carbohydrate, and substituted carbohydrate; and its pharmaceutically acceptable salts, esters, prodrugs, analogs, isomers, stereoisomers or tautomers thereof. |003311 "Carbohydrate" as used herein, includes, but not limited to, monosaccharides, disaccharides, oligosaccharides, or polysaccharides. Monosaccharide for example includes, but not limited to, allose, altrose, mannose, gulose, Idose, glucose, galactose, talose, and fructose. Disaccharides for example includes, but not limited to, glucorhamnose, trehalose, sucrose, lactose, maltose, galactosucrose, ./V-acetyllactosamine, cellobiose, gentiobiose, isomaltose, melibiose, primeverose, hesperodinose, and rutinose. Oligosaccharides for example includes, but not limited to, raffmose, nystose, panose, cellotriose, maltotriose, maltotetraose, xylobiose, galactotetraose, isopanose, cyclodextrin (α-CD) or cyclomaltohexaose, β-cyclodextrin (β-CD) or cyclomaltoheptaose and γ-cyclodextrin (γ-CD) or cyclomaltooctaose. Polysaccharide for example includes, but not limited to, xylan, mannan, galactan, glucan, arabinan, pustulan, gellan, guaran, xanthan, and hyaluronan. Some examples include, but not limited to, starch, glycogen, cellulose, inulin, chitin, amylose and amylopectin.

1003321 In some embodiments, the invention utilizes a flavonoid where the molecule is planar. In some embodiments, the invention utilizes a flavonoid where the 2-3 bond is unsaturated. In some embodiments, the invention utilizes a flavonoid where the 3-position is hydroxylated. In some embodiments, the invention utilizes a flavonoid where the 2-3 bond is unsaturated and the 3-position is hydroxylated (e.g., flavonols). |00333| In some embodiments, the invention utilizes one or more flavonoids selected from the group consisting of quercetin, isoquercetin, flavone, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin. In some embodiments, the invention utilizes one or more flavonoids selected from the group consisting of quercetin, isoquercetin, apigenin, rhoifolin, galangin, fisetin, morin, rutin, kaempferol, myricetin, naringenin, hesperetin, phloretin, and genistein. Structures of these compounds are well-known in the art. See, e.g., Critchfield et al. (1994) Biochem. Pharmacol 7: 1437-1445. [00334] In some embodiments, the invention utilizes a flavonol. In some embodiments, the flavonol is selected from the group consisting of quercetin, fisetin, morin, rutin, myricetin, galangin, and kaempherol, and combinations thereof. In some embodiments, the flavonol is selected from the group consisting of quercetin, galangin, fisetin and kaempherol, and combinations thereof. In some embodiments, the flavonol is quercetin or a quercetin derivative. In some embodiments, the flavonol is fisetin or a fisetin derivative. In some embodiments, the flavonol is galangin or a galangin derivative. In some embodiments, the flavonol is kaempherol or a kaempherol derivative.

|00335) In some embodiments, the pyrone analog is modified with a phosphate group to increase the solubility of the pyrone analog. The phosphate group can be attached to any suitable part of the pyrone analog. Useful phosphorylated pyrone analogs of the present invention are phosphorylated polyphenols of the structure of formula (XXXVI) or its pharmaceutically or veterinarily acceptable salts, glycosides, esters, or prodrugs:

Formula XXXVI

[00336J wherein Ri, R₂, R₃, R₄, and R₅ are independently selected from the group of hydrogen, -PO₃XY, and - PO₃Z, wherein X and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, wherein Z is a multivalent cation, and wherein at least one of the Ri-R₅ is -PO₃XY, Or -PO₃Z. |00337| In some embodiments of the invention, the phosphorylated pyrone analog can comprise a cyclic phosphate. In some embodiments, the invention is a composition comprising a compound of formula (XXXVII), its pharmaceutically or veterinarily acceptable salts, glycosides, esters, or prodrugs:

Formula XXXVlI

[00338J wherein Rj, R₂, and R₃ are each independently selected from the group of hydrogen, -PO₃XY, and -PO₃Z, wherein X and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, wherein Z is a multivalent cation, and wherein R4 is selected from the group of hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation.

[00339| Accordingly, in some embodiments, the invention utilizes a phosphorylated flavonoid where the molecule is planar. In some embodiments, the invention utilizes a phosphorylated flavonoid where the 2-3 bond is unsaturated. In some embodiments, the invention utilizes a phosphorylated flavonoid where the 3-position is hydroxylated. In some embodiments, the invention utilizes a phosphorylated flavonoid where the 2-3 bond is unsaturated and the 3-position is hydroxylated (e.g., flavonols).

[00340J In some embodiments, the invention utilizes one or more phosphorylated flavonoids selected from the group consisting of phosphorylated quercetin, phosphorylated isoquercetin, phosphorylated flavone, phosphorylated chrysin, phosphorylated apigenin, phosphorylated rhoifolin, phosphorylated diosmin, phosphorylated galangin, phosphorylated fisetin, phosphorylated morin, phosphorylated rutin, phosphorylated kaempferol, phosphorylated myricetin, phosphorylated taxifolin, phosphorylated naringenin, phosphorylated naringin, phosphorylated hesperetin, phosphorylated hesperidin, phosphorylated chalcone, phosphorylated phloretin, phosphorylated phlorizdin, phosphorylated genistein, phosphorylated biochanin A, phosphorylated catechin, and phosphorylated epicatechin. In some embodiments, the invention utilizes one or more phosphorylated flavonoids selected from the group consisting of phosphorylated quercetin, phosphorylated isoquercetin, phosphorylated apigenin, phosphorylated rhoifolin, phosphorylated galangin, phosphorylated fisetin, phosphorylated morin, phosphorylated rutin, phosphorylated kaempferol, phosphorylated myricetin, phosphorylated naringenin, phosphorylated hesperetin, phosphorylated phloretin, and phosphorylated genistein. [00341 ] In some embodiments, the invention utilizes a phosphorylated flavonol. In some embodiments, the phosphorylated flavonol is selected from the group consisting of phosphorylated quercetin, phosphorylated fisetin, phosphorylated morin, phosphorylated rutin, phosphorylated myricetin, phosphorylated galangin, and phosphorylated kaempherol, and combinations thereof. In some embodiments, the phosphorylated flavonol is selected from the group consisting of phosphorylated quercetin, phosphorylated galangin, phosphorylated fisetin and phosphorylated kaempherol, and combinations thereof. In some embodiments, the phosphorylated flavonol is phosphorylated quercetin or a phosphorylated quercetin derivative. In some embodiments, the phosphorylated flavonol is phosphorylated fisetin or a phosphorylated fisetin derivative. In some embodiments, the phosphorylated flavonol is phosphorylated galangin or a phosphorylated galangin derivative. In some embodiments, the phosphorylated flavonol is phosphorylated kaempherol or a phosphorylated kaempherol derivative. Preferably, the flavonol is a phosphorylated quercetin, fisetin or a phosphorylated fisetin. |00342| In some embodiments, the phosphorylated polyphenol comprises a monophosphate, diphosphate, triphosphate, tetraphosphate, or pentaphosphate.

(00343| It will be appreciated that the various forms of phosphorylated polyphenols, including quercetin or fisetin, may have different properties useful in the compositions and methods of the invention, and that the route of administration can determine the choice of forms, or combinations of forms, used in the composition or method. It will also be appreciated that the various forms of quercetin or fisetin, including phosphorylated quercetin or fisetin, vary in the toxicity (or lack thereof) and/or effectiveness in reducing or eliminating hypogonadism or adverse effects of the hypothalamic/pituitary /endocrine axis induced by an anti-hypertensive agent or an opiate . For example, certain forms of quercetin or fisetin, e.g. quercetin phosphate, fisetin or fisetin phosphate, may differ by reducing or eliminating hypogonadism induced by the administration of a therapeutic agent. Preferred embodiments herein include phosphorylated quercetin, fisetin and/or fisetin phosphate based on increased solubility characteristics as well as increased bioavailability.

[00344J An useful flavonol is quercetin or a quercetin derivative. Quercetin may be used to illustrate formulations and methods useful in the invention, however, it is understood that the discussion of quercetin applies equally to other flavonoids, flavonols, and polyphenols useful in the invention, e.g., kaempferol, fisetin and galangin. [00345] The structure of quercetin is shown below (formula XXXVI):

Formula XXXVI wherein each OR is an OH (i.e., 3-OH, 5-OH, 7-OH, 3'-OH, and 4'-OH) and each R is an H. The numbering of the carbons is the same as in Formula XXXV. This form of quercetin is used in some embodiments of the invention. In addition, metabolites of quercetin, e.g., quercetin 3-O-glucouronide, are encompassed by the term "quercetin" as used herein. [00346] In some embodiments, the quercetin is in a carbohydrate-derivatized form, e.g., a quercetin-O- saccharide. Quercetin-O-saccharides useful in the invention include, but are not limited to, quercetin 3-O- glycoside, quercetin 3-O-glucorhamnoside, quercetin 3-O-galactoside, quercetin 3-O-xyloside, and quercetin 3- O-rhamnoside. In some embodiments, the invention utilizes a quercetin 7-O-saccharide. In some embodiments, the phosphorylated quercetin is in a carbohydrate-derivatized form, e.g., a phosphorylated quercetin-O- saccharide. Phosphorylated quercetin-O-saccharides useful in the invention include, but are not limited to, phosphorylated quercetin 3-O-glycoside, phosphorylated quercetin 3-O-glucorhamnoside, phosphorylated quercetin 3-O-galactoside, phosphorylated quercetin 3-O-xyloside, and phosphorylated quercetin 3-O- rhamnoside. In some embodiments, the invention utilizes a phosphorylated quercetin 7-O-saccharide. |00347| In some embodiments, the invention utilizes a quercetin aglycone. In some embodiments, a combination of aglycones and carbohydrate-derivatized quercetins is used. In some embodiments, the invention utilizes a phosphorylated quercetin aglycone. In some embodiments, a combination of aglycones and carbohydrate-derivatized phosphorylated quercetins is used. It will be appreciated that the various forms of quercetin may have different properties useful in the compositions and methods of the invention, and that the route of administration can determine the choice of forms, or combinations of forms, used in the composition or method.

[00348] In some embodiments, the invention utilizes a modified quercetin or quercetin derivative. In some embodiments, the modified quercetin or quercetin derivative is phosphorylated, glycosylated, or acylated. In some embodiments, quercetin may be modified to increase its solubility by derivatizing with at least one phosphate group. The phosphate group can be attached to any suitable part of the quercetin molecule. Examples of quercetin molecules modified by attaching a phosphate group include (Formula XXXVlI and XXXV[II):

and Formula XXXVII Formula XXXVTII

|00349| In some embodiments, the modified quercetin or quercetin derivative is 3'-quercetin phosphate, 4'- quercetin phosphate, 5,7-dideoxyquercetin phosphate, or combinations thereof. In some embodiments, the modified quercetin is 3'-quercetin phosphate. In some embodiments, the modified quercetin is 4'-quercetin phosphate. In some embodiments, the quercetin phosphate composition is a mixture of 3 '-quercetin phosphate and 4'-quercetin phosphate. In some embodiments, the composition comprises at least 5%, 15%. 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 86%, 97%, 98%, 99%, 99.1% or 99.9% 3'-quercetin phosphate. In some embodiments, the composition comprises at least 5%, 15%. 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 86%, 97%, 98%, 99%, 99.1% or 99.9% 4'-quercetin phosphate. [00350| In some embodiments, the phosphorylated quercetin is in a carbohydrate-derivatized form, e.g., a phosphorylated quercetin-O-saccharide. Phosphorylated quercetin-O-saccharides useful in the invention include, but are not limited to, phosphorylated quercetin 3-O-glycoside, phosphorylated quercetin 3-O- glucorhamnoside, phosphorylated quercetin 3-O-galactoside, phosphorylated quercetin 3-O-xyloside, and phosphorylated quercetin 3-O-rhamnoside. In some embodiments, the invention utilizes a phosphorylated quercetin 7-O-saccharide.

|00351] In some embodiments, the invention utilizes a phosphorylated quercetin aglycone. In some embodiments, a combination of aglycones and carbohydrate-derivatized phosphorylated quercetins is used. It will be appreciated that the various forms of phosphorylated quercetin may have different properties useful in the compositions and methods of the invention, and that the route of administration can determine the choice of forms, or combinations of forms, used in the composition or method.

[00352] In some embodiments, quercetin may be modified to increase its solubility by attaching an amino acid such as glycine, alanine, dimethyl glycine, sarcosine, aspartic acid, or arginine. The amino acid can be attached to any suitable part of the quercetin molecule.

[00353] Thus, in some embodiments the invention features a composition or method utilizing quercetin or a quercetin derivative to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, such as an opiate. In some embodiments the invention features a composition or method utilizing phosphorylated quercetin or a phosphorylated quercetin derivative to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, such as an opiate. [00354] In some embodiments, fisetin (5 deoxyquercetin; 5 desoxyquercetin; 3,3',4',7-tetrahydroxyflavone) or a fisetin derivative may be used in the compositions and formulations disclosed herein. The structure of fisetin is shown below (Formula XXXIX):

Formula XXXIX

[00355] In addition, metabolites of fisetin are encompassed by the term "fisetin" as used herein. The term "fisetin" optionally includes glycosides of fisetin, wherein one or more of the Ri-R₅ comprise a carbohydrate. In some embodiments, fisetin may be modified to increase its solubility by derivatizing with at least one phosphate group. The phosphate group can be attached to any suitable part of the fisetin molecule. In some embodiments, fisetin may be modified to increase its solubility by attaching an amino acid such as glycine, alanine, dimethyl glycine, sarcosine, aspartic acid, or arginine. The amino acid can be attached to any suitable part of the fisetin molecule.

[003561 Thus, in some embodiments the invention features a composition or method utilizing fisetin or a fiseetin derivative to reduce or eliminate one or more symptoms of hypergonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, such as an opiate. In some embodiments the invention features a composition or method utilizing phosphorylated fisetin or a phosphorylated fisetin derivative to reduce or eliminate one or more symptoms of hypergonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, such as an opiate. [00357| In some embodiments, a pyrone analog, such as a polyphenol or a polyphenol derivative, is administered with an excipient to increase the solubility of the pyrone analog. In some embodiments, the excipient is an oligosaccharide. In other embodiments, the excipient is a cyclic oligosaccharide, such as cyclodextrin. In some embodiments, the excipient is a sulfo-alkyl ether substituted cyclodextrin, or a sulfobutyl- ether substituted cyclodextrin. In some embodiments, the excipient is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfoburylether- β-cyclodextrin, suIfobutylether-7- β-cyclodextrin, or combinations thereof. In some embodiments, the excipient is Captisol®.

1003581 In some embodiments, quercetin or a quercetin derivative is administered with an excipient to increase the solubility of the quercetin or quercetin derivative. In some embodiments, the excipient is an oligosaccharide. In other embodiments, the excipient is a cyclic oligosaccharide, such as cyclodextrin. In some embodiments, the excipient is a sulfo-alkyl ether substituted cyclodextrin, or a sulfobutyl-ether substituted cyclodextrin. In some embodiments, the excipient is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β- cyclodextrin, sulfobutylether-7- β-cyclodextrin, or combinations thereof. In some embodiments, the excipient is Captisol®

[00359| In some embodiments, fisetin or a fisetin derivative is administered with an excipient to increase the solubility of the fisetin or fisetin derivative. In some embodiments, the excipient is an oligosaccharide. In other embodiments, the excipient is a cyclic oligosaccharide, such as cyclodextrin. In some embodiments, the excipient is a sulfo-alkyl ether substituted cyclodextrin, or a sulfobutyl-ether substituted cyclodextrin. In some embodiments, the excipient is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β- cyclodextrin, sulfobutylether-7- β-cyclodextrin, or combinations thereof. In some embodiments, the excipient is Captisol®

|00360| In some embodiments, the composition comprises quercetin or a quercetin derivative in an amount of from about 0.1 % to about 1% (w/v); a sulfobutylether-7-β-cyclodextrin in an amount of from about 0.1 % to about 5 % (w/v); water; and a pH adjusting agent sufficient to adjust the pH of the formulation to from about 6.5 to about 8. In some embodiments the composition further comprises a co-solvent in an amount of from about 1 % to about 35% (w/v, g/ml). In some embodiments the co-solvent is an alcohol. In some embodiments the composition further comprises an effective amount of an antimicrobial preservative. In some embodiments the composition further comprises an effective amount of an antioxidant.

|003611 In some embodiments, the composition comprises fisetin or a fisetin derivative in an amount of from about 0.1 % to about 1 % (w/v); a sulfobutylether-7-β-cyclodextrin in an amount of from about 0.1 % to about 5 % (w/v); water; and a pH adjusting agent sufficient to adjust the pH of the formulation to from about 6.5 to about 8. In some embodiments the composition further comprises a co-solvent in an amount of from about 1 % to about 35% (w/v). In some embodiments the co-solvent is an alcohol. In some embodiments the composition further comprises an effective amount of an antimicrobial preservative. In some embodiments the composition further comprises an effective amount of an antioxidant. 1003621 One embodiment provides a solid pharmaceutical formulation comprising cyclodextrin and a BTB protein modulator. In some embodiments, cyclodextin is sulfobutylether-7-β-cyclodextrin. In some embodiments the cyclodextrin is Captisol (TM). In some embodiments the flavonoid is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin. In some embodiments the flavonoid is quercetin, galangin, fisetin or kaempferol. In some embodiments the flavonoid is quercetin or a quercetin derivative or fisetin or a fisetin derivative.

1003631 In some embodiments the formulation is suitable for oral administration. In some embodiments water is substantially removed from the composition in order to make the solid formulation. In some embodiments the removal of water is performed by a process comprising freeze-drying or lyophilization.

[00364] In some embodiments the formulation is suitable for intravenous administration. In some embodiments the molar ratio of quercetin to sulfobutylether-7-β-cyclodextrin is between about 1 : 1 to about 1 :5.

[00365| In some embodiments the molar ratio of quercetin to sulfobutyIether-7-β-cyclodextrin is between about

1 :2 to about 1 :4. In some embodiments the weight ratio of quercetin to the sulfobutylether-7-β-cyclodextrin is between about 1 : 10 to about 1 :40. In some embodiments the weight ratio of quercetin to sulfobutylether-7-β- cyclodextrin is between about 1 : 15 to about 1 :20.

[003661 In some embodiments, pharmaceutical compositions comprising a flavonoid, a cyclodextrin, a basic amino acid or a sugar-amine and a pharmaceutically or veterinarily acceptable carrier are provided. In some embodiments the basic amino acid is arginine. In some embodiments the basic amino acid is lysine. In some embodiments the sugar-amine is meglumine.

[00367| In some embodiments the flavonoid is quercetin, galangin, fisetin or kaempferol. In some embodiments the flavonoid is quercetin or fisetin.

[00368| In some embodiments the cyclodextrin is sulfobutylether-7-β-cyclodextrin.

|00369| In some embodiments, the cyclodextrin is Captisol®

|00370) In some embodiments the flavonoid is quercetin or fisetin, and the cyclodextrin is sulfobutylether-7-β- cyclodextrin.

J00371 ) In some embodiments the carrier comprises water. In some embodiments the sulfobutylether-7-β- cyclodextrin is present at a concentration of about 20% w/v or greater. In some embodiments the sulfobutylether-7-β-cyclodextrin is present at a concentration in a range of about 20% w/v to about 30% w/v. In some embodiments the quercetin is present in a range between about 1 mM to about 50 mM In some embodiments the quercetin is present in a range between about 2 mM to about 40 mM. In some embodiments the amino acid is arginine. In some embodiments the amino acid is lysine. In some embodiments the pH is greater than about 8.5.

|003721 In some embodiments the composition is a dry powder formulation. In some embodiments the molar ratio of the quercetin to the sulfobutylether-7-β-cyclodextrin is between about 1 :3 and 1 : 12.

[00373[ In some embodiments, methods of preparing a solution of a flavonoid comprising mixing a cyclodextrin, a flavonoid, and a basic amino acid or a sugar-amine with water at a pH greater than 8.5 is provided. In some embodiments the method comprises dissolving the cyclodextrin in water to produce a cyclodextrin solution, then mixing the flavonoid and the basic amino acid or sugar-amine with the cyclodextrin solution. In some embodiments the basic amino acid is arginine. In some embodiments the basic amino acid is lysine. In some embodiments the sugar-amine is meglumine. In some embodiments the flavonoid is quercetin, galangin, fisetin or kaempferol. In some embodiments the flavonoid is quercetin or fisetin. In some embodiments the cyclodextrin is sulfobutylether-7-β-cyclodextrin. In some embodiments the flavonoid is quercetin or fisetin, and the cyclodextrin is sulfobutylether-7-β-cyclodextrin.

|00374| In some embodiments of the method the suIfobutylether-7-β-cyclodextrin is present at a concentration of about 20% w/v or greater. In some embodiments the sulfobutylether-7-β-cyclodextrin is present at a concentration in a range of about 20% w/v to about 30% w/v. In some embodiments the quercetin is present in a range between about 1 mM to about 50 mM. In some embodiments the quercetin is present in a range between about 2 mM to about 40 mM. In some embodiments the amino acid is arginine. In some embodiments the amino acid is lysine.

|00375| In some embodiments, the polyphenol is provided in a form for oral consumption. In some embodiments the polyphenol is quercetin or a quercetin derivative, or fisetin or a fisetin derivative, and is provided in a form for oral consumption. Oral bioavailability of quercetin O-saccharides or fisetin-O- saccharides is generally superior to that, respectively, of quercetin aglycones or fisetin aglycones. The bioavailability of the various components is dependent on 1) the site of carbohydrate moiety or moieties and ii) the pendant sugar unit. In addition it is believed that specific carriers are responsible for the absorption of various quercetin glycosides and fisetin glycosides, as well as specific intestinal betaglucosidases. After distribution in the body, the major metabolite, quercetin glucuronide (e.g., quercetin 3-O-glucouronid), is found. Oral bioavailability is sensitive to the presence of food factors.

[00376| In compositions for oral delivery of polyphenols, for example, quercetin or fisetin, carbohydrate- derivatized forms (also referred to herein as "quercetin saccharides" or "fisetin saccharides") are used in some embodiments. In some embodiments, quercetin-3-O-glycoside or fisetin-3-O-glycoside is used in an oral preparation of quercetin or fisetin, respectively; in some embodiments, a pharmaceutically acceptable excipient is included in the composition. In some embodiments, quercetin 3-O-glucorhamnoside or fisetin-3-O- glycorhamnoside is used in an oral preparation of quercetin or fisetin, respectively; in some embodiments, a pharmaceutically acceptable excipient is included in the composition. In some embodiments, a combination of quercetin-3-O-glycoside or fisetin-3-O-glycoside and quercetin 3-O-glucorhamnoside or fisetin -3-O- glycorhamnoside is used in an oral preparation of quercetin or fisetin, respectively; in some embodiments, a pharmaceutically acceptable excipient is included in the composition. Other carbohydrate-derivatized forms of quercetin or fisetin, or other forms of quercetin or fisetin which are derivatives as described above, can also be used, based on their oral bioavailability, their metabolism, their incidence of gastrointestinal or other side effects, and other factors known in the art. See, e.g., Graefe et al. , J. Clin. Pharmacol. (2001) 451 :492-499; Arts et al.(2004) Brit. J. Nutr. 91 :841-847; Moon et al. (2001) Free Rad. Biol. Med. 30: 1274-1285; Hollman et al. (1995) Am. J. Clin. Nutr. 62: 1276-1282; Jenaelle et al. (2005) Nutr. J. 4: 1, and Cermak et al. (2003) J. Nutr. 133: 2802-2807, all of which are incorporated by reference herein in their entirety. (003771 In compositions for oral delivery of phosphorylated polyphenols, for example, phosphorylated quercetin or phosphorylated fisetin, carbohydrate-derivatized forms (also referred to herein as "phosphorylated quercetin saccharides" or "phosphorylated fisetin saccharides") are used in some embodiments. In some embodiments, for example, phosphorylated quercetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside is used in an oral preparation of phosphorylated quercetin or phosphorylated fisetin, respectively; in some embodiments, a pharmaceutically acceptable excipient is included in the composition. In some embodiments, phosphorylated quercetin 3-O-glucorhamnoside or phosphorylated fisetin 3-O-glucorhamnoside is used in an oral preparation of phosphorylated quercetin or phosphorylated fisetin, respectively; in some embodiments, a pharmaceutically acceptable excipient is included in the composition. In some embodiments, a combination of phosphorylated quercetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside and phosphorylated quercetin 3-O-glucorhamnoside or phosphorylated fisetin 3-O-glucorhamnoside is used in an oral preparation of phosphorylated quercetin or phosphorylated fisetin, respectively; in some embodiments, a pharmaceutically acceptable excipient is included in the composition. Other carbohydrate-derivatized forms of phosphorylated quercetin or phosphorylated fisetin, or other forms of phosphorylated quercetin or phosphorylated fisetin which are derivatives as described above, can also be used, based on their oral bioavailability, their metabolism, their incidence of gastrointestinal or other side effects, and other factors known in the art.

|00378) In some embodiments, modified forms of polyphenols, for example, modified quercetin or modified fisetin, are derivatized with carbohydrate moieties. In some embodiments, for example, phosphorylated quercetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside is used in an oral preparation of quercetin or fisetin; in some embodiments, a pharmaceutically acceptable excipient is included in the composition. In some embodiments, phosphorylated quercetin 3-O-glucorhamnoside or phosphorylated fisetin 3-O-glucorhamnoside is used in an oral preparation of quercetin or fisetin; in some embodiments, a pharmaceutically acceptable excipient is included in the composition. In some embodiments, a combination of phosphorylated fisetin-3-O- glycoside and phosphorylated quercetin 3-O-glucorhamnoside or phosphorylated fisetin 3-O-glucorhamnoside is used in an oral preparation of quercetin or fisetin; in some embodiments, a pharmaceutically acceptable excipient is included in the composition.

[00379] In some embodiments, also provided are compositions for administration of quercetin or quercetin phosphate, or fisetin or fisetin phosphate, to an animal to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin or fisetin, that contain at least about 1 , 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, or 99.99% quercetin-O-saccharide or phosphorylated quercetin-O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition for the oral delivery of quercetin or fisetin that contains no more than about 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9,99.99, or 100% quercetin-O-saccharide or phosphorylated quercetin-O- saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition that contains about 1-100%, or about 10-100%, or about 20-100%, or about 50-100%, or about 80-100%, or about 90-100%, or about 95-100%, or about 99- 100% quercetin-O-saccharide or phosphorylated quercetin-O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition that contains about 1-90%, or about 10-90%, or about 20- 90%, or about 50-90%, or about 80-90% quercetin-O-saccharide or phosphorylated quercetin-O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition that contains about 1-75%, or about 10-75%, or about 20-75%, or about 50-75% quercetin-O- saccharide or phosphorylated quercetin-O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O- saccharide. In some embodiments, the invention provides a composition that contains about 1-50%, or about 10- 50%, or about 20-50%, or about 30-50%, or about 40-50 % quercetin-O-saccharide or phosphorylated quercetin- O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition that contains about 1-40%, or about 10-40%, or about 20-40%, or about 30- 40% quercetin-O-saccharide or phosphorylated quercetin-O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition that contains about 1-30%, or about 10-30%, or about 20-30% quercetin-O-saccharide or phosphorylated quercetin-O- saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition that contains about 1-20%, or about 10-20% quercetin-O-saccharide or phosphorylated quercetin-O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition that contains about 1-10% quercetin-O-saccharide or phosphorylated quercetin-O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide. In some embodiments, the invention provides a composition that contains about 1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99% quercetin-O-saccharide or phosphorylated quercetin-O-saccharide, or fisetin-O-saccharide or phosphorylated fisetin-O-saccharide.

[00380] In some embodiments, the invention provides a composition for administration of quercetin or phosphorylated quercetin, or fisetin or phosphorylated fisetin, to an animal to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin or fisetin, that contain at least about 1 , 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, or 99.99% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition for the oral delivery of quercetin that contains no more than about 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9,99.99, or 100% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition that contains about 1-100%, or about 10-100%, or about 20-100%, or about 50-100%, or about 80-100%, or about 90-100%, or about 95-100%, or about 99-100% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition that contains about 1-90%, or about 10-90%, or about 20-90%, or about 50-90%or about 80-90% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition that contains about 1-75%, or about 10-75%, or about 20-75%, or about 50-75% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O- glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition that contains about 1-50%, or about 10-50%, or about 20-50%, or about 30-50%, or about 40-50 % quercetin-3- O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O- glycoside. In some embodiments, the invention provides a composition that contains about 1-40%, or about 10- 40%, or about 20-40%, or about 30-40% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition that contains about 1-30%, or about 10-30%, or about 20-30% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition that contains about 1-20%, or about 10-20% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition that contains about 1-10% quercetin-3-O-glycoside or phosphorylated quercetin-3-O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside. In some embodiments, the invention provides a composition that contains about 1 , 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99% quercetin-3-O-glycoside or phosphorylated quercetin-3- O-glycoside, or fisetin-3-O-glycoside or phosphorylated fisetin-3-O-glycoside.

[003811 In some embodiments, the invention provides a composition for administration of quercetin or quercetin phosphate, or fisetin or fisetin phosphate, to an animal to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin or fisetin, that contain at least about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, or 99.99% quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O- glucorhamnoside, or fϊsetin-3-O-glucorhamnoside or phosphorylated fisetin-3-O-glucorhamnoside. In some embodiments, the invention provides a composition for the oral delivery of quercetin that contains no more than about 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9,99.99, or 100% quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3-O-glucorhamnoside or phosphorylated fϊsetin-3- O-glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1-100%, or about 10-100%, or about 20-100%, or about 50-100%, or about 80-100%, or about 90-100%, or about 95- 100%, or about 99-100% quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3-O-glucorhamnoside or phosphorylated fisetin-3-O-glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1-90%, or about 10-90%, or about 20-90%, or about 50- 90%, or about 80-90% quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3-O-glucorhamnoside or phosphorylated fisetin-3-O-glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1-75%, or about 10-75%, or about 20-75%, or about 50- 75% quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3-O- glucorhamnoside or phosphorylated fisetin-3-O-glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1-50%, or about 10-50%, or about 20-50%, or about 30-50%, or about 40-50 % quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3-O- glucorhamnoside or phosphorylated fisetin-3-O-glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1-40%, or about 10-40%, or about 20-40%, or about 30-40% quercetin-3-O- glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3-O-glucorhamnoside or phosphorylated fisetin-3-O-glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1-30%, or about 10-30%, or about 20-30% quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3-O-glucorhamnoside or phosphorylated fisetin-3-O- glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1 -20%, or about 10-20% quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3- O-glucorhamnoside or phosphorylated fisetin-3-O-glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1-10% quercetin-3-O-glucorhamnoside or phosphorylated quercetin- 3-O-glucorhamnoside, or fisetin-3-O-glucorhamnoside or phosphorylated fisetin-3-O-glucorhamnoside. In some embodiments, the invention provides a composition that contains about 1 , 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99% quercetin-3-O-glucorhamnoside or phosphorylated quercetin-3-O-glucorhamnoside, or fisetin-3-O-glucorhamnoside or phosphorylated fϊsetin-3-O-glucorhamnoside.

[00382| [n some embodiments, the invention provides a composition for administration of quercetin or quercetin phosphate, or fisetin or fisetin phosphate, to an animal to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary /endocrine function induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin or quercetin phosphate, that contain at least about 1 , 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, or 99.99% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition for the oral delivery of quercetin or quercetin phosphate, or fisetin or fisetin phosphate, that contains no more than about 2, 5, 10, 20, 30, 40, 50, 60, 10, 80, 90, 95, 99, 99.5, 99.9, 99.99, or 100% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1-100%, or about 10-100%, or about 20- 100%, or about 50-100%, or about 80-100%, or about 90-100%, or about 95-100%, or about 99-100% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1-90%, or about 10-90%, or about 20- 90%, or about 50-90%, or about 80-90% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1-75%, or about 10-75%, or about 20-75%, or about 50-75% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1-50%, or about 10-50%, or about 20- 50%, or about 30-50%, or about 40-50 % quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1-40%, or about 10-40%, or about 20-40%, or about 30-40% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1-30%, or about 10-30%, or about 20- 30% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1 -20%, or about 10- 20% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1-10% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone. In some embodiments, the invention provides a composition that contains about 1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99% quercetin aglycone or phosphorylated quercetin aglycone, or fisetin aglycone or phosphorylated fisetin aglycone.

|00383| In some embodiments, the invention provides a composition for administration of quercetin or a quercetin derivative, or fisetin or a fisetin derivative, to an animal to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin that contains a combination of quercetin-O-saccharides. In some embodiments, the invention provides a composition for administration of quercetin or a quercetin derivative, or fisetin or a fisetin derivative, to an animal to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin, that contain a combination of quercetin-3-O-glycoside and quercetin-3-O- glucorhamnoside, or fisetin-3-O-glycoside and fϊsetin-3-O-glucorhamnoside. In these compositions, the ranges or amounts of the quercetin-O-saccharides or fisetin-O-saccharides, e.g., quercetin-3-O-glycoside and quercetin- 3-O-glucorhamnoside, or fisetin-3-O-glycoside and fisetin-3-O-glucorhamnoside, may be any suitable combination of the ranges or amounts, as described above. In some embodiments, the quercetin derivative is phosphorylated.In some embodiments, the fisetin derivative is phosphorylated.

1003841 In some embodiments, the invention provides a composition for administration of quercetin or a quercetin derivative, or fisetin or a fisetin derivative, to an animal to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin or a quercetin derivative, or fisetin or a fisetin derivative, that contains a combination of, for example, one or more quercetin-O-saccharides and quercetin aglycone, or fisetin- O-saccharides and fisetin aglycone. In some embodiments, the invention provides a composition for administration of quercetin or a quercetin derivative, or fisetin or a fisetin derivative, to an animal to reduce or eliminate one or more symptoms of hypogonadism induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin or fisetin, that contain a combination of quercetin-O-saccharides and quercetin aglycone, or fisetin-O-saccharides and fisetin aglycone. In these compositions, the ranges or amounts of the carbohydrate- derivatized polyphenols, may be any suitable combination of the ranges or amounts, above. In some embodiments, the invention provides a composition for administration of quercetin or fisetin to an animal to reduce or eliminate one or more symptoms of hypogonadism induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin or fisetin, that contain a combination of quercetin-3-O- glucorhamnoside and quercetin aglycone, or fisetin-3-O- glucorhamnoside and fisetin aglycone. In these compositions, the ranges or amounts of, for example, quercetin-3-O- glucorhamnoside and quercetin aglycone, or fisetin-3-O- glucorhamnoside and fisetin aglycone, may be any suitable combination of the ranges or amounts, above. In some embodiments, the invention provides a composition for administration of quercetin to an animal to reduce or eliminate one or more symptoms of hypogonadism induced by a therapeutic agent, e.g. an opiate, for the oral delivery of quercetin or fisetin, that contain a combination of quercetin-3-O-glycoside, quercetin-3-O- glucorhamnoside and quercetin aglycone, or fisetin-3-O-glycoside, fisetin-3-O- glucorhamnoside and fisetin aglycone. In these compositions, the ranges or amounts of quercetin-3-O-glycoside, quercetin-3-O- glucorhamnoside and quercetin aglycone, or fisetin-3-O-glycoside, fisetin-3-O- glucorhamnoside and fisetin aglycone, for example, may be any suitable combination of the ranges or amounts, above. Other quercetin saccharides or fisetin saccharides, as described herein and as known in the art or developed, may be used as well. In some embodiments, the quercetin derivative is phosphorylated.In some embodiments, the fisetin derivative is phosphorylated.

|00385| Examples of quercetin derivatives and fisetin derivatives are described in US Appn. No. 60/953,187, entitled: Polyhydroxylated Aromatic Compositions and Methods; US Appn. No. 61/076,584 and 12/182,323, entitled: Pyrone Analog Compositions and Methods; US Appn. No. 60/953, 188, entitled: Flavonoid Phosphate Compositions and Methods; US application No. 61/076,608 and 12/182,992 entitled: Phosphorylated Pyrone Analogs and Methods; US Appn No. 60/953, 186, 61/067,612 and 12/182,979, entitled: Soluble Pyrone Analogs Methods and Compositions; all of which are incorporated by reference herein in their entirety. 1003861 In some embodiments the administration is rectal, buccal, intranasal, transdermal, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, orally, topical, as an inhalant, or via an impregnated or coated device such as a stent. In some embodiments the administration is intravenous. In some embodiments administration is transdermal. In some embodiments the administration is oral. [00387| In some of these embodiments, a pharmaceutically acceptable excipient is also included.

Hypogonadism

1003881 Hypogonadism is a medical term for a defect of the reproductive system that results in lack of function of the gonads (ovaries or testes). The gonads have two functions: to produce hormones (testosterone, estradiol, antimullerian hormone, progesterone, inhibin B), and to produce gametes (eggs or sperm). Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., premature menopause) in adults. Defective egg or sperm development results in infertility. [00389| There are many possible types of hypogonadism and several ways to categorize them. Hypogonadism can be categorized as congenital or acquired. An example of congenital hypogonadism (present at birth) is Turner syndrome. An example of acquired hypogonadism (develops in childhood or adult life) is castration. Hypogonadism can also be categorized by hormones or fertility. Hypogonadism can involve just hormone production or just fertility, but most commonly involves both. Examples of hypogonadism that affect hormone production more than fertility are hypopituitarism and Kallmann syndrome; in both cases, fertility is reduced until hormones are replaced but can be achieved solely with hormone replacement. Examples of hypogonadism that affect fertility more than hormone production are Klinefelter syndrome and Kartagener syndrome. Furthermore, hypogonadism can be categorized by the affected system. Hypogonadism is also categorized by endocrinologists by the level of the reproductive system that is defective. Hypogonadism resulting from defects of the gonads is traditionally referred to as primary hypogonadism. Some causes of primary hypogonadism include surgery, radiation, genetic and developmental disorders, liver and kidney disease, infection and certain autoimmune disorders. The most common genetic disorders that cause primary hypogonadism are Turner syndrome (in women) and Klinefelter syndrome (in men). Hypogonadism resulting from hypothalamic or pituitary defects are termed secondary hypogonadism or central hypogonadism (referring to the central nervous system). Some causes of central hypogonadism include tumors, surgery, radiation, infections, trauma, bleeding, genetic problems, nutritional deficiencies, iron excess (hemochromatosis). A genetic cause of central hypogonadism that also produces an inability to smell is Kallmann syndrome (males). The most common tumors affecting the pituitary area are craniopharyngioma (in children) and prolactinoma (in adults). Examples of Pituitary defects include hypopituitarism. An example of a hypogonadism resulting from hormone response is androgen insensitivity |00390| syndrome.

A. Substance-Induced Hypogonadism

|003911 The invention provides compositions and methods utilizing an agent that reduces or eliminates one or more symptoms of hypogonadism induced by one or more substances. In some embodiments, the invention provides compositions and methods utilizing a combination of a therapeutic agent and an agent that reduces or eliminates one or more symptoms of hypogonadism induced by one or more substances. [00392J It is known that some therapeutic agents depresses levels of circulating testosterone and produces secondary changes associated with hypogonadism. For instance, opioids have negative effects on the endocrine system. These effects include decreased testosterone, with loss of libido and other expected effects, in men, and menstrual irregularities and infertility in women. Chronic morphine exposure depresses levels of circulating testosterone in males and produces secondary changes associated with hypogonadism. Figure 4 shows the incidence of hypogonadism in healthy males and males under chronic morphine treatment. Figure 4 shows that in healthy males the incidence of hypogonadism increase with age. However, a profound hypogonadism is observed in patients receiving opioids. Figure 4 shows that 68 to 90 percent of patients receiving opioids suffer from hypogonadism.

|00393] In addition, Figure 1 1 - 12 show a decrease in circulating total and free testosterone, respectively, in human males after treatment with morphine (solid and dotted gray lines). Figure 13 shows a decrease in free androgen index in human males after treatment with morphine (solid and dotted gray lines). |00394] Opioids have been used for medicinal and analgesic purposes for millennia and today remain a critical part of the medical armamentarium against pain, diarrhea, cough, and other symptoms. Without being limited to any theory, opioids may impair secretion of primary sex hormones thus decreasing testosterone and other androgen production. The hypothalamic-pituitary-gonadal process of controlling the secretion of gonadal hormones, testosterone, and estrogen, begins with secretion by the hypothalamus of gonadotropin-releasing hormone (GNRH). GNRH stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). These two hormones are released into the systemic circulation and interact with the gonads, the testes and ovaries, to secrete testosterone or estrogen, respectively. These sex hormones then feed back to the hypothalamus and pituitary to form a complete feedback loop. Testosterone and estrogen support normal sexual and reproductive growth and behavior. This system is modulated by a complex series of outside influences as well. Opioids can be one of a number of such influences and evidence suggests that opioids — both endogenous and exogenous - can bind to opioid receptors primarily in the hypothalamus, but potentially also in the pituitary and the testes, to modulate gonadal function. Decreased release, or interference with the normal pulsatility of release of GNRH at the level of the hypothalamus, has been documented, with consequent decreased release of LH and FSH from the pituitary. Direct effects of opioids on the testes, including decreased secretion of testosterone and testicular interstitial fluid, have been documented. In addition, opioids have been shown to increase pituitary release of prolactin in preclinical studies, with secondary effects of decreasing testosterone secretion

|00395] Studies performed in animals have demonstrated the acute and chronic effects of opioids on the endocrine system, including decreasing testosterone levels by central reductions of LH release (decreased hypothalamic release of luteinizing-hormone releasing hormone (LHRH), leading to reduced pituitary release of LH), and peripheral effects on the testicle as well. In addition, it has been demonstrated in studies in heroin addicts, compared to healthy controls, decreased testosterone levels in males, with an associated decrease in LH and/or FSH consistent with central hypogonadism. In one study measuring hormonal status one month after cessation of heroin use, testosterone levels returned to normal. In methadone-maintained male patients, several studies have demonstrated decreased testosterone levels consistent with central hypogonadism. One of these studies demonstrated a dose-response effect, in that patients on "low dose" methadone (10-60 mg/day) had no evidence of suppression compared with those on "high dose" (80-150 mg/day). Other studies demonstrated a peripheral effect on the testicle, with decreased secretion of testosterone and testicular interstitial fluid, and decreased spermmotility. One case series described amenorrhea and galactorrhea in female heroin addicts. (00396| Several studies have compared patients undergoing intrathecal opioid treatment for nonmalignant pain with patients with a comparable pain syndrome, but not on opioid therapy. These studies have documented hypogonadism associated with low LH values and normal or low FSH levels in both males and females. When compared to the chronic pain control group, these laboratory findings were associated with decreased libido or impotence in males and irregular or absent menses in females. Symptoms were reported to have improved in most patients with hormone supplementation. None of these studies reported elevation of prolactin levels, suggesting that prolactin is not significantly related to the mechanism by which opioids produce hypogonadism. (00397) Several studies have been published on the effects of long-term oral opioid therapy in males with chronic pain. In one of these studies, endocrine function was measured in patients on sustained-release opioids and compared to healthy controls. Hormone levels were much lower in opioid users than in control subjects in a dose-related pattern (POOOl for all comparisons) and total testosterone levels were subnormal in 74% of the opioid group, with an apparent dose-response effect. Eighty-seven percent (39 of 45) of the opioid-ingesting men who reported normal erectile function before opioid use, reported severe erectile dysfunction or diminished libido after beginning opioid therapy.

|00398| Another study was a case series in cancer survivors with chronic pain taking opioids that had abnormally low testosterone levels. This was confirmed with a follow-up case-control study comparing cancer survivors on opioids to matched controls. Among the opioid group, 18/20 (90%) exhibited hypogonadism, compared to 8/20 controls (40%) (median testosterone levels were statistically significantly lower in the opioid group). LH, but not FSH levels, were statistically significantly lower in the cases. Importantly, clinically significant consequences of these laboratory abnormalities were also demonstrated. Sexual desire (measured by the Sexual Desire Inventory); anxiety and depression (measured by the Hospital Anxiety and Depression Scale); and overall quality of life (measured by the Functional Assessment of Chronic Illness Therapy with general and fatigue subscales [FACT-G/FACIT-F]) were all significantly lower in the opioid group than in the controls. |00399] Antihypertensive also have been shown to depress levels of circulating sex hormones. (00400) The invention provides compositions and methods utilizing an agent that reduces or eliminates one or more symptoms of hypogonadism induced by treatment with a therapeutic agent. In some embodiments, the invention provides compositions and methods utilizing a combination of a therapeutic agent and an agent that reduces or eliminates one or more symptoms of hypogonadism induced by treatment with the therapeutic agent. Typically, the symptom-decreasing agent is a modulator of a blood tissue barrier (BTB). (00401 | The methods and compositions are useful in the treatment of an animal in need of treatment, where it is desired that one or more symptoms of hypogonadism induced by the therapeutic agent be reduced or eliminated. In some embodiments further utilizing a therapeutic agent, the methods and compositions are useful in the treatment of an animal in need of treatment, where it is desired that one or more symptoms of hypogonadism induced by a therapeutic agent be reduced or eliminated while one or more of the therapeutic effects (e.g., peripheral effects) of the therapeutic agent are retained or enhanced.

1004021 In some embodiments of the invention, the therapeutic agent is an agent capable of inducing one or more symptoms of hypogonadism. In some embodiments of the invention, the therapeutic agent is an analgesic agent, such as an opiate. In some embodiments, the therapeutic agent is an opiate. Examples of opiates include, but are not limited to, codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu-enkephalin, met- enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the therapeutic agent is morphine. In some embodiments the therapeutic agent is sufentanyl. In some embodiments, the therapeutic agent is alfentanyl. In some embodiments, the therapeutic agent is remifentanyl. |00403| In some embodiments of the invention, the therapeutic agent is a non-analgesic agent. In some embodiments, the agent is an anti hypertensive agent. Examples of anti hypertensive agents include, but are not limited to, diuretics, adrenergic receptor antagonists, adrenergic receptor agonist, calcium channel blockers, ace inhibitors, angiotensin ii receptor antagonists, aldosterone antagonists, vasodilators, centrally acting adrenergic drugs. Example of antihypertensive agents include, but are not limited to, loop diuretics: bumetanide, ethacrynic acid, furosemide, torsemide; thiazide diuretics: chlortalidone, epitizide, hydrochlorothiazide and chlorothiazide, bendroflumethiazide; thiazide-like diuretics: indapamide, chlorthalidone, metolazone; potassium-sparing diuretics: amiloride, triamterene, spironolactone, beta blockers: atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol; alpha blockers: doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline; mixed alpha + beta blockers: bucindolol, carvedilol, labetalol, alpha-2 agonists: clonidine, methyldopa, dihydropyridines: amlodipine, felodipine, isradipine, lercanidipine, nifedipine(Adalat®), nimodipine, nitrendipine; non-dihydropyridines: diltiazem, verapamil, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandopril, benzapril, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, eplerenone, spironolactone, sodium nitroprusside, clonidine, guanabenz, methyldopa, moxonidine, and guanethidine, reserpine.

1004041 In some embodiments, one or more symptoms of hypogonadism induced by the therapeutic agent are substantially eliminated. Example of symptoms of hypogonadism include, but are not limited to, premature menopause, decrease of energy, fatigue, muscle mass decline, increase visceral fat, decreased positive mood factors and an increased negative mood factors, anxiety, depression, decrease in fertility, decrease in libido and sexual function, impotence, amenorrhea, irregular menses, galactorrhea, increased risk for osteoporosis, increased pain sensitization, hematological abnormalities, decrease in cognitive skills, sleep disturbances, vasomotor instability, increase CAD risk, changes in secondary sex characteristic and decrease in circulating sex hormones.

|00405| In some embodiments, the symptom of hypogonadism is a decrease in circulating sex hormones. Examples of sex hormones include, but are not limited to, androgen, estrogen, and progestagen. In some embodiments, the symptom of hypogonadism is one or more of decrease in the levels of circulating testosterone, decrease in circulating androstenedione levels, decrease in circulating dihydrotestosterone levels, decrease in circulating dehydroepiandrosterone levels, or decrease in circulating anabolic steroids levels. In some embodiments, the symptom of hypogonadism is a decrease in the levels of circulating testosterone. Circulating testosterone may be free, bound, or total testosterone. Other hormones whose circulating levels may decrease in the presence of hypogonadism include LH, FSH, and/or prolactin. Thus, decreased circulating levels of these hormones, alone or in addtion to sex hormones, may be considered a symptom of hypogonadism. [00406| The agent causing a decrease in one or more symptoms of hypogonadism induced by the therapeutic agent, e.g. morphine, a modulator of a BTB transport protein may be an activator or an inhibitor of the protein. The modulatory effect may be dose-dependent, e.g., some modulators act as activators in one dosage range and inhibitors in another. In some embodiments, a modulator of a BTB transport protein is used in a dosage wherein it acts primarily as an activator.

|00407| The use of the BTB transport protein modulator, e.g., activator, may result in a decrease in one or more symptoms of hypogonadism induced by the therapeutic agent. The therapeutic effect(s) of the therapeutic agent may be decreased, remain the same, or increase; however, in preferred embodiments, if the therapeutic effect is decreased, it is not decreased to the same degree as the symptom of hypogonadism. It will be appreciated that a given therapeutic agent may have more than one therapeutic effect and or one or more symptoms of hypogonadism, and it is possible that the therapeutic ratio (in this case, the ratio of change in desired effect to change in undesired effect) may vary depending on which effect is measured. However, at least one therapeutic effect of the therapeutic agent is decreased to a lesser degree than at least one symptom of hypogonadism induced by the therapeutic agent.

[00408] In addition, in some embodiments, one or more therapeutic effects of the therapeutic agent are enhanced by use in combination with a BTB transport protein modulator, while one or more symptoms of hypogonadism induced by the therapeutic agent are reduced or substantially eliminated. [00409| Without being bound by theory, and as an example only of a possible mechanism, it is thought that the methods and compositions of the invention operate by reducing or eliminating the concentration of the therapeutic agent from the CNS (e.g., brain) while retaining or even increasing the effective concentration of the therapeutic agent in the periphery. Therapeutic agents act at least in part by peripheral mechanisms and may thus retain some or all of their activity, or even display enhanced therapeutic activity, while at the same time CNS effects are reduced or eliminated. However, it is recognized that the mechanism of action of a particular BTB transport protein modulator in decreasing one or more symptoms as described herein may be different, or in addition to, modulation of a BTB transport protein, and that an agent that has BTB transport protein- modulating activity may nonetheless act by a different mechanism than BTB transport protein modulation. It is also possible for an agent to modulate more than one BTB transport protein, and the overall effect will depend on the summation of all mechanisms by which an agent works.

[00410| It will be appreciated that the therapeutic effect and/or symptoms of hypogonadism of a therapeutic agent may be mediated in part or in whole by one or more metabolites of the therapeutic agent, and that a BTB transport protein modulator that reduces or eliminates one or more symptoms of hypogonadism induced by the therapeutic agent and/or of one or more active metabolites of the therapeutic agent, while retaining or enhancing a peripheral concentration of the therapeutic agent and/or one or more metabolites producing a therapeutic effect, is also encompassed by the methods and compositions of the invention. In addition, a BTB transport modulator itself may be metabolized to metabolites that have differing activities in the modulation of one or more BTB transport proteins, and these metabolites are also encompassed by the compositions and methods of the invention.

[004111 Hence, in some embodiments the invention provides compositions that include a therapeutic agent and a blood-tissue barrier (BTB) transport protein modulator, where the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the BTB protein modulator is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by the therapeutic agent when compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal. The decrease in the symptom of hypogonadism can be measurable. The BTB transport protein modulator is a BTB transport protein activator in some embodiments. In some embodiments the BTB transport protein modulator is a modulator of ATP binding cassette (ABC) transport proteins. In some embodiments the BTB transport protein modulator is a modulator of P-glycoprotein (P-gP).

[00412| In some embodiments, compositions of the invention include one or more therapeutic agent as well as one or more than one BTB transport protein modulators. One or more of the therapeutic agents may have one or more symptoms of hypogonadism which are desired to be decreased.

[00413] It will be appreciated that when a BTB transport protein that is the target of the BTB transport modulator is present on the cells where the therapeutic agent is exerting its therapeutic effect, the dosage of the BTB transport modulator may be adjusted such that one or more symptoms of hypogonadism of the therapeutic agent are reduced without a substantial reduction of the therapeutic effect in the target cells. In some embodiments, it is desirable to inhibit a BTB transport protein present in the cells where the therapeutic agent is exerting its therapeutic effect while activating the same or another BTB transport protein at other site(s) such that the symptom of hypogonadism induced by the therapeutic agent are reduced. Therefore, the dosage of the BTB transport modulator may be adjusted such that a BTB transport protein that is the target of the BTB transport modulator is inhibited on the cells where the therapeutic agent is exerting its therapeutic effect, while the same or another BTB transport protein is activated on other site(s) to reduced the symptom of hypogonadism induced by the therapeutic agent.

[00414] Compositions of the invention may be prepared in any suitable form for administration to an animal. In some embodiments, the invention provides pharmaceutical compositions.

[00415| In some embodiments, the invention provides compositions suitable for oral administration. In some embodiments, compositions are suitable for transdermal administration. In some embodiments, compositions are suitable for injection by any standard route of injection, e.g., intravenous, subcutaneous, intramuscular, or intraperitoneal. Compositions suitable for other routes of administration are also encompassed by the invention, as described herein.

[00416] BTB transport protein modulators of use in the invention include any suitable BTB transport modulators. In some embodiments, the BTB transport protein modulator is one or more pyrone analogs. In some embodiments, the BTB transport protein modulator is one or more polyphenols. In some embodiments, the BTB transport protein modulator is one or more flavonoids. In some embodiments, the BTB transport protein modulator is quercetin or a quercetin derivative. In some embodiments, the BTB transport protein modulator is 5,7-dideoxyquercetin (3,3',4' trihydroxyflavone). In some embodiments, the BTB transport protein modulator is phosphorylated quercetin or a phosphorylated quercetin derivative. In some embodiments, the BTB transport protein is 3' quercetin phosphate, 4' quercetin phosphate, 5,7-dideoxyquercetin phosphate, or combinations thereof. In some embodiments, the BTB transport protein modulator is fisetin or a fisetin derivative. In some embodiments, the BTB transport protein modulator is phosphorylated fisetin or a phosphorylated fisetin derivative.

[00417] In some embodiments of the invention, the compositions further comprise an oligosaccharide. In some embodiments, the oligosaccharide is a cyclic oligosaccharide. In some embodiments, the oligosaccharide is a cyclodextrin. In some embodiments, the cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin. In some embodiments, the cyclodextrin is hydroxypropyl-β- cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, or combinations thereof.

[00418| In some embodiments the invention provides methods of treatment. In certain embodiments, the invention provides a method of treating a condition by administering to an animal suffering from the condition an effective amount of a therapeutic agent and an amount of a BTB transport protein modulator, e.g., activator, sufficient to reduce or eliminate one or more symptoms of hypogonadism induced by the therapeutic agent. In some embodiments the BTB transport protein modulator is a BTB transport protein activator. In some embodiments, the therapeutic agent is an opiate. In some embodiments, the opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu-enkephalin, met- enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the therapeutic agent is morphine. In some embodiments the therapeutic agent is sufentanyl. In some embodiments, the therapeutic agent is alfentanyl. In some embodiments, the therapeutic agent is remifentanyl. [00419] In certain embodiments the invention provides methods of treatment of pain with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism induced by the therapeutic agent. In some embodiments, the invention provides methods for treatment of acute pain such as post-operative pain with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism induced by the therapeutic agent. In some embodiments, the invention provides methods for treatment of severe, chronic, disabling pain of terminal conditions such as cancer with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism induced by the therapeutic agent. In certain embodiments the invention provides methods of treatment of depression with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism induced by the therapeutic agent. In certain embodiments the invention provides methods of treatment of conditions selected from the group consisting of cough, diarrhea, anxiety, and detoxification. [00420[ In some embodiments, the invention provides methods to reduce or eliminate one or more symptoms of hypogonadism induced by a therapeutic agent used for analgesia and/or anesthesia

[00421) In certain embodiments the invention provides methods of treatment of hypertension with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism induced by the therapeutic agent. [004221 In some embodiments the invention provides methods of decreasing one or more symptoms of hypogonadism in an animal, e.g. a human, that has received an amount of the therapeutic agent sufficient to produce a symptom of hypogonadism by administering to the animal, e.g., human, an amount of a BTB transport protein modulator sufficient to reduce or eliminate the symptom. 1004231 Hence, in some embodiments, the methods and compositions of the present invention can be used to modulate transport of a variety of therapeutic agents. In some embodiments, the dosage of the therapeutic agent will be modulated according to the effect of the transport protein modulator. For instance, less therapeutic agent may be needed to reach optimal effect when co-administered with the transport protein modulator. In other embodiments co-administering the transport protein 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 transport protein modulator will allow for the elimination of a therapeutic agent from a physiological compartment. In some embodiments, the physiological compartment is central nervous system.

1004241 If a symptom is measured objectively (e.g., decrease of circulating sex hormones levels) or subjectively, any suitable method for evaluation of objective or subjective effect may be used. Examples include measuring total testosterone, free testosterone (and/or sex hormone-binding globulin), estradiol, progesterone, LH, and FSH. These and other methods of objective and subjective evaluation of symptoms of hypogonadism by an objective observer, the individual, or both, are well-known in the art.

1004251 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.

1004261 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 the central nervous system, the fetal compartment and internal structures contained within organs, such as the ovaries and testes.

Physiology of Endocrine Interactions

|00427| The endocrine system is an integrated system of small organs that involve the release of extracellular signaling molecules known as hormones. The endocrine system is instrumental in regulating metabolism, growth, development and puberty, tissue function, and also plays a part in mood. The field of medicine that deals with disorders of endocrine glands is endocrinology, a branch of the wider field of internal medicine. (00428| The Endocrine system is an information signal system much like the nervous system. However, the nervous system uses nerves to conduct information, whereas the endocrine system mainly uses blood vessels as information channels. Glands located in many regions of the body release into the bloodstream specific chemical messengers called hormones. Hormones regulate the many and varied functions of an organism, e.g., mood, growth and development, tissue function, and metabolism, as well as sending messages and acting on them.

(00429| A number of glands that signal each other in sequence is usually referred to as an axis, for example the

Hypothalamic-pituitary-adrenal axis.

A. Hypothalamic-pituitary-adrenal axis

|00430] The hypothalamic-pituitary-adrenal axis (HPA or HTPA axis) is a complex set of direct influences and feedback interactions between: the hypothalamus, a hollow, funnel-shaped part of the brain; the pituitary gland, a pea-shaped structure located below the hypothalamus; and the adrenal or suprarenal gland, a small, paired, pyramidal organ located at the top of each kidney. The fine, homeostatic interactions between these three organs constitute the HPA axis, a major part of the neuroendocrine system that controls reactions to stress and regulates various body processes including digestion, the immune system, mood and sexuality, and energy usage. Species from humans to the most ancient organisms share components of the HPA axis. It is the mechanism for a set of interactions among glands, hormones and parts of the mid-brain that mediate a general adaptation syndrome. |004311 The paraventricular nucleus of the hypothalamus contains neuroendocrine neurons that synthesize and secrete vasopressin and corticotropin-releasing hormone (CRH). These two peptides regulate the anterior lobe of the pituitary gland. In particular, CRH and vasopressin stimulate the secretion of adrenocorticotropic hormone (ACTH), once known as corticotropin. ACTH in turn acts on the adrenal cortices, which produce glucocorticoid hormones (mainly Cortisol in humans) in response to stimulation by ACTH. Glucocorticoids in turn act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle.

[004321 CRH and vasopressin are released from neurosecretory nerve terminals at the median eminence and are transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk. There, CRH and vasopressin act synergistically to stimulate the secretion of stored ACTH from corticotrope cells. ACTH is transported by the blood to the adrenal cortex of the adrenal gland, where it rapidly stimulates biosynthesis of corticosteroids such as Cortisol from cholesterol. Cortisol is a major stress hormone and has effects on many tissues in the body, including on the brain. In the brain, Cortisol acts at two types of receptor - mineralocorticoid receptors and glucocorticoid receptors, and these are expressed by many different types of neuron. One important target of glucocorticoids is the hippocampus, which is a major controlling centre of the HPA axis.

1004331 Vasopressin can be thought of as "water conservation hormone" and is also known as "antidiuretic hormone". It is released when the body is dehydrated and has potent water-conserving effects on the kidney. It is also a potent vasoconstrictor. Important to the function of the HPA axis are some of the feedback loops: (i) Cortisol produced in the adrenal cortex will negatively feedback to inhibit both the hypothalamus and the pituitary gland. This reduces the secretion of CRH and vasopression, and also directly reduces the cleavage of proopiomelanocortin into ACTH and β-endorphins (ii) epinephrine and norepinephrine is produced from the adrenal medulla through sympathetic stimulation and the local effects of Cortisol (upregulation enzymes to make E/NE). E/NE will positively feedback to the pituitary and increase the breakdown of POMCs into ACTH and β- endorphins. [00434| Release of CRH from the hypothalamus is influenced by stress, by blood levels of Cortisol and by the sleep/wake cycle. In healthy individuals, Cortisol rises rapidly after wakening, reaching a peak within 30-45 minutes. It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night. An abnormally flattened circadian Cortisol cycle has been linked with chronic fatigue syndrome, insomnia and burnout.

[004351 Anatomical connections between brain areas such as the amygdala, hippocampus, and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdala is processed and conveyed to the central nucleus, which projects to several parts of the brain involved in responses to fear. At the hypothalamus, fear-signaling impulses activate both the sympathetic nervous system and the modulating systems of the HPA axis.

[00436] Increased production of Cortisol mediates alarm reactions to stress, facilitating an adaptive phase of a general adaptation syndrome in which alarm reactions including the immune response are suppressed, allowing the body to attempt counter measures.

[00437] Glucocorticoids have many important functions, including modulation of stress reactions, but in excess they can be damaging. Atrophy of the hippocampus in humans and animals exposed to severe stress is believed to be caused by prolonged exposure to high concentrations of glucocorticoids. Deficiencies of the hippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress. [00438| The HPA axis is involved in the neurobiology of mood disorders and functional illnesses, including anxiety disorder, bipolar disorder, post-traumatic stress disorder, clinical depression, burnout, chronic fatigue syndrome and irritable bowel syndrome.

B. Hypothalamic-Pituitary-Gonadal Axis

[00439] The hypothalamic-pituitary-gonadal axis (also HPTA) is a way of referring to the combined effects of the hypothalamus, pituitary gland, and gonads as if these individual endocrine glands were a single entity. Because these glands often behave in cooperation, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

[00440] The hypothalamic-pituitary-gonadal process of controlling the secretion of gonadal hormones, testosterone, and estrogen, begins with secretion by the hypothalamus of gonadotropin-releasing hormone (GNRH). GNRH stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). These two hormones are released into the systemic circulation and interact with the gonads, the testes and ovaries, to secrete testosterone or estrogen, respectively. These sex hormones then feed back to the hypothalamus and pituitary to form a complete feedback loop. Testosterone and estrogen support normal sexual and reproductive growth and behavior.

C. Hypothalamus

[00441 | The hypothalamus links the nervous system to the endocrine system via the pituitary gland (hypophysis). The hypothalamus is located below the thalamus, just above the brain stem. This gland occupies the major portion of the ventral region of the diencephalon. It is found in all mammalian brains. In humans, it is roughly the size of an almond. [00442] The hypothalamus regulates certain metabolic processes and other activities of the Autonomic Nervous

System. It synthesizes and secretes neurohormones, often called hypothalamic-releasing hormones, and these in turn stimulate or inhibit the secretion of pituitary hormones.

[00443) The hypothalamus controls body temperature, hunger, thirst, fatigue, anger, and circadian cycles.

1004441 The hypothalamus is a very complex region in the brain of humans, and even small nuclei within the hypothalamus are involved in many different functions. The paraventricular nucleus for instance contains oxytocin and vasopressin (also called antidiuretic hormone) neurons which project to the posterior pituitary, but also contains neurons that regulate ACTH and TSH secretion (which project to the anterior pituitary), gastric reflexes, maternal behavior, blood pressure, feeding, immune responses, and temperature.

[00445] The hypothalamus co-ordinates many hormonal and behavioral circadian rhythms, complexity patterns of neuroendocrine outputs, complex homeostatic mechanisms, and many important behaviors. The hypothalamus must therefore respond to many different signals, some of which are generated externally and some internally. It is thus richly connected with many parts of the CNS, including the brainstem reticular formation and autonomic zones, the limbic forebrain (particularly the amygdala, septum, diagonal band of

Broca, and the olfactory bulbs, and the cerebral cortex).

[00446| The hypothalamus is responsive to: (i) light: day length and photoperiod for regulating circadian and seasonal rhythms; (ii) olfactory stimuli, including pheromones; (iii) steroids, including gonadal steroids and corticosteroids; (iv) neurally transmitted information arising in particular from the heart, the stomach, and the reproductive tract; (v) autonomic inputs; (vi) blood-borne stimuli, including leptin, ghrelin, angiotensin, insulin, pituitary hormones, cytokines, plasma concentrations of glucose and osmolarity etc; (viii) stress; and (vix) invading microorganisms by increasing body temperature, resetting the body's thermostat upward.

[00447J The outputs of the hypothalamus can be divided into two categories: neural projections, and endocrine hormones.

[00448] Neural projections : Most fiber systems of the hypothalamus run in two ways (bidirectional).

Projections to areas caudal to the hypothalamus go through the medial forebrain bundle, the mammillotegmental tract and the dorsal longitudinal fasciculus. Projections to areas rostral to the hypothalamus are carried by the mammillothalamic tract, the fornix and terminal stria.

[00449) Endocrine hormones: The hypothalamus affects the endocrine system and governs emotional behavior, such as, anger and sexual activity. Most of the hypothalamic hormones generated are distributed to the pituitary via the hypophyseal portal system. The hypothalamus maintains homeostasis this includes a regulation of blood pressure, heart rate, and temperature. The primary hypothalamic hormones are corticotropin-releasing hormone

(CRH), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, and thyrotropin-releasing hormone (TRH).

D. Pituitary Gland

|00450| The pituitary gland, or hypophysis, is an endocrine gland about the size of a pea. It sits in a small, bony cavity (sella turcica) covered by a dural fold (diaphragma sellae) at the base of the brain. The pituitary fossa, in which the pituitary gland sits, is situated in the sphenoid bone in the middle cranial fossa at the base of the brain. [004511 The pituitary gland secretes hormones regulating homeostasis, including trophic hormones that stimulate other endocrine glands. It is functionally connected to the hypothalamus by the median eminence. 1004521 Located at the base of the brain, the pituitary is functionally linked to the hypothalamus. It is composed of two lobes: the adenohypophysis and neurohypophysis. The adenohypophysis, also referred to as the anterior pituitary is divided into anatomical regions known as the pars tuberalis and pars distalis. The neurohypophysis, also referred to as the posterior pituitary. The pituitary is functionally linked to the hypothalamus by the pituitary stalk, whereby hypothalamic releasing factors are released and in turn stimulate the release of pituitary hormones.

1004531 The pituitary hormones help control some of the following body processes: growth, blood pressure, some aspects of pregnancy and childbirth including stimulation of uterine contractions during childbirth, breast milk production, sex organ functions in both women and men, thyroid gland function, the conversion of food into energy (metabolism), water and osmolariry regulation in the body.

1004541 Disorders involving the pituitary gland include acromegaly, growth hormone deficiency, syndrome of inappropriate antidiuretic hormone, neurogenic diabetes insipidus, sheehan syndrome, pituitary adenoma, and hypopituitarism underproduction,

E. Substance-Induced Impairment in hypothalamic/pituitary/endocrine function

|00455| The invention provides compositions and methods utilizing an agent that reduces or eliminates one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by one or more substances. In some embodiments, the invention provides compositions and methods utilizing a combination of a therapeutic agent and an agent that reduces or eliminates one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by one or more substances.

[00456| It is known that some therapeutic agents have negative effects on the endocrine system. For instance, opioids depress levels of circulating testosterone, with loss of libido and other expected effects, in men, and menstrual irregularities and infertility in women. Chronic morphine exposure depresses levels of circulating testosterone in males and produces secondary changes associated with hypogonadism. Figure 4 shows a graph incidence of hypogonadism in healthy males and males under chronic morphine treatment. Figure 4 shows that in healthy males the incidence of hypogonadism increase with age. However, a profound hypogonadism is observed in patients receiving opioids. Figure 4 shows that 68 to 90 percent of patients receiving opioids suffer from hypogonadism.

|00457| Figure 1 1 - 12 show a decrease in circulating total and free testosterone, respectively, in human males after treatment with morphine (solid and dotted gray lines). Figure 13 shows a decrease in free androgen index in human males after treatment with morphine (solid and dotted gray lines).

|00458] Opioids have been used for medicinal and analgesic purposes for millennia and today remain a critical part of the medical armamentarium against pain, diarrhea, cough, and other symptoms. Without being limited to any theory, opioids may impair secretion of primary sex hormones thus decreasing testosterone and other androgen production. The hypothalamic-pituitary-gonadal process of controlling the secretion of gonadal hormones, testosterone, and estrogen, begins with secretion by the hypothalamus of gonadotropin-releasing hormone (GNRH). GNRH stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). These two hormones are released into the systemic circulation and interact with the gonads, the testes and ovaries, to secrete testosterone or estrogen, respectively. These sex hormones then feed back to the hypothalamus and pituitary to form a complete feedback loop. Testosterone and estrogen support normal sexual and reproductive growth and behavior. This system is modulated by a complex series of outside influences as well. Opioids can be one of a number of such influences and evidence suggests that opioids - both endogenous and exogenous - can bind to opioid receptors primarily in the hypothalamus, but potentially also in the pituitary and the testes, to modulate gonadal function. Decreased release, or interference with the normal pulsatility of release of GNRH at the level of the hypothalamus, has been documented, with consequent decreased release of LH and FSH from the pituitary. Direct effects of opioids on the testes, including decreased secretion of testosterone and testicular interstitial fluid, have been documented. In addition, opioids have been shown to increase pituitary release of prolactin in preclinical studies, with secondary effects of decreasing testosterone secretion

[00459| Studies performed in animals have demonstrated the acute and chronic effects of opioids on the endocrine system, including decreasing testosterone levels by central reductions of LH release (decreased hypothalamic release of luteinizing-hormone releasing hormone (LHRH), leading to reduced pituitary release of LH), and peripheral effects on the testicle as well. In addition, it has been demonstrated in studies in heroin addicts, compared to healthy controls, decreased testosterone levels in males, with an associated decrease in LH and/or FSH consistent with central hypogonadism. In one study measuring hormonal status one month after cessation of heroin use, testosterone levels returned to normal. In methadone-maintained male patients, several studies have demonstrated decreased testosterone levels consistent with central hypogonadism. One of these studies demonstrated a dose-response effect, in that patients on "low dose" methadone (10-60 mg/day) had no evidence of suppression compared with those on "high dose" (80-150 mg/day). Other studies demonstrated a peripheral effect on the testicle, with decreased secretion of testosterone and testicular interstitial fluid, and decreased spermmotility. One case series described amenorrhea and galactorrhea in female heroin addicts. |00460] Several studies have compared patients undergoing intrathecal opioid treatment for nonmalignant pain with patients with a comparable pain syndrome, but not on opioid therapy. These studies have documented hypogonadism associated with low LH values and normal or low FSH levels in both males and females. When compared to the chronic pain control group, these laboratory findings were associated with decreased libido or impotence in males and irregular or absent menses in females. Symptoms were reported to have improved in most patients with hormone supplementation. None of these studies reported elevation of prolactin levels, suggesting that prolactin is not significantly related to the mechanism by which opioids produce hypogonadism. |004611 Several studies have been published on the effects of long-term oral opioid therapy in males with chronic pain. In one of these studies, endocrine function was measured in patients on sustained-release opioids and compared to healthy controls. Hormone levels were much lower in opioid users than in control subjects in a dose-related pattern (POOOl for all comparisons) and total testosterone levels were subnormal in 74% of the opioid group, with an apparent dose-response effect. Eighty-seven percent (39 of 45) of the opioid-ingesting men who reported normal erectile function before opioid use, reported severe erectile dysfunction or diminished libido after beginning opioid therapy.

[004621 Another study was a case series in cancer survivors with chronic pain taking opioids that had abnormally low testosterone levels. This was confirmed with a follow-up case-control study comparing cancer survivors on opioids to matched controls. Among the opioid group, 18/20 (90%) exhibited hypogonadism, compared to 8/20controls (40%) (median testosterone levels were statistically significantly lower in the opioid group). LH, but not FSH levels, were statistically significantly lower in the cases. Importantly, clinically significant consequences of these laboratory abnormalities were also demonstrated. Sexual desire (measured by the Sexual Desire Inventory); anxiety and depression (measured by the Hospital Anxiety and Depression Scale); and overall quality of life (measured by the Functional Assessment of Chronic Illness Therapy with general and fatigue subscales [FACT-G/F ACIT-F]) were all significantly lower in the opioid group than in the controls. 1004631 Opioids have been found in several studies to decrease Cortisol levels, as well as Cortisol responses to adrenocorticotropin (ACTH) challenges. One study also documented decreased growth hormone secretion in the setting of opioid therapy.

|00464) Antihypertensive also have been shown to alter the endocrine system.

[00465] The invention provides compositions and methods utilizing an agent that reduces or eliminates one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by treatment with a therapeutic agent. In some embodiments, the invention provides compositions and methods utilizing a combination of a therapeutic agent and an agent that reduces or eliminates one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by treatment with the therapeutic agent. Typically, the symptom-decreasing agent is a modulator of a blood tissue barrier (BTB) transport protein. [00466| The methods and compositions are useful in the treatment of an animal in need of treatment, where it is desired that one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent be reduced or eliminated. In some embodiments further utilizing a therapeutic agent, the methods and compositions are useful in the treatment of an animal in need of treatment, where it is desired that one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent be reduced or eliminated while one or more of the therapeutic effects (e.g., peripheral effects) of the therapeutic agent are retained or enhanced.

|00467| In some embodiments of the invention, the therapeutic agent is an agent capable of inducing one or more symptoms of impairment in hypothalamic/pituitary/endocrine function. In some embodiments of the invention, the therapeutic agent is an analgesic agent, such as an opiate or a non-opiate analgesic. In some embodiments, the therapeutic agent is an opiate. Examples of opiates include, but are not limited to, codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu-enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the therapeutic agent is morphine. In some embodiments the therapeutic agent is sufentanyl. In some embodiments, the therapeutic agent is alfentanyl. In some embodiments, the therapeutic agent is remifentanyl. [00468| In some embodiments of the invention, the therapeutic agent is a non-analgesic agent. In some embodiments, the agent is an anti hypertensive agent. Examples of anti hypertensive agents include, but are not limited to, diuretics, adrenergic receptor antagonists, adrenergic receptor agonist, calcium channel blockers, ace inhibitors, angiotensin ii receptor antagonists, aldosterone antagonists, vasodilators, centrally acting adrenergic drugs. Example of antihypertensive agents include, but are not limited to, loop diuretics: bumetanide, ethacrynic acid, furosemide, torsemide; thiazide diuretics: chlortalidone, epitizide, hydrochlorothiazide and chlorothiazide, bendroflumethiazide; thiazide-like diuretics: indapamide, chlorthalidone, metolazone; potassium-sparing diuretics: amiloride, triamterene, spironolactone, beta blockers: atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol; alpha blockers: doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline; mixed alpha + beta blockers: bucindolol, carvedilol, labetalol, alpha-2 agonists: clonidine, methyldopa, dihydropyridines: amlodipine, felodipine, isradipine, lercanidipine, nifedipine(Adalat®), nimodipine, nitrendipine; non-dihydropyridines: diltiazem, verapamil, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandopril, benzapril, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, eplerenone, spironolactone, sodium nitroprusside, clonidine, guanabenz, methyldopa, moxonidine, and guanethidine, reserpine.

|00469| In some embodiments the symptom is at least partially a result of impairment of secretion of one or more hypothalamic-releasing hormone. Examples of hypothalamic-releasing hormone include corticotrop in- releasing hormone (CRH), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, and thyrotropin-releasing hormone (TRH). In some embodiments the symptom is at least partially a result of impairment in hypothalamic response to one or more stimuli. Examples of stimuli include light, olfactory stimuli, steroids, neurally transmitted information, autonomic inputs, blood-borne stimuli, stress, changes in temperature and an invading microorganism. In some embodiments the symptom is at least partially a result of impairment in pituitary response to one or more hypothalamic-releasing hormones. In some embodiments, the symptom is at least partially a result of impairment of secretion of one or more pituitary hormones. In some embodiments the symptom is at least partially a result of impairment in a response of one or more endocrine glands to one or more pituitary hormones. The symptom may be a decrease in the circulating levels of one or more pituitary hormones. Examples of pituitary hormones included ACTH, TSH, prolactin, growth hormone, endorphins, FSH, LH, oxytocin, and antidiuretic hormone (ADH). The symptom may also be a result of the decrease of the pituitary hormone or of the hormone whose release is caused by stimulation with the pituitary hormone. Symptoms due to decreases in pituitary hormone levels are well-known in the art. Examples of hormones whose release is caused by pituitary hormones include Cortisol from the adrenal cortex in response to ACTH, thyroxin from the thyroid gland in response to TSH, testosterone or estrogen from the gonads in response to FSH and LH. The decrease may be either acute or chronic. |00470) The agent causing a decrease in one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent, e.g. morphine, can be a modulator of a BTB transport protein and may be an activator or an inhibitor of the protein. The modulatory effect may be dose-dependent, e.g., some modulators act as activators in one dosage range and inhibitors in another. In some embodiments, a modulator of a BTB transport protein is used in a dosage wherein it acts primarily as an activator.

[004711 Typically, the use of the BTB transport protein modulator, e.g., activator, results in a decrease in one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. The therapeutic effect(s) of the therapeutic agent may be decreased, remain the same, or increase; however, in preferred embodiments, if the therapeutic effect is decreased, it is not decreased to the same degree as the symptom of impairment in hypothalamic/pituitary/endocrine function. It will be appreciated that a given therapeutic agent may have more than one therapeutic effect and or one or more symptoms of impairment in hypothalamic/pituitary/endocrine function, and it is possible that the therapeutic ratio (in this case, the ratio of change in desired effect to change in undesired effect) may vary depending on which effect is measured. However, at least one therapeutic effect of the therapeutic agent is decreased to a lesser degree than at least one symptom of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. (00472| In addition, in some embodiments, one or more therapeutic effects of the therapeutic agent are enhanced by use in combination with a BTB transport protein modulator, while one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent are reduced or substantially eliminated.

|00473] Without being bound by theory, and as an example only of a possible mechanism, it is thought that the methods and compositions of the invention operate by reducing or eliminating the concentration of the therapeutic agent in certain compartments, such as from the CNS (e.g., brain) while retaining or even increasing the effective concentration of the therapeutic agent in the periphery. Therapeutic agents act at least in part by peripheral mechanisms and may thus retain some or all of their activity, or even display enhanced therapeutic activity, while at the same time CNS effects are reduced or eliminated. However, it is recognized that the mechanism of action of a particular BTB transport protein modulator in decreasing one or more symptoms as described herein may be different, or in addition to, modulation of a BTB transport protein, and that an agent that has BTB transport protein-modulating activity may nonetheless act by a different mechanism than BTB transport protein modulation. It is also possible for an agent to modulate more than one BTB transport protein, and the overall effect will depend on the summation of all mechanisms by which an agent works. [00474| It will be appreciated that the therapeutic and/or symptoms of impairment in hypothalamic/pituitary/endocrine function of a therapeutic agent may be mediated in part or in whole by one or more metabolites of the therapeutic agent, and that a BTB transport protein modulator that reduces or eliminates one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent and/or of one or more active metabolites of the therapeutic agent, while retaining or enhancing a peripheral concentration of the therapeutic agent and/or one or more metabolites producing a therapeutic effect, is also encompassed by the methods and compositions of the invention. In addition, a BTB transport modulator itself may be metabolized to metabolites that have differing activities in the modulation of one or more BTB transport proteins, and these metabolites are also encompassed by the compositions and methods of the invention. |00475| Hence, in some embodiments the invention provides compositions that include a therapeutic agent and a blood-tissue barrier (BTB) transport protein modulator, where the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the BTB protein modulator is present in an amount sufficient to decrease one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent when compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal. The decrease in the symptom of impairment in hypothalamic/pituitary/endocrine function can be measurable. The BTB transport protein modulator is a BTB transport protein activator in some embodiments. In some embodiments the BTB transport protein modulator is a modulator of ATP binding cassette (ABC) transport proteins. In some embodiments the BTB transport protein modulator is a modulator of P-glycoprotein (P-gP).

[00476] In some embodiments, compositions of the invention include one or more therapeutic agents as well as one or more than one BTB transport protein modulators. One or more of the therapeutic agents may have one or more symptoms of impairment in hypothalamic/pituitary/endocrine function that are desired to be decreased. [00477| It will be appreciated that when a BTB transport protein that is the target of the BTB transport modulator is present on the cells where the therapeutic agent is exerting its therapeutic effect, the dosage of the BTB transport modulator may be adjusted such that one or more symptoms of impairment in hypothalamic/pituitary/endocrine function of the therapeutic agent are reduced without a substantial reduction of the therapeutic effect in the target cells. In some embodiments, it is desirable to inhibit a BTB transport protein present in the cells where the therapeutic agent is exerting its therapeutic effect while activating the same or another BTB transport protein at other site(s) such that the symptom of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent are reduced. Therefore, the dosage of the BTB transport modulator may be adjusted such that a BTB transport protein that is the target of the BTB transport modulator is inhibited on the cells where the therapeutic agent is exerting its therapeutic effect, while the same or another BTB transport protein is activated on other site(s) to reduced the symptom of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent.

|00478] Compositions of the invention may be prepared in any suitable form for administration to an animal. In some embodiments, the invention provides pharmaceutical compositions.

[00479| In some embodiments, the invention provides compositions suitable for oral administration. In some embodiments, compositions are suitable for transdermal administration. In some embodiments, compositions are suitable for injection by any standard route of injection, e.g., intravenous, subcutaneous, intramuscular, or intraperitoneal. Compositions suitable for other routes of administration are also encompassed by the invention, as described herein.

1004801 BTB transport protein modulators of use in the invention include any suitable BTB transport modulators. In some embodiments, the BTB transport protein modulator is one or more polyphenols. In some embodiments, the BTB transport protein modulator is one or more flavonoids. In some embodiments, the BTB transport protein modulator is quercetin or a quercetin derivative.

[004811 In some embodiments the invention provides methods of treatment. In certain embodiments, the invention provides a method of treating a condition by administering to an animal suffering from the condition an effective amount of a therapeutic agent and an amount of a BTB transport protein modulator, e.g., activator, sufficient to reduce or eliminate one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments the BTB transport protein modulator is a BTB transport protein activator. In some embodiments, the therapeutic agent is an opiate. In some embodiments, the opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu-enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the therapeutic agent is morphine. In some embodiments the therapeutic agent is sufentanyl. In some embodiments, the therapeutic agent is alfentanyl. In some embodiments, the therapeutic agent is remifentanyl.

1004821 In certain embodiments the invention provides methods of treatment of pain with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments, the invention provides methods for treatment of acute pain such as post-operative pain with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments, the invention provides methods for treatment of severe, chronic, disabling pain of terminal conditions such as cancer with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In certain embodiments the invention provides methods of treatment of depression with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In certain embodiments the invention provides methods of treatment of conditions selected from the group consisting of cough, diarrhea, anxiety, detoxification.

|00483] In some embodiments, the invention provides methods to reduce or eliminate one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent used for analgesia and anesthesia

1004841 In certain embodiments the invention provides methods of treatment of hypertension with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent.

[00485] In some embodiments the invention provides methods of decreasing one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induce by a in an animal, e.g. a human, that has received an amount of the therapeutic agent sufficient to produce a symptom by administering to the animal, e.g., human, an amount of a BTB transport protein modulator sufficient to reduce or eliminate the symptom. 100486] Hence, in some embodiments, the methods and compositions of the present invention can be used to modulate transport of a variety of therapeutic agents. In some embodiments, the dosage of the therapeutic agent will be modulated according to the effect of the transport protein modulator. For instance, less therapeutic agent may be needed to reach optimal effect when co-administered with the transport protein modulator. In other embodiments co-administering the transport protein 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 transport protein modulator will allow for the elimination of a therapeutic agent from a physiological compartment. In some embodiments, the physiological compartment is central nervous system.

[00487] If a symptom is measured objectively (e.g., decrease of circulating hormone levels) or subjectively, any suitable method for evaluation of objective or subjective effect may be used. Examples include measuring one or more of total testosterone, free testosterone (and/or sex hormone-binding globulin), estradiol, progesterone, LH, FSH, ACTH, TSH, prolactin, growth hormone, endorphins, oxytocin, Cortisol, thyroxin, and antidiuretic hormone (ADH). These and other methods of objective and subjective evaluation of symptoms of impairment in hypothalamic/pituitary/endocrine function by an objective observer, the individual, or both, are well-known in the art. [00488] 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.

[00489] 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 the central nervous system, the fetal compartment and internal structures contained within organs, such as the ovaries and testes.

Therapeutic Agents Whose Side Effect Are Desired To Be Reduced (e.g., drugs)

[00490] The invention provides compositions and methods to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent. It will be appreciated that some therapeutic agents are also agents produced naturally in an animal. 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 capable of inducing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments, the compositions and methods of the invention utilize an analgesic agent. In some embodiments, the analgesic agent is an opiate analgesic. In some embodiments, the analgesic is a non-opiate analgesic. In some embodiments, the compositions and methods of the invention utilize a non-analgesic therapeutic agent. 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 nonsteroidal 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 analgesic effect also have other therapeutic effects, while some agents that have primarily a non-analgesic effect also provide some degree of analgesia. The invention encompasses these therapeutic agents as well.

A. Analgesic agents

|004911 The compositions and methods of the invention encompass the use of one or more analgesic agents in combination with an agent that reduces or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced the analgesic agent, such as a BTB transport protein modulator.

(004921 Analgesic agents are agents used to reduce or eliminate pain. An analgesic (colloquially known as painkiller) is any member of the diverse group of drugs used to relieve pain and to achieve analgesia ("absence of pain"). Analgesic drugs act in various ways on the peripheral and central nervous system; analgesics may be employed for symptomatic relief and include broadly two major groups: 1) opiate analgesics; 2) nonopiate analgesics, including analgesics and antipyretics, nonsteroidal antiinflammatory drugs, acetominophen, paracetamol, indomethacin, tricyclic antidepressants (for example desipramine, imipramine, amytriptiline, nortriptile), anticonvulsants (for example, carbamazepine, valproate), and serotonin reuptake inhibitors (for example, fluoxetine, paraoxetine, sertraline), mixed serotonin-norepinephrine reuptake inhibitors (for example venlafaxine, duloxetine), serotonin receptor agonists and antagonists, cholinergic (muscarinic and nicotinic) analgesics, adrenergic agents, and neurokinin antagonists.

Opiate analgesics

[00493| In some embodiments of the invention utilizing an analgesic agent, the analgesic agent is an opiate. Opiates bind stereospecific receptors predominantly in the CNS and peripheral nervous system. The mu, kappa, and delta opiate receptors are the receptors most responsible for the analgesic effects. Mu activation produces analgesia but also has the usually undesired effects of respiratory depression, addiction, and euphoria. Kappa receptors are generally located in the spinal cord and help with spinal analgesia but also cause miosis and sedation. Delta sites are also involved in analgesia. There is no ceiling effect with the analgesia provided by additional amounts of opiates. Thus side-effects also tend to increase with increasing dosage. [00494| Should the pain still prove debilitating, the clinician may choose to use stronger narcotics. Morphine is a pure agonist and makes for an excellent analgesic. Other mixed agonist/antagonist opiates, such as pantazocine, nalbuphine, and butorphanol, will selectively block mu receptors and activate kappa receptors. These drugs do exhibit a ceiling effect. Partial agonists act similarly by activating the mu receptor and block occupation of the kappa site.

|00495| Opioid alkaloids used in pain treatment and useful in embodiments of the invention include morphine (morphine sulfate), codeine, and thebaine. Semisynthetic derivatives include diamorphine (heroin), oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, and nicomorphine. Synthetic opioids include phenylheptylamines such as methadone and levomethadyl acetate hydrochloride (LAAM); phenylpiperidines such as pethidine (meperidine), fentanyl, alfentanyl, sufentanil, remifentanil, ketobemidone, and carfentanyl; diphenylpropylamine derivatives such as propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, and piritramide; benzomorphan derivatives such as pentazocine and phenazocine; oripavine derivatives such as buprenorphine; and morphinan derivatives such as butorphanol and nalbufine; and other opioids such as dezocine, etorphine, tilidine, tramadol, loperamide, nalbuphine, dextromethorphan, and diphenoxylate. Analgesic combinations that include opioids include analgesic combinations such as codeine/acetaminophen, codeine/aspirin, hydrocodone/acetaminophen, hydrocodone/ibuprofen, oxycodone/acetaminophen, oxycodone/aspirin, propoxyphene/aspirin or acetaminophen.

[00496| In some embodiments, compositions and methods of the invention encompass the use of an opioid analgesic in combination with an agent that reduces or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opioid analgesic, such as a BTB transport protein modulator. In some embodiments the opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu-enkephalin, met-enkephalin, dynoφhin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the therapeutic agent is morphine. In some embodiments the therapeutic agent is sufentanyl. In some embodiments, the therapeutic agent is alfentanyl. In some embodiments, the therapeutic agent is remifentanyl.

[00497| True opioids have no ceiling dose, and dosing is often limited by side effects. Thus, the compositions and methods of the invention allow greater pain relief by increasing dose, if necessary, without increasing side effects or with less increase in side effects. In some embodiments, the methods and compositions of the invention allow greater pain relief for a given dose of opioid, in some embodiments together with decreased in side effects such as symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function.

Non-opiate analgesics

[00498| In some embodiments, the invention encompasses the use of a non-opiate analgesic. In some embodiments, the non-opiate analgesic is used in combination with an agent that reduces one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the non-opiate analgesic.

|00499| In some embodiments, the non-opiate analgesic is used in addition to another analgesic, in combination with an agent that reduces one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the other analgesic.

|00500| Antidepressants and anticonvulsants In neuropathic and other opioid-insensitive pain conditions, antidepressants, e.g., tricyclic antidepressants ("TCAs") and anticonvulsant therapy is typically used.

|005011 TCAs have been hypothesized to have their own analgesic effect, potentiate narcotics, and treat neuropathic pain as their modes of action for analgesia. Exemplary TCAs include Amitriptyline, Amoxapine,

Clomipramine, Desipramine, Doxepin, Imipramine, Nortriptyline, Protriptyline, and Trimipramine.

[00502] In addition, other types of antidepressants may be used in treatment of, e.g., chronic pain. These include Escitalopram, Sertraline, Citalopram, Paroxetine, Paroxetin, controlled release, Fluoxetine, Venlafaxine;

Reboxetine, Milnacipran, Mirtazapine, Nefazodone, Duloxetin Bupropion, Maprotiline, Mianserin, Trazodone,

Dexmethylphenidate, Methyphenidate, and Amineptine, Fluoxetine weekly, Fluvoxamine, olanzapine/fluoxetine combination.

[00503] Anticonvulsants such as carbamazapine, topiramate, gabapentin, and pregabalin are used in neuropathic pains such as trigeminal neuralgia. Mexiletine and clonazepam have also been shown to be effective in other neuronally mediated types of pain. Further anticonvulsant agents include clorazepate dipotassium, diazepam, ethosuximide, ethotoin, felbamate, fosphenytoin, lamotrigine, levetiracetam, lorazepam, mephenytoin, mephobarbital, oxycarbazepine, pentobarbital sodium, phenobarbital, phenytoin, primidone, tiagabine, trimethadione, and valproic acid.

|00504] In some embodiments, compositions and methods of the invention encompass the use of an anticonvulsant in combination with an agent that reduces one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the anticonvulsant, such as a BBB transport protein modulator. In some embodiments, the anticonvulsant is gabapentin, pregabalin, or topiramate. In some embodiments, the anticonvulsant is gabapentin. In some embodiments, the anticonvulsant is pregabalin. In some embodiments, the anticonvulsant is topiramate.

|00505| Antiinflammatory compounds, both steroidal and non-steroidal, also find use in pain relief, and may be used in the compositions and methods of the invention.

|00506] Non-limiting examples of steroidal anti-inflammatory agents suitable for use herein include corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof may be used. The preferred steroidal anti-inflammatory for use is hydrocortisone.

[005071 Additional nonopiate analgesics of use in the invention include the non-steroidal antiinflammatory compounds. NSAIDS are typically used as analgesics, antipyretics and antiinflammatories. Acetaminophen, while not normally classified as an NSAID because it is not anti-inflammatory, has similar analgesic effects and is often used similarly. Salicylates are hydrolyzed by the body into salicylic acid whereas salicylamide and diflunisal have structural and functional similarities but do not get hydrolyzed. At sites of inflammation, NSAIDS typically inhibit prostaglandin synthesis by irreversibly acetylating cyclooxygenase and may inhibit nitric oxide synthetase, TNF-alpha, IL-I and change other lymphocytic activity decreasing inflammation. Diclofenac, ibuprofen, indomethacin, and ketoprofen have been shown to have direct analgesic activity as well. Clinically, NSAIDs are typically used for mild to moderate pain, and are generally considered for some types of pain, most notably post-surgical pain, as being more effective than opioids.

|00508] NSAIDS used in pain treatment include salicylates such as aspirin, methyl salicylate, and diflunisal; arylalkanoic acids such as indomethacin, sulindac, diclofenac, and tolmetin; N-arylanthranilic acids (fenamic acids) such as mefenamic acid and mecflofenamate; oxicams such as piroxicam and meloxicam; coxibs such as celecoxib, rofecoxib, valdecoxib, parecoxib, and etoricoxib; sulphonanilides such as nimesulide; naphthylalkanones such as nabumetone; anthranilic acids such as pyrazolidinediones and phenylbutazone; proprionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, and oxaprozin; pyranocarboxylic acids such as etodolac; pyrrolizine carboxylic acids such as ketorolac; and carboxylic acids. |00509| Sedative-Hypnotic Drugs, may also be used, and include drugs that bind to the GABA_A receptor such as the benzodiazepines (including alprazolam, chlordiazepoxide, clorazepate, clonazepam, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, triazolam), the barbiturates (such as amobarbital, pentobarbital, phenobarbital, secobarbita), and non-benzodiazepines (such as Zolpidem and zaleplon), as well as the benzodiazepine antagonists (such as flumazenil). Other sedative-hypnotic drugs appear to work through non-GABA-ergic mechanisms such as through interaction with serotonin and dopaminergic receptors, and include buspirone, isapirone, geprirone, and tandospirone. Older drugs work through mechanisms that are not clearly elucidated, and include chloral hydrate, ethchlorvynol, meprobamate, and paraldehyde. [005101 Ergot alkaloids are useful in the treatment of, e.g., migraine headache, and act on a variety of targets, including alpha adrenoceptors, serotonin receptors, and dopamine receptors. They include bromocriptine, cabergoline, pergolide, ergonovine, ergotamine, lysergic acid diethylamide, and methysergide. Available preparations include dihydroergotamine, ergonovine, ergotamine, ergotamine tartrate, and methylergonovine.

Other pain-reducing modalities

[005111 In some embodiments, the compositions and methods of the invention encompass the use of an analgesic agent in combination with a modulator of a BBB transport protein, and further in combination with another pain-reducing modality. Treatment may also be by mechanical modalities of massage, ultrasound, stretching, traction, hydrotherapy or application of heat and cold. Electrical modalities of transcutaneous electrical nerve stimulation (TENS) or microcurrent electrical therapy (MET) might be used. Other therapies such as magnetic biostimulation, acupuncture, pulsed signal therapy, physical therapy, and electromedicine have all been used to treat pain conditions. Alternative and Eastern approaches have also been utilized. As part of a pain treatment or diagnosis plan, neural blockade by the introduction of local anesthetic or, rarely, a neurolytic can be used, usually combined with a steroid.

B. Non-analgesic agents

[00512] The methods and compositions of the invention are also useful in relation to non-analgesic therapeutic agents.

[00513] Thus, other suitable drugs for use herein include diuretics, vasopressin, agents affecting the renal conservation of water, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, antihypertensive agents, angiotensin converting enzyme inhibitors, β-adrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.

[00514| Additional suitable drugs include drugs used for control of gastric acidity, agents for the treatment of peptic ulcers, agents for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary disease, agents used for pancreatic disease. The compounds and methods of the invention can be used to modulate transport of drugs used to treat protozoal infections, drugs used to treat Malaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs used in the chemotherapy of helminthiasis. Other drugs include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, and other, /?-Lactam antibiotics, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in the chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy, antifungal agents, antiviral agents including nonretroviral agents and antiretroviral agents.

|00515| In addition, drugs used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants can be modulated. In addition, drugs acting on the blood and the blood-forming organs, hematopoietic agents, growth factors, minerals, and vitamins, anticoagulant, thrombolytic, and antiplatelet drugs can also be modulated. The invention can be used to modulate transport of hormones and hormone antagonists, pituitary hormones and their hypothalamic releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas, agents affecting calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, and other compounds. Further transport of vitamins such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E can be modulated.

[00516| 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.

|00517| Antihypertensives In some embodiments, compositions and methods of the invention encompass the use of an antihypertensive in combination with an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the antihypertensive, such as a BTB transport protein modulator.

[00518| Antihypertensives are a class of drugs that are used in medicine and pharmacology to treat hypertension (high blood pressure). There are many classes of antihypertensives, which — by varying means — act by lowering blood pressure. Examples of antihypertensives useful in the methods and compositions of the invention include but are not limited to: atenolol, captopril, clonidine, guanethidine, hydralazine, hydrochorothiazide, lisinopril, losartan, methyldopa, minoxidil, nifedipine, prazosin, propranolol, reserpine, verapamil; centrally acting sympathoplegic drugs such as methyldopa, clonidine, guanabenz, guanfacine; ganglion-blocking agents such as mecamylamine (inversine); adrenergic neuron-blocking agents such as guanethidine, guanadrel, bethanidine, debrisoquin, reserpine; adrenoceptor antagonists such as propranolol; other beta-adrenoceptor-blocking agents such as metoprolol, nadolol, carteolol, atenolol, betaxolol, bisoprolol, pindolol, acebutolol, penbutolol, labetalol, carvedilol, esmolol, timolol; prazosin and other alpha blockers such as prazosin, terazosin, doxazosin; other alpha adrenoceptor-blocking agents such as pinacidil, urapidil, cromakalim; nonselective agents, phentolamine and phenoxybenzamine; vasodilators such as hydralazine and minoxidil; sodium nitroprusside, diazoxide, fenoldopam; calcium channel blockers such as verapamil, diltiazem and dihydrophyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine); inhibitors of angiotensin such as renin, angiotensin, aldosterone; angiotensin-converting enzyme (ACE) inhibitors such as captopril, enalapril, lisinopril, benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, trandolapril; angiotensin receptor-blocking agents such as losartan, valsartan, candesartan, eprosartan, irbesartan and telmisartan, and olmisartan. [00519] Antiinfectives In some embodiments, compositions and methods of the invention encompass the use of an antiinfective agent in combination with an agent that reduces one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the antibacterial agent, such as a BBB transport protein modulator.

[00520| Non-limiting examples of antiinfective agents useful in the invention include β-lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, amikacin, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'- trichlorocarbanilide, phenoxyethanol, phenoxy propanol, phenoxyisopropanol, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline, ethambutol, hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, lineomycin, methacycline, methenamine, minocycline, neomycin, netilmicin, paromomycin, streptomycin, tobramycin, miconazole, tetracycline hydrochloride, erythromycin, zinc erythromycin, erythromycin estolate, erythromycin stearate, amikacin sulfate, doxycycline hydrochloride, capreomycin sulfate, chlorhexidine gluconate, chlorhexidine hydrochloride, chlortetracycline hydrochloride, oxytetracycline hydrochloride, clindamycin hydrochloride, ethambutol hydrochloride, metronidazole hydrochloride, pentamidine hydrochloride, gentamicin sulfate, kanamycin sulfate, lineomycin hydrochloride, methacycline hydrochloride, methenamine hippurate, methenamine mandelate, minocycline hydrochloride, neomycin sulfate, netilmicin sulfate, paromomycin sulfate, streptomycin sulfate, tobramycin sulfate, miconazole hydrochloride, amanfadine hydrochloride, amanfadine sulfate, octopirox, parachlorometa xylenol, nystatin, tolnaftate, zinc pyrithione and clotrimazole.

Compositions

|00521 ] In one aspect the invention provides compositions that include an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary /endocrine function induced by a therapeutic agent. In some embodiments, the therapeutic agent is co-administered with the agent that reduces the hypogonadism or impairment in hypothalamic/pituitary/endocrine function symptom. "Co-administration," "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.

[00522] In some embodiments, the invention provides compositions containing a combination of a therapeutic agent and an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, e.g. an opiate. In some embodiments the invention provides pharmaceutical compositions that further include a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions are suitable for oral administration. In some embodiments, the pharmaceutical compositions are suitable for transdermal administration. In some embodiments, the pharmaceutical compositions are suitable for injection. Other forms of administration are also compatible with embodiments of the pharmaceutical compositions of the invention, as described herein. [00523| In some embodiments, the BTB transport protein is an ABC transport protein. In some embodiments, the BBB transport protein modulator is a BTB transport protein activator. In some embodiments, the BTB transport protein modulator is a modulator of P-gP.

[00524| In some embodiments, the BTB transport protein modulator comprises a pyrone analog. In some embodiments, the BTB transport protein modulator comprises a polyphenol. In other embodiments, the invention includes a polyphenol which acts to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent through a non-BTB transport protein-mediated mechanism, or that acts to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent through a BTB transport protein-mediated mechanism and a non-BTB transport protein-mediated mechanism. In some embodiments utilizing a polyphenol, the polyphenol is a flavonoid. In some embodiments utilizing a polyphenol, the polyphenol is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin. In some embodiments utilizing a polyphenol, the polyphenol is a flavonol. In certain embodiments, the flavonol is selected from the group consisting of quercetin, galangin, fisetin and kaempferol, or combinations thereof. In some embodiments, the flavonol is quercetin or a quercetin derivative. In some embodiments, the flavonol is fisetin or a fisetin derivative. In some embodiments, the flavonol is galangin or a galangin derivative. In some embodiments, the flavonol is kaempferol or a kaempferol derivative.

[00525| In some embodiments, the BTB transport protein modulator comprises a phosphorylated pyrone analog. In some embodiments, the BTB transport protein modulator comprises a phosphorylated polyphenol. In other embodiments, the invention includes a phosphorylated polyphenol which acts to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent through a non-BTB transport protein-mediated mechanism, or that acts to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent through a BTB transport protein-mediated mechanism and a non-BTB transport protein- mediated mechanism. In some embodiments utilizing a phosphorylated polyphenol, the phosphorylated polyphenol is a phosphorylated flavonoid. In some embodiments utilizing a phosphorylated polyphenol, the phosphorylated polyphenol is selected from the group consisting of phosphorylated quercetin, phosphorylated isoquercetin, phosphorylated flavon, phosphorylated chrysin, phosphorylated apigenin, phosphorylated rhoifolin, phosphorylated diosmin, phosphorylated galangin, phosphorylated fisetin, phosphorylated morin, phosphorylated rutin, phosphorylated kaempferol, phosphorylated myricetin, phosphorylated taxifolin, phosphorylated naringenin, phosphorylated naringin, phosphorylated hesperetin, phosphorylated hesperidin, phosphorylated chalcone, phosphorylated phloretin, phosphorylated phlorizdin, phosphorylated genistein, phosphorylated biochanin A, phosphorylated catechin, and phosphorylated epicatechin. In some embodiments utilizing a phosphorylated polyphenol, the phosphorylated polyphenol is a phosphorylated flavonol. In certain embodiments, the phosphorylated flavonol is selected from the group consisting of phosphorylated quercetin, phosphorylated galangin, phosphorylated fisetin and phosphorylated kaempferol, or combinations thereof. In some embodiments, the phosphorylated flavonol is phosphorylated quercetin or a phosphorylated quercetin derivative. In some embodiments, the phosphorylated flavonol is phosphorylated fisetin or a phosphorylated fisetin derivative. In some embodiments, the phosphorylated flavonol is phosphorylated galangin or a phosphorylated galangin derivative. In some embodiments, the phosphorylated flavonol is phosphorylated kaempferol or a phosphorylated kaempferol derivative.

[00526| In some embodiments, the symptom of hypogonadism induced by the therapeutic agents that is reduced is selected from the group consisting of premature menopause, decrease of energy, fatigue, muscle mass decline, increase visceral fat, decreased positive mood factors and an increased negative mood factors, anxiety, depression, decrease in fertility, decrease in libido and sexual function, impotence, amenorrhea, irregular menses, galactorrhea, increased risk for osteoporosis, increased pain sensitization, hematological abnormalities, decrease in cognitive skills, sleep disturbances, vasomotor instability, increase CAD risk, changes in secondary sex characteristic and decrease in circulating sex hormones, and combinations thereof. In some embodiments, the symptom of hypogonadism induced by a therapeutic agent that is reduced is selected from the group consisting of changes in secondary sex characteristic and decrease in circulating sex hormones. In some embodiments, the symptom of hypogonadism induced by a therapeutic agent that is reduced is decrease in circulating sex hormones. In some embodiments, the symptom of hypogonadism induced by a therapeutic agent that is reduced is decrease in circulating levels of testosterone.

|00527| In some embodiments the symptom is at least partially a result of impairment of secretion of one or more hypothalamic-releasing hormone. Examples of hypothalamic-releasing hormone include corticotropin- releasing hormone (CRH), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, and thyrotropin-releasing hormone (TRH). In some embodiments the symptom is at least partially a result of impairment in hypothalamic response to one or more stimuli. Examples of stimuli include light, olfactory stimuli, steroids, neurally transmitted information, autonomic inputs, blood-borne stimuli, stress, changes in temperature and an invading microorganism. In some embodiments the symptom is at least partially a result of impairment in pituitary response to one or more hypothalamic-releasing hormones. In some embodiments, the symptom is at least partially a result of impairment of secretion of one or more pituitary hormones. In some embodiments the symptom is at least partially a result of impairment in a response of one or more endocrine glands to one or more pituitary hormones. Examples of pituitary hormones included ACTH, TSH, prolactin, growth hormone, endorphins, FSH, LH, oxytocin, and antidiuretic hormone (ADH). Examples of hormones whose release is caused by pituitary hormones include Cortisol from the adrenal cortex in response to ACTH, thyroxin from the thyroid gland in response to TSH, testosterone or estrogen from the gonads in response to FSH and LH.

100528] In some embodiments of the invention, the therapeutic agent is an agent capable of inducing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments of the invention, the therapeutic agent is an analgesic agent, such as an opiate or a non-opiate analgesic. In some embodiments, the therapeutic agent is an opiate. Examples of opiates include, but are not limited to, codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu-enkephalin, met- enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the therapeutic agent is morphine. In some embodiments the therapeutic agent is sufentanyl. In some embodiments, the therapeutic agent is alfentanyl. In some embodiments, the therapeutic agent is remifentanyl. In some embodiments, the therapeutic agent is oxycodone.

|00529| In some embodiments of the invention, the therapeutic agent is a non-analgesic agent. In some embodiments, the agent is an anti hypertensive agent. Examples of anti hypertensive agents include, but are not limited to, diuretics, adrenergic receptor antagonists, adrenergic receptor agonist, calcium channel blockers, ace inhibitors, angiotensin ii receptor antagonists, aldosterone antagonists, vasodilators, centrally acting adrenergic drugs.

|00530| In some embodiments, the invention provides a composition containing a therapeutic agent and an blood-tissue barrier (BTB) transport protein modulator, where the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is present in an amount sufficient to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/eπdocrine function induced by the therapeutic agent by a measurable amount, compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is decreased 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 the symptom without the BTB transport protein modulator. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is decreased by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50%, compared to the symptom without the BTB transport protein modulator. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/piruitary/endocrine function induced by the therapeutic agent is decreased by an average of at least about 10%, compared to the symptom without the BTB transport protein modulator. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is decreased by an average of at least about 15%, compared to the symptom without the BTB transport protein modulator. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is decreased by an average of at least about 20%, compared to the symptom without the BBB transport protein modulator. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is decreased by an average of at least about 30%, compared to the symptom without the BBB transport protein modulator. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is decreased by an average of at least about 50%, compared to the symptom without the BBB transport protein modulator. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is decreased by an average of at least about 75%, compared to the symptom without the BBB transport protein modulator. In some embodiments the symptom that is decreased is a decrease in circulating sex hormone. In some embodiments, a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is substantially eliminated compared to the symptom without the BTB transport protein modulator. "Substantially eliminated" as used herein encompasses no measurable or no statistically significant symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by (one or more symptoms) the therapeutic agent, when administered in combination with the BTB transport protein modulator.

[00531| In some embodiments, the invention provides compositions that contain a polyphenol, e.g., a flavonol, and a therapeutic agent, where the therapeutic agent is present in an amount sufficient to exert an therapeutic effect and the polyphenol, e.g., a flavonol is present in an amount sufficient to decrease or eliminate a symptom of hypogonadism or impairment in hypothalamic/pituitary /endocrine function induced by the therapeutic agent by a measurable amount, compared to the symptom without the polyphenol, e.g., a flavonol 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%, as described herein. The symptom of hypogonadism induced by the therapeutic agent may be any symptom as described herein. In some embodiments, the symptom of hypogonadism induced by the therapeutic agents that is reduced is selected from the group consisting of premature menopause, decrease of energy, fatigue, muscle mass decline, increase visceral fat, decreased positive mood factors and an increased negative mood factors, anxiety, depression, decrease in fertility, decrease in libido and sexual function, impotence, amenorrhea, irregular menses, galactorrhea, increased risk for osteoporosis, increased pain sensitization, hematological abnormalities, decrease in cognitive skills, sleep disturbances, vasomotor instability, increase CAD risk, changes in secondary sex characteristic and decrease in circulating sex hormones, and combinations thereof. In some embodiments, the symptom of hypogonadism induced by a therapeutic agent that is reduced is selected from the group consisting of changes in secondary sex characteristic and decrease in circulating sex hormones. In some embodiments, the symptom of hypogonadism induced by a therapeutic agent that is reduced is decrease in circulating sex hormones. In some embodiments, the symptom of hypogonadism induced by a therapeutic agent that is reduced is decrease in circulating levels of testosterone

[00532| In some embodiments the symptom is at least partially a result of impairment of secretion of one or more hypothalamic-releasing hormone. Examples of hypothalamic-releasing hormone include corticotropin- releasing hormone (CRH), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, and thyrotropin-releasing hormone (TRH). In some embodiments the symptom is at least partially a result of impairment in hypothalamic response to one or more stimuli. Examples of stimuli include light, olfactory stimuli, steroids, neurally transmitted information, autonomic inputs, blood-borne stimuli, stress, changes in temperature and an invading microorganism. In some embodiments the symptom is at least partially a result of impairment in pituitary response to one or more hypothalamic-releasing hormones. In some embodiments, the symptom is at least partially a result of impairment of secretion of one or more pituitary hormones. In some embodiments the symptom is at least partially a result of impairment in a response of one or more endocrine glands to one or more pituitary hormones. Examples of pituitary hormones included ACTH, TSH, prolactin, growth hormone, endorphins, FSH, LH, oxytocin, and antidiuretic hormone (ADH). Examples of hormones whose release is caused by pituitary hormones include Cortisol from the adrenal cortex in response to ACTH, thyroxin from the thyroid gland in response to TSH, testosterone or estrogen from the gonads in response to FSH and LH.

[00533] In some embodiments, the invention provides compositions that contain a phosphorylated polyphenol, e.g., a phosphorylated flavonol, and a therapeutic agent, where the therapeutic agent is present in an amount sufficient to exert an therapeutic effect and the phosphorylated polyphenol, e.g., a phosphorylated flavonol is present in an amount sufficient to decrease or eliminate a symptom of hypergonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent by a measurable amount, compared to the symptom without the phosphorylated polyphenol, e.g., a phosphorylated flavonol 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%, as described herein. In some embodiments, the invention provides compositions that contain a flavonoid that is quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, or epicatechin, or a combination thereof, and a therapeutic agent that is an opiate, where the opiate is present in an amount sufficient to exert a therapeutic effect and the flavonol is present in an amount sufficient to decrease or eliminate a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate by a measurable amount, compared to the symptom without the flavonol 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%, as described herein.

[005341 In some embodiments, the invention provides compositions that contain a phosphorylated flavonol that is phosphorylated quercetin, phosphorylated isoquercetin, phosphorylated flavon, phosphorylated chrysin, phosphorylated apigenin, phosphorylated rhoifolin, phosphorylated diosmin, phosphorylated galangin, phosphorylated fisetin, phosphorylated morin, phosphorylated rutin, phosphorylated kaempferol, phosphorylated myricetin, phosphorylated taxifolin, phosphorylated naringenin, phosphorylated naringin, phosphorylated hesperetin, phosphorylated hesperidin, phosphorylated chalcone, phosphorylated phloretin, phosphorylated phlorizdin, phosphorylated genistein, phosphorylated biochanin A, phosphorylated catechin, or phosphorylated epicatechin, or a combination thereof, and a therapeutic agent that is an opiate, where the opiate is present in an amount sufficient to exert a therapeutic effect and the phosphorylated flavonol is present in an amount sufficient to decrease or eliminate a symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate by a measurable amount, compared to the symptom without the phosphorylated flavonol 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%, as described herein.

[00535| In some embodiments, the invention provides compositions that contain a flavonol that is quercetin, galangin, fisetin or kaempferol, or combination thereof, and a therapeutic agent that is an opiate, where the opiate is present in an amount sufficient to exert a therapeutic effect and the flavonol is present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate by a measurable amount, compared to symptom without the flavonol 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%, as described herein.

[00536| In some embodiments, the invention provides compositions that contain a phosphorylated flavonol that is phosphorylated quercetin, phosphorylated galangin, phosphorylated fisetin or phosphorylated kaempferol, or combination thereof, and a therapeutic agent that is an opiate, where the opiate is present in an amount sufficient to exert a therapeutic effect and the phosphorylated flavonol is present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary /endocrine function induced by the opiate by a measurable amount, compared to symptom without the phosphorylated flavonol 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%, as described herein. [00537] In some embodiments, the invention provides compositions that contain quercetin or a quercetin derivative and morphine where morphine is present in an amount sufficient to exert a therapeutic effect and quercetin or a quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by morphine by a measurable amount, compared to the symptom without quercetin or a quercetin derivative 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%, as described herein. |00538| In some embodiments, the invention provides compositions that contain phosphorylated quercetin or a phosphorylated quercetin derivative and morphine where morphine is present in an amount sufficient to exert a therapeutic effect and phosphorylated quercetin or a phosphorylated quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by morphine by a measurable amount, compared to the symptom without phosphorylated quercetin or a phosphorylated quercetin derivative 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%, as described herein. |00539| In some embodiments, the invention provides compositions that contain quercetin or a quercetin derivative and sufentanyl where sufentanyl is present in an amount sufficient to exert a therapeutic effect and quercetin or a quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by sufentanyl by a measurable amount, compared to the symptom without quercetin or a quercetin derivative 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%, as described herein.

[00540| In some embodiments, the invention provides compositions that contain phosphorylated quercetin or a phosphorylated quercetin derivative and sufentanyl where sufentanyl is present in an amount sufficient to exert a therapeutic effect and phosphorylated quercetin or a phosphorylated quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by sufentanyl by a measurable amount, compared to the symptom without phosphorylated quercetin or a phosphorylated quercetin derivative 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%, as described herein. [00541 ] In some embodiments, the invention provides compositions that contain quercetin or a quercetin derivative and alfentanyl where alfentanyl is present in an amount sufficient to exert a therapeutic effect and quercetin or a quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by alfentanyl by a measurable amount, compared to the symptom without quercetin or a quercetin derivative 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%, as described herein.

[00542] In some embodiments, the invention provides compositions that contain phosphorylated quercetin or a phosphorylated quercetin derivative and alfentanyl where alfentanyl is present in an amount sufficient to exert a therapeutic effect and phosphorylated quercetin or a phosphorylated quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by alfentanyl by a measurable amount, compared to the symptom without phosphorylated quercetin or a phosphorylated quercetin derivative 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%, as described herein. |00543| In some embodiments, the invention provides compositions that contain quercetin or a quercetin derivative and remifentanyl where remifentanyl is present in an amount sufficient to exert a therapeutic effect and quercetin or a quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by remifentanyl by a measurable amount, compared to the symptom without quercetin or a quercetin derivative 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%, as described herein.

|00544| In some embodiments, the invention provides compositions that contain phosphorylated quercetin or a phosphorylated quercetin derivative and remifentanyl where remifentanyl is present in an amount sufficient to exert a therapeutic effect and phosphorylated quercetin or a phosphorylated quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by remifentanyl by a measurable amount, compared to the symptom without phosphorylated quercetin or a phosphorylated quercetin derivative 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%, as described herein. (00545) In some embodiments, the invention provides compositions that contain quercetin or a quercetin derivative and oxycodone where oxycodone is present in an amount sufficient to exert a therapeutic effect and quercetin or a quercetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by oxycodone by a measurable amount, compared to the symptom without quercetin or a quercetin derivative 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%, as described herein.

[00546] In some embodiments, the invention provides compositions that contain quercetin or a quercetin derivative, or fisetin or a fisetin derivative, and an anti-hypertensive where the anti-hypertensive is present in an amount sufficient to exert a therapeutic effect and quercetin or a quercetin derivative, or fisetin or a fisetin derivative, is present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the anti-hypertensive by a measurable amount, compared to the symptom without quercetin or a quercetin derivative, or fisetin or a fisetin derivative, 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%, as described herein. [00547] In some embodiments, the invention provides compositions that contain phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative, and an anti-hypertensive where the anti-hypertensive is present in an amount sufficient to exert a therapeutic effect and phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative, is present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the anti-hypertensive by a measurable amount, compared to the symptom without phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative, 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%, as described herein.

[00548] In some embodiments, the invention provides compositions that contain fisetin or a fisetin derivative and an opiate where the opiate is present in an amount sufficient to exert a therapeutic effect and fisetin or a fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by the opiate by a measurable amount, compared to the symptom without the fisetin or a fisetin derivative 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%, as described herein. [00549| In some embodiments, the invention provides compositions that contain phosphorylated fisetin or a phosphorylated fisetin derivative and an opiate where the opiate is present in an amount sufficient to exert a therapeutic effect and phosphorylated fisetin or a phosphorylated fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by the opiate by a measurable amount, compared to the symptom without the phosphorylated fisetin or a phosphorylated fisetin derivative 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%, as described herein. |00550| In some embodiments, the invention provides compositions that contain fisetin or a fisetin derivative and morphine where morphine is present in an amount sufficient to exert a therapeutic effect and fisetin or a fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by morphine by a measurable amount, compared to the symptom without fisetin or a fisetin derivative 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%, as described herein. |005511 In some embodiments, the invention provides compositions that contain phosphorylated fisetin or a phosphorylated fisetin derivative and morphine where morphine is present in an amount sufficient to exert a therapeutic effect and phosphorylated fisetin or a phosphorylated fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by morphine by a measurable amount, compared to the symptom without phosphorylated fisetin or a phosphorylated fisetin derivative 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%, as described herein. |00552] In some embodiments, the invention provides compositions that contain fisetin or a fisetin derivative and sufentanyl where sufentanyl is present in an amount sufficient to exert a therapeutic effect and fisetin or a fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by sufentanyl by a measurable amount, compared to the symptom without fisetin or a fisetin derivative 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%, as described herein. |00553| In some embodiments, the invention provides compositions that contain phosphorylated fisetin or a phosphorylated fisetin derivative and sufentanyl where sufentanyl is present in an amount sufficient to exert a therapeutic effect and phosphorylated fisetin or a phosphorylated fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by sufentanyl by a measurable amount, compared to the symptom without phosphorylated fisetin or a phosphorylated fisetin derivative 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%, as described herein. |00554] In some embodiments, the invention provides compositions that contain fisetin or a fisetin derivative and alfentanyl where alfentanyl is present in an amount sufficient to exert a therapeutic effect and fisetin or a fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by alfentanyl by a measurable amount, compared to the symptom without fisetin or a fisetin derivative 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%, as described herein. [00555| In some embodiments, the invention provides compositions that contain phosphorylated fisetin or a phosphorylated fisetin derivative and alfentanyl where alfentanyl is present in an amount sufficient to exert a therapeutic effect and phosphorylated fisetin or a phosphorylated fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by alfentanyl by a measurable amount, compared to the symptom without phosphorylated fisetin or a phosphorylated fisetin derivative 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%, as described herein. |00556] In some embodiments, the invention provides compositions that contain fisetin or a fisetin derivative and remifentanyl where remifentanyl is present in an amount sufficient to exert a therapeutic effect and fisetin or a fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by remifentanyl by a measurable amount, compared to the symptom without fisetin or a fisetin derivative 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%, as described herein.

[00557] In some embodiments, the invention provides compositions that contain phosphorylated fisetin or a phosphorylated fisetin derivative and remifentanyl where remifentanyl is present in an amount sufficient to exert a therapeutic effect and phosphorylated fisetin or a phosphorylated fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by remifentanyl by a measurable amount, compared to the symptom without phosphorylated fisetin or a phosphorylated fisetin derivative 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%, as described herein. [00558] In some embodiments, the invention provides compositions that contain fisetin or a fisetin derivative and oxycodone where oxycodone is present in an amount sufficient to exert a therapeutic effect and fisetin or a fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by oxycodone by a measurable amount, compared to the symptom without fisetin or a fisetin derivative 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%, as described herein. [00559] In some embodiments, the invention provides compositions that contain phosphorylated fisetin or a phosphorylated fisetin derivative and oxycodone where oxycodone is present in an amount sufficient to exert a therapeutic effect and phosphorylated fisetin or a phosphorylated fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by oxycodone by a measurable amount, compared to the symptom without phosphorylated fisetin or a phosphorylated fisetin derivative 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%, as described herein. [00560] In some embodiments, the invention provides compositions that contain fisetin or a fisetin derivative and an anti-hypertensive where the anti-hypertensive is present in an amount sufficient to exert a therapeutic effect and fisetin or a fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by the anti-hypertensive by a measurable amount, compared to the symptom without fisetin or a fisetin derivative 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%, as described herein.

(005611 [n some embodiments, the invention provides compositions that contain phosphorylated fisetin or a phosphorylated fisetin derivative and an anti-hypertensive where the anti-hypertensive is present in an amount sufficient to exert a therapeutic effect and phosphorylated fisetin or a phosphorylated fisetin derivative is present in an amount sufficient to decrease one or more symptoms of hypogonadism induced by the anti-hypertensive by a measurable amount, compared to the symptom without phosphorylated fisetin or a phosphorylated fisetin derivative 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%, as described herein.

[005621 In some embodiments, the BTB transport protein modulator is present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent by a measurable amount and to increase a therapeutic effect of the therapeutic agent by a measurable amount, compared to the symptom and therapeutic effect without the BTB transport protein modulator, 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 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 BTB transport protein modulator.

[00563] In some embodiments, the phosphorylated BTB transport protein modulator is present in an amount sufficient to decre ase one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent by a measurable amount and to increase a therapeutic effect of the therapeutic agent by a measurable amount, compared to the symptom and therapeutic effect without the phosphorylated BTB transport protein modulator, 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 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 phosphorylated BTB transport protein modulator. [00564] Thus, in some embodiments, the invention provides compositions containing a BTB transport protein modulator present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50% compared to symptom and therapeutic effect without the BTB transport protein modulator, when the composition is administered to an animal in combination with the therapeutic agent. In some embodiments, the invention provides compositions containing a BTB transport protein modulator present in an amount sufficient to decrease a one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 10%, compared to the symptom and therapeutic effect without the BTB transport protein modulator, when the composition is administered to an animal in combination with the therapeutic agent. In some embodiments, the invention provides compositions containing a BTB transport protein modulator present in an amount sufficient to one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 20% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 20%, compared to the symptom and therapeutic effect without the BTB transport protein modulator, when the composition is administered to an animal in combination with the therapeutic agent. In some embodiments, the invention provides compositions containing a BTB transport protein modulator present in an amount sufficient to decrease a one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 20%, compared to the symptom and therapeutic effect without the BTB transport protein modulator, when the composition is administered to an animal in combination with the therapeutic agent. [00565| In some embodiments, the invention provides compositions containing a BTB transport protein modulator present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 30%, compared to the symptom and therapeutic effect without the BTB transport protein modulator, when the composition is administered to an animal in combination with the therapeutic agent. In some embodiments, the invention provides compositions containing a BTB transport protein modulator present in an amount sufficient to decrease one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 40%, compared to the symptom and therapeutic effect without the BTB transport protein modulator, when the composition is administered to an animal in combination with the therapeutic agent. In some embodiments, the invention provides compositions containing a BTB transport protein modulator present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 50%, compared to the symptom and therapeutic effect without the BTB transport protein modulator, when the composition is administered to an animal in combination with the therapeutic agent.

|00566] In some embodiments, the invention provides compositions containing a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50%, when the composition is administered to an animal in combination with the therapeutic agent, compared to symptom and therapeutic effect without the polyphenol, e.g., flavonol such as quercetin or a quercetin derivative, or fisetin or a fisetin derivative. In some embodiments, the invention provides compositions containing a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 10%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative. In some embodiments, the invention provides compositions containing a polyphenol, e.g., a flavonol such as quercetin or a quercetin, or a fisetin or a fisetin derivative, derivative present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 20% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 20%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or fisetin or a fisetin derivative. In some embodiments, the invention provides compositions containing a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 20%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative. In some embodiments, the invention provides compositions containing a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 30%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative. In some embodiments, the invention provides compositions containing a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 40%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative. In some embodiments, the invention provides compositions containing a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 50%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the a polyphenol, e.g., a flavonol such as quercetin or a quercetin derivative, or a fisetin or a fisetin derivative. |00567| In some embodiments, the invention provides compositions containing a phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or a phosphorylated fisetin or a phosphorylated fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 5%, at least about 7%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, at least about 20%, at least about 22%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50%when the composition is administered to an animal in combination with the therapeutic agent, compared to symptom and therapeutic effect without the polyphenol, e.g., phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or a phosphorylated fisetin or a phosphorylated fisetin derivative. In some embodiments, the invention provides compositions containing a phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or a phosphorylated fisetin or a phosphorylated fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 10%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative. In some embodiments, the invention provides compositions containing a phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or aphosphorylated quercetin, or phosphorylated fisetin or a phosphorylated fisetin derivative, derivative present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 20% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 20%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or a phosphorylated fisetin or a phosphorylated fisetin derivative. In some embodiments, the invention provides compositions containing a phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or a phosphorylated fisetin or a phosphorylated fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 20%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or a phosphorylated fisetin or a phosphorylated fisetin derivative. In some embodiments, the invention provides compositions containing a phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 30%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or a phosphorylated fisetin or a phosphorylated fisetin derivative. In some embodiments, the invention provides compositions containing a phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 40%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative. In some embodiments, the invention provides compositions containing a phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative, present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary /endocrine function induced by a therapeutic agent by an average of at least about 10% and to increase a therapeutic effect of the therapeutic agent by an average of at least about 50%, when the composition is administered to an animal in combination with the therapeutic agent, compared to the symptom and therapeutic effect when the therapeutic agent is administered without the phosphorylated polyphenol, e.g., a phosphorylated flavonol such as phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative. [00568] In exemplary embodiments, the invention provides a composition that contains a polyphenol that is quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, or epicatechin, or combinations thereof, and a therapeutic agent, such as an opiate, where the therapeutic agent is present in an amount sufficient to exert a therapeutic effect, and the polyphenol is present in an amount effective to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent by a measurable amount (e.g., 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) and to increase the therapeutic effect of the therapeutic agent by a measurable amount (e.g., 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).

(00569| In other embodiments, the invention provides a composition that contains a phosphorylated polyphenol that is phosphorylated quercetin, phosphorylated isoquercetin, phosphorylated flavon, phosphorylated chrysin, phosphorylated apigenin, phosphorylated rhoifolin, phosphorylated diosmin, phosphorylated galangin, phosphorylated fisetin, phosphorylated morin, phosphorylated rutin, phosphorylated kaempferol, phosphorylated myricetin, phosphorylated taxifolin, phosphorylated naringenin, phosphorylated naringin, phosphorylated hesperetin, phosphorylated hesperidin, phosphorylated chalcone, phosphorylated phloretin, phosphorylated phlorizdin, phosphorylated genistein, phosphorylated biochanin A, phosphorylated catechin, or phosphorylated epicatechin, or combinations thereof, and a therapeutic agent, such as an opiate, where the therapeutic agent is present in an amount sufficient to exert a therapeutic effect, and the polyphenol is present in an amount effective to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent by a measurable amount (e.g., 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) and to increase the therapeutic effect of the therapeutic agent by a measurable amount (e.g., 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). [00570| In another exemplary embodiments, the invention provides a composition that contains quercetin or a quercetin derivative, or fisetin or a fisetin derivative and an opiate, where the opiate is present in an amount sufficient to exert a therapeutic effect, and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in an amount effective to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate by a measurable amount (e.g., 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) and to increase the therapeutic effect of the opiate by a measurable amount (e.g., 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).

In another exemplary embodiments, the invention provides a composition that contains phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative, and an opiate, where the opiate is present in an amount sufficient to exert a therapeutic effect, and phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or phosphorylated fisetin derivative, is present in an amount effective to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate by a measurable amount (e.g., 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) and to increase the therapeutic effect of the opiate by a measurable amount (e.g., 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).

[005711 In another exemplary embodiments, the invention provides a composition that contains quercetin or a quercetin derivative, or fisetin or a fisetin derivative, and morphine, where morphine is present in an amount sufficient to exert a therapeutic effect, and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in an amount effective to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by morphine by a measurable amount (e.g., 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) and to increase the therapeutic effect of the opiate by a measurable amount (e.g., 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).

[00572| In another exemplary embodiments, the invention provides a composition that contains phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or a phosphorylated fisetin derivative, and morphine, where morphine is present in an amount sufficient to exert a therapeutic effect, and phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or phosphorylated fisetin derivative, is present in an amount effective to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by morphine by a measurable amount (e.g., 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) and to increase the therapeutic effect of the opiate by a measurable amount (e.g., 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).

(00573| 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.

100574] In some embodiments, the invention provides a composition that contains a therapeutic agent and a BTB transport protein modulator, e.g. a pyrone analog, including a polyphenol such as a flavonoid. In some embodiments, the concentration of one or more of the therapeutic agents and/or BTB transport protein modulator, e.g. a polyphenol such as a flavonol is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 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.

|00575J In some embodiments, the invention provides a composition that contains a therapeutic agent and a phosphorylated BTB transport protein modulator, e.g. a phosphorylated pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonoid. In some embodiments, the concentration of one or more of the therapeutic agents and/or BTB transport protein modulator, e.g. a polyphenol such as a flavonol is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 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.

[005761 In some embodiments, the concentration of one or more of the therapeutic agents and/or BTB transport protein modulator, e.g. a pyrone analog, including a polyphenol such as a flavonoid 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%, 1 1.75%, 1 1.50%, 1 1.25% 1 1%, 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.

|00577) In some embodiments, the concentration of one or more of the therapeutic agents and/or phosphorylated BTB transport protein modulator, e.g. a phosphorylated pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonoid 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%, 1 1.75%, 1 1.50%, 1 1.25% 1 1%, 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.

|00578| In some embodiments, the concentration of one or more of the therapeutic agents and/or BTB transport protein modulator, e.g. a pyrone analog, including a polyphenol such as a flavonoid 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.

[00579] In some embodiments, the concentration of one or more of the therapeutic agents and/or phosphorylated BTB transport protein modulator, e.g. a phosphorylated pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonoid 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/vv, w/v or v/v.

J00580| flavonoid 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. 1005811 In some embodiments, the amount of one or more of the therapeutic agents and/or BTB transport protein modulator, e.g. a pyrone analog, including a polyphenol such as a flavonoid 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.

1005821 In some embodiments, the amount of one or more of the therapeutic agents and/or phosphorylated BTB transport protein modulator, e.g. a phosphorylated pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonoid is equal to or less than 1 O 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.

[00583| In some embodiments, the amount of one or more of the therapeutic agents and/or BTB transport protein modulator, e.g. a pyrone analog, including a polyphenol such as a flavonoid 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 .

[00584] In some embodiments, the amount of one or more of the therapeutic agents and/or phosphorylated BTB transport protein modulator, e.g. a phosphorylated pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonoid 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 . [00585| In some embodiments, the amount of one or more of the therapeutic agents and/or BTB transport protein modulator, e.g. a pyrone analog, including a polyphenol such as a flavonoid 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. 1005861 In some embodiments, the amount of one or more of the therapeutic agents and/or phosphorylated BTB transport protein modulator, e.g. a phosphorylated pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonoid 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 l -3 g.

|00587| In exemplary embodiments, compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and morphine, where quercetin or a quercetin derivative, or fϊsetin or fisetin derivative, is present in an amount from about 1- 1000 mg, or about 10-1000 mg, or about 50-1000 mg, or about 100-1000 mg, or about 1-500 mg, or about 5-500 mg, or about 50-500 mg, or about 100-500 mg, or about 200- 1000 mg, or about 200-800 mg, or about 200-700 mg, or about 10 mg, or about 25 mg, or about 50 mg, or about 100 mg, or about 200 mg, or about 250 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, and morphine is present in an amount from 1 to 1000 mg, or about 5-500 mg, or about 10, 15, 30, 50, 60, 80, 100, 120, 150, 180, 200, 300 or 400 mg. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol. |00588] In some embodiments, morphine/quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 0.1/50 mg (morphine/quercetin or a quercetin derivative, or morphine/fisetin or fisetin derivative,). In some embodiments, morphine is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, morphine is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, morphine is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, morphine is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, morphine is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, morphine is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 250 mg. In some embodiments, morphine is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 500 mg. In some embodiments, morphine is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, morphine is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, morphine is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 250 mg. In some embodiments, morphine is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 500 mg. In some embodiments, morphine is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, morphine is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, morphine is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, morphine is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, morphine is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, morphine is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, morphine is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, morphine is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, morphine is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, moφhine is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, morphine is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, morphine is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, morphine is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, morphine is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, morphine is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, morphine is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, morphine is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, morphine is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, morphine is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, morphine is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, morphine is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol.

|00589] In liquid preparations, morphine can be present at about 0.01 -1000 mg/ml, or 0.5-100 mg/ml, or 0.5-50 mg/ml, or about 0.5, 1, 5, 15, 20, 30 or 40 mg/ml and quercetin or a quercetin derivative, or fisetin or fisetin derivative, at about 1-1000 mg/ml, or about 10-1000 mg/ml, or about 50-1000 mg/ml, or about 100-1000 mg/ml, or about 1-500 mg/ml, or about 5-500 mg/ml, or about 50-500 mg/ml, or about 100-500 mg/ml, or about 200- 1000 mg/ml, or about 200-800 mg/ml, or about 200-700 mg/ml, or about 10 mg/ml, or about 25 mg/ml, or about 50 mg/ml, or about 100 mg/ml, or about 200 mg/ml, or about 250 mg/ml, or about 300 mg/ml, or about 400 mg/ml, or about 500 mg/ml, or about 600 mg/ml, or about 700 mg/ml, or about 800 mg/ml, or about 900 mg/ml, or about 1000 mg/ml At higher levels of quercetin or a quercetin derivative, solubility can be enhanced by adjusting the type of diluent. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol. [00590| In exemplary embodiments, compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and sufentanyl, where quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in an amount from about 1-1000 mg, or about 10-1000 mg, or about 50-1000 mg, or about 100-1000 mg, or about 1-500 mg, or about 5-500 mg, or about 50-500 mg, or about 100-500 mg, or about 200- 1000 mg, or about 200-800 mg, or about 200-700 mg, or about 10 mg, or about 25 mg, or about 50 mg, or about 100 mg, or about 200 mg, or about 250 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, and sufentanyl is present in an amount from 1 to 1000 mg, or about 5-500 mg, or about 10, 15, 30, 50, 60, 80, 100, 120, 150, 180, 200, 300 or 400 mg. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol. [005911 In some embodiments, sufentanyl /quercetin or a quercetin derivative, or sulfetanyl/fϊsetin or fisetin derivative, is present at about 0.1/50 mg (sufentanyl/quercetin or a quercetin derivative, or sulfetanyl/fisetin or fisetin derivative). In some embodiments, sufentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, sufentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, sufentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, sufentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, sufentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, sufentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 250 mg. In some embodiments, sufentanyl is present at about 15 mg and quercetin or a quercetin derivative is present at about 500 mg. In some embodiments, sufentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, sufentanyl is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, sufentanyl is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 250 mg. In some embodiments, sufentanyl is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 500 mg. In some embodiments, sufentanyl is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, sufentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, sufentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, sufentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, sufentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, sufentanyl is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, sufentanyl is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, sufentanyl is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, sufentanyl is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, sufentanyl is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, sufentanyl is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, sufentanyl is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, sufentanyl is present at about 80 mg and quercetin or a quercetin derivative is present at about 1000 mg. In some embodiments, sufentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, sufentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, sufentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, sufentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, sufentanyl is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, sufentanyl is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, sufentanyl is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, sufentanyl is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol.

[00592J In liquid preparations, sufentanyl can be present at about 0.01-1000 mg/ml, or 0.05-500 mg/ml, or 0.05- 10 mg/ml, or about 0.01, 0.05, 1, or 10 mg/ml and quercetin or a quercetin derivative, or fisetin or fisetin derivative, at about 1-1000 mg/ml, or about 10-1000 mg/ml, or about 50-1000 mg/ml, or about 100-1000 mg/ml, or about 1-500 mg/ml, or about 5-500 mg/ml, or about 50-500 mg/ml, or about 100-500 mg/ml, or about 200- 1000 mg/ml, or about 200-800 mg/ml, or about 200-700 mg/ml, or about 10 mg/ml, or about 25 mg/ml, or about 50 mg/ml, or about 100 mg/ml, or about 200 mg/ml, or about 250 mg/ml, or about 300 mg/ml, or about 400 mg/ml, or about 500 mg/ml, or about 600 mg/ml, or about 700 mg/ml, or about 800 mg/ml, or about 900 mg/ml, or about 1000 mg/ml At higher levels of quercetin or a quercetin derivative, , or fisetin or fisetin derivative, solubility can be enhanced by adjusting the type of diluent. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol.

|00593| In exemplary embodiments, compositions of the invention include quercetin or a quercetin derivative and alfentanyl, where quercetin or a quercetin derivative is present in an amount from about 1-1000 mg, or about 10-1000 mg, or about 50-1000 mg, or about 100-1000 mg, or about 1-500 mg, or about 5-500 mg, or about 50- 500 mg, or about 100-500 mg, or about 200-1000 mg, or about 200-800 mg, or about 200-700 mg, or about 10 mg, or about 25 mg, or about 50 mg, or about 100 mg, or about 200 mg, or about 250 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, and alfentanyl is present in an amount from 1 to 1000 mg, or about 5-500 mg, or about 10, 15, 30, 50, 60, 80, 100, 120, 150, 180, 200, 300 or 400 mg. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative and a cyclodextrin such as captisol.

[00594| In some embodiments, alfentanyl /quercetin or a quercetin derivative, or fisetin or fϊsetin derivative, is present at about 0.1/50 mg (alfentanyl /quercetin or a quercetin derivative, or alfentanyl/fisetin or fisetin derivative). In some embodiments, alfentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, alfentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, alfentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, alfentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, alfentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, alfentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 250 mg. In some embodiments, alfentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 500 mg. In some embodiments, alfentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, alfentanyl is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, alfentanyl is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 250 mg. In some embodiments, alfentanyl is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 500 mg. In some embodiments, alfentanyl is present at about 30 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, alfentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, alfentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, alfentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, alfentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, alfentanyl is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, alfentanyl is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, alfentanyl is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, alfentanyl is present at about 60 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, alfentanyl is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, alfentanyl is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, alfentanyl is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, alfentanyl is present at about 80 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, alfentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, alfentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, alfentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, alfentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, alfentanyl is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, alfentanyl is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, alfentanyl is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, alfentanyl is present at about 200 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol.

|00595| In liquid preparations, alfentanyl can be present at about 0.01-1000 mg/ml, or 0.5-500 mg/ml, or 0.5-30 mg/ml, or about 0.01, 0.5, 1, 5, 10, 15, or 20 mg/ml and quercetin or a quercetin derivative, or fisetin or fisetin derivative, at about 1-1000 mg/ml, or about 10-1000 mg/ml, or about 50-1000 mg/ml, or about 100-1000 mg/ml, or about 1-500 mg/ml, or about 5-500 mg/ml, or about 50-500 mg/ml, or about 100-500 mg/ml, or about 200- 1000 mg/ml, or about 200-800 mg/ml, or about 200-700 mg/ml, or about 10 mg/ml, or about 25 mg/ml, or about 50 mg/ml, or about 100 mg/ml, or about 200 mg/ml, or about 250 mg/ml, or about 300 mg/ml, or about 400 mg/ml, or about 500 mg/ml, or about 600 mg/ml, or about 700 mg/ml, or about 800 mg/ml, or about 900 mg/ml, or about 1000 mg/ml At higher levels of quercetin or a quercetin derivative, or fisetin or fisetin derivative, solubility can be enhanced by adjusting the type of diluent. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol.

[00596| In exemplary embodiments, compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and remifentanyl, where quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in an amount from about 1-1000 mg, or about 10-1000 mg, or about 50- 1000 mg, or about 100-1000 mg, or about 1-500 mg, or about 5-500 mg, or about 50-500 mg, or about 100-500 mg, or about 200- 1000 mg, or about 200-800 mg, or about 200-700 mg, or about 10 mg, or about 25 mg, or about 50 mg, or about 100 mg, or about 200 mg, or about 250 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, and remifentanyl is present in an amount from 1 to 1000 mg, or about 5-500 mg, or about 1 , 2, 5, 10, 15, 30, 50, 60, 80, 100, 120, 150, 180, 200, 300 or 400 mg. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol.

(00597| In some embodiments, remifentanyl /quercetin or a quercetin derivative, or remifentanyl/fisetin or fisetin derivative, is present at about 0.1/50 mg (remifentanyl /quercetin or a quercetin derivative, or remifentanyl/fisetin or fisetin derivative,). In some embodiments, remifentanyl is present at about 1 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, remifentanyl is present at about 1 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, remifentanyl is present at about 1 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, remifentanyl is present at about 1 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, remifentanyl is present at about 2 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, remifentanyl is present at about 2 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 250 mg. In some embodiments, remifentanyl is present at about 2 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 500 mg. In some embodiments, remifentanyl is present at about 2 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, remifentanyl is present at about 5 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, remifentanyl is present at about 5 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 250 mg. In some embodiments, remifentanyl is present at about 5 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 500 mg. In some embodiments, remifentanyl is present at about 5 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, remifentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, remifentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, remifentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, remifentanyl is present at about 10 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, remifentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, remifentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, remifentanyl is present at about 15 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, remifentanyl is present at about 15 mg and quercetin or a quercetin derivative is present at about 1000 mg. In some embodiments, remifentanyl is present at about 20 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, remifentanyl is present at about 20 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, remifentanyl is present at about 20 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, remifentanyl is present at about 20 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, remifentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, remifentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, remifentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, remifentanyl is present at about 50 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, remifentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 100 mg. In some embodiments, remifentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 200 mg. In some embodiments, remifentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 300 mg. In some embodiments, remifentanyl is present at about 100 mg and quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present at about 1000 mg. In some embodiments, the quercetin is in the form of quercetin phosphate. In some embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol.

|00598] In liquid preparations, remifentanyl can be present at about 0.01-1000 mg/ml, or 0.5-100 mg/ml, or 0.5- 50 mg/ml, or about 0.5, 1, 5, 15, 20, 30 or 40 mg/ml and quercetin or a quercetin derivative, or fisetin or fisetin derivative, at about 1-1000 mg/ml, or about 10-1000 mg/ml, or about 50-1000 mg/ml, or about 100-1000 mg/ml, or about 1-500 mg/ml, or about 5-500 mg/ml, or about 50-500 mg/ml, or about 100-500 mg/ml, or about 200- 1000 mg/ml, or about 200-800 mg/ml, or about 200-700 mg/ml, or about 10 mg/ml, or about 25 mg/ml, or about 50 mg/ml, or about 100 mg/ml, or about 200 mg/ml, or about 250 mg/ml, or about 300 mg/ml, or about 400 mg/ml, or about 500 mg/ml, or about 600 mg/ml, or about 700 mg/ml, or about 800 mg/ml, or about 900 mg/ml, or about 1000 mg/ml At higher levels of quercetin or a quercetin derivative, or fisetin or fisetin derivative,solubility can be enhanced by adjusting the type of diluent. In some embodiments, the quercetin is in the form of quercetin phosphate. In some of the embodiments, the fisetin is in the form of fisetin phosphate. In some embodiments, the compositions of the invention include quercetin or a quercetin derivative, or fisetin or fisetin derivative, and a cyclodextrin such as captisol.

|00599] In some embodiments, a molar ratio of one or more of the therapeutic agents to the BTB transport protein modulator, e.g. a pyrone analog, including apolyphenol such as a flavonoid 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 BTB transport protein modulator, e.g. a polyphenol such as a flavonoid 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.

|00600] In some embodiments, a molar ratio of one or more of the therapeutic agents to the phosphorylated BTB transport protein modulator, e.g. a phosphorylated pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonoid 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 BTB transport protein modulator, e.g. a polyphenol such as a flavonoid 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. |006011 Without limiting the scope of the present invention, the molar ratio of one or more of the therapeutic agents to the flavonoid can be about 0.03x10-5:1, 0.1x10-5:1, 0.04x10-3:1, 0.03x10-5:1, 0.02x10-5:1, 0.01x10- 3:1, 0.1x10-3:1, 0.15x10-3:1, 0.2x10-3:1, 0.3x10-3:1, 0.4x10-3:1, 0.5x10-3:1, 0.15x10-2:1, 0.1x10-2:1, 0.2x10- 2:1, 0.3x10-2:1, 0.4x10-2:1, 0.5x10-2:1, 0.6x10-2:1, 0.8x10-2:1, 0.01:1, 0.1:1; or0.2:l per dose. In one embodiment, the therapeutic agent is an opiate. In one embodiment, the flavonoid is quercetin or a quercetin derivative. In one embodiment, the flavonoid is a fisetin or a fisetin derivative.

[ 006021 Without limiting the scope of the present invention, the molar ratio of one or more of the therapeutic agents to the phosphorylated flavonoid can be about 0.03x10-5:1, 0.1x10-5:1, 0.04x10-3:1, 0.03x10-5:1, 0.02x10-5:1, 0.01x10-3:1, 0.1x10-3:1, 0.15x10-3:1, 0.2x10-3:1, 0.3x10-3:1, 0.4x10-3:1, 0.5x10-3:1, 0.15x10- 2:1, 0.1x10-2:1, 0.2x10-2:1, 0.3x10-2:1, 0.4x10-2:1, 0.5x10-2:1, 0.6x10-2:1, 0.8x10-2:1, 0.01:1, 0.1:1; or 0.2:1 per dose. In one embodiment, the therapeutic agent is an opiate. In one embodiment, the phosphorylated flavonoid is phosphorylated quercetin or a phosphorylated quercetin derivative. In one embodiment, the phosphorylated flavonoid is a phosphorylated fisetin or a fphosphorylated isetin derivative. 1006031 Without limiting the scope of the present invention, the molar ratio of one or more of the therapeutic agents to the BTB transport protein modulator, e.g. a pyrone analog, including a polyphenol such as a flavonoid can be about 0.001:1, 0.002:1, 0.003:1, 0.004:1, 0.005:1, 0.006:1, 0.007:1, 0.008:1, 0.009:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 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 per dose. In one embodiment, the therapeutic agent is an opiate. In one embodiment, the flavonoid is quercetin or a quercetin derivative. In one embodiment, the flavonoid is a fisetin or a fisetin derivative.

1006041 Without limiting the scope of the present invention, the molar ratio of one or more of the therapeutic agents to the phosphorylated BTB transport protein modulator, e.g. a phosphorylated pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonoid can be about 0.001:1, 0.002:1, 0.003:1, 0.004:1, 0.005:1, 0.006:1, 0.007:1, 0.008:1, 0.009:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 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 per dose. In one embodiment, the therapeutic agent is an opiate. In one embodiment, the phosphorylated flavonoid is phosphorylated quercetin or a phosphorylated quercetin derivative. In one embodiment, the phosphorylated flavonoid is a phosphorylated fisetin or a phosphorylated fisetin derivative.

A. Pharmaceutical Compositions

1006051 The transport protein modulators of the invention are usually administered in the form of pharmaceutical compositions. The drugs described above are also administered in the form of pharmaceutical compositions. When the transport protein modulators and the drugs 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.

[00606| This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, a BTB transport protein modulator 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. |00607| This invention further provides pharmaceutical compositions that contain, as the active ingredient, a BTB transport protein modulator or a pharmaceutically acceptable salt and/or coordination complex thereof, 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. [00608| The BBB transport protein modulator and/or the therapeutic agent may be prepared into pharmaceutical compositions in dosages as described herein (see, e.g., Compositions). Such compositions are prepared in a manner well known in the pharmaceutical art.

|00609) Pharmaceutical compositions for oral administration In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a combination of a therapeutic agent and an agent that decreases one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent, and a pharmaceutical excipient suitable for oral administration. In some embodiments, the agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is a BTB transport protein modulator, e.g. a pyrone analog, including a polyphenol such as a flavonol, as described elsewhere herein. In some embodiments, the agent that reduces or eliminates one or more symptoms of impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is a phosphorylated BTB transport protein modulator, e.g. a phosphoryalted pyrone analog, including a phosphorylated polyphenol such as a phosphorylated flavonol, as described elsewhere herein.

[00610] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing:

(i) an effective amount of a therapeutic agent;

(ii) an effective amount of an agent capable of reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent; and

(iii) a pharmaceutical excipient suitable for oral administration.

|006111 In some embodiments, the composition further contains: (iv) an effective amount of a second therapeutic agent.

[00612) In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.

(00613] In some embodiments, the therapeutic agent is an opiate. In some embodiments, the therapeutic agent is an antihypertensive. In some embodiments, the agent capable of reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is a BTB transport protein modulator, e.g., a BTB transport protein activator. In some embodiments, the agent capable of reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is a pyrone analog, including a polyphenol, e.g., a flavonoid such as a flavonol. In some embodiments, the agent capable of reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent is a phosphorylated pyrone analog, including a phosphorylated polyphenol, e.g., a phosphorylated flavonoid such as a phosphorylated flavonol. |00614| In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing:

(i) an effective amount of a therapeutic agent that is an opiate or anti-hypertensive; (ii) an effective amount of a pyrone analog, including a polyphenol that is quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, or epicatechin; and (iii) a pharmaceutical excipient suitable for oral administration.

|00615] In some embodiments, the composition further contains (iv) an effective amount of a second therapeutic agent.

|006I6| In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing:

(i) an effective amount of a therapeutic agent that is an opiate or anti-hypertensive; (ii) an effective amount of a phosphorylated pyrone analog, including a phosphorylated polyphenol that is phosphorylated quercetin, phosphorylated isoquercetin, phosphorylated flavon, phosphorylated chrysin, phosphorylated apigenin, phosphorylated rhoifolin, phosphorylated diosmin, phosphorylated galangin, phosphorylated fisetin, phosphorylated morin, phosphorylated rutin, phosphorylated kaempferol, phosphorylated myricetin, phosphorylated taxifolin, phosphorylated naringenin, phosphorylated naringin, phosphorylated hesperetin, phosphorylated hesperidin, phosphorylated chalcone, phosphorylated phloretin, phosphorylated phlorizdin, phosphorylated genistein, phosphorylated biochanin A, phosphorylated catechin, or phosphorylated epicatechin; and

[00617] (iii) a pharmaceutical excipient suitable for oral administration.

(00618) In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.

|00619] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing:

(i) an effective amount of a therapeutic agent that is an opiate or anti-hypertensive;

(ii) an effective amount of a pyrone analog, including a polyphenol that is quercetin, galangin, fisetin or kaempferol; and

(iii) a pharmaceutical excipient suitable for oral administration.

(00620] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing:

(i) an effective amount of a therapeutic agent that is an opiate or anti-hypertensive; (ii) an effective amount of a phosphorylated pyrone analog, including a phosphorylated polyphenol that is phosphorylated quercetin, phosphorylated galangin, phosphorylated fisetin or phosphorylated kaempferol; and

|006211 (iii) a pharmaceutical excipient suitable for oral administration.

J00622J In some embodiments, the composition further contains (iv) an effective amount of a second therapeutic agent. [00623| In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.

(00624 J In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing an effective amount of an opiate, an amount of quercetin or a quercetin derivative, or fisetin or fisetin derivative, that is effective in reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate, and a pharmaceutically acceptable excipient. In some embodiments, the invention provides a liquid pharmaceutical composition for oral administration containing an effective amount of an opiate, an amount of quercetin or a quercetin derivative, or fisetin or fisetin derivative, that is effective in reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate, and a pharmaceutically acceptable excipient.

[00625| In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing an effective amount of an opiate, an amount of phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or phosphorylated fisetin derivative, that is effective in reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate, and a pharmaceutically acceptable excipient. In some embodiments, the invention provides a liquid pharmaceutical composition for oral administration containing an effective amount of an opiate, an amount of phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or phosphorylated fisetin derivative, that is effective in reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the opiate, and a pharmaceutically acceptable excipient. [00626] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing an opiate at about 0.5- 300 mg, quercetin or a quercetin derivative, or fisetin or fisetin derivative, at about 10-1000 mg and a pharmaceutically acceptable excipient. In some embodiments, the invention provides a liquid pharmaceutical composition for oral administration containing an opiate at about 0.01- 100 mg/ml, quercetin or a quercetin derivative, or fisetin or fisetin derivative, at about 10-1000 mg/ml and a pharmaceutically acceptable excipient.

[00627) In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing an opiate at about 0.5- 300 mg, phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or phosphorylated fisetin derivative, at about 10-1000 mg and a pharmaceutically acceptable excipient. In some embodiments, the invention provides a liquid pharmaceutical composition for oral administration containing an opiate at about 0.01- 100 mg/ml, phosphorylated quercetin or a phosphorylated quercetin derivative, or phosphorylated fisetin or phosphorylated fisetin derivative, at about 10-1000 mg/ml and a pharmaceutically acceptable excipient.

[00628| 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. |00629) This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. 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.

|00630] 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.

|006311 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.

1006321 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. |00633] 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.

1006341 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. |00635| 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.

[00636| 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. [00637] The tablet can be prepared for immediate-relase. For example, the tablet can be an erodible tablet. A solubilizer, such as captisol when compressed, that erodes rather than disintegrates can be mixed with the active ingredient to form the erodible tablet. Formulation for oral use can also be present as a hard gelatin capsule using suboptimal lyophilization process.

[00638] 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. [00639| 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. [00640| 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.

|006411 Within the aforementioned group, preferred ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, 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.

1006421 Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof. [00643| Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide. [00644| Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG- 40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl- 1 Ooleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers. 1006451 Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

(00646| In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the therapeutic agent and/or BTB transport protein modulator (e.g., flavonol) and to minimize precipitation of the therapeutic agent and/or BTB transport protein modulator (e.g., flavonol). 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.

(00647] Cyclodextrins and their derivatives can be used to enhance the aqueous solubility of hydrophobic compounds. Cyclodextrins are cyclic carbohydrates derived from starch. The unmodified cyclodextrins differ by the number of glucopyranose units joined together in the cylindrical structure. The parent cyclodextrins typically contain 6, 7, or 8 glucopyranose units and are referred to as alpha-, beta-, and gamma-cyclodextrin respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3-positions and a primary hydroxyl group at the 6-position. The cyclodextrins may be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities can incorporate hydrophobic organic compounds, which can fit all, or part of their structure into these cavities. This process, sometimes referred to as inclusion complexation, may result in increased apparent aqueous solubility and stability for the complexed drug. The complex is stabilized by hydrophobic interactions and does not generally involve the formation of any covalent bonds. 1006481 Cyclodextrins can be derivatized to improve their properties. Cyclodextrin derivatives that are particularly useful for pharmaceutical applications include the hydroxypropyl derivatives of alpha-, beta- and gamma-cyclodextrin, sulfoalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin, alkylated cyclodextrins such as the randomly methylated beta.-cyclodextrin, and various branched cyclodextrins such as glucosyl- and maltosyl-beta.-cyclodextrin. Chemical modification of the parent cyclodextrins (usually at the hydroxyl moieties) has resulted in derivatives with sometimes improved safety while retaining or improving the complexation ability of the cyclodextrin. The chemical modifications, such as sulfoalkyl ether and hydroxypropyl, can result in rendering the cyclodextrins amorphous rather than crystalline, leading to improved solubility.

[00649] Particularly useful cyclodextrin for the present invention are the sulfoalkyl ether derivatives. The sulfoalkyl ether -CDs are a class of negatively charged cyclodextrins, which vary in the nature of the alkyl spacer, the salt form, the degree of substitution and the starting parent cyclodextrin. A particularly useful form of cyclodextrin is sulfobutylether-7-β-cyclodextrin, which is available under the trade name Captisol (TM) form CyDex, Inc. which has an average of about 7 substituents per cyclodextrin molecule. The anionic sulfobutyl ether substituents improve the aqueous solubility of the parent cyclodextrin. Reversible, non-covalent, complexation of flavonoids with the sulfobutylether-7-β-cyclodextrin cyclodextrin can provide for increased solubility and stability in aqueous solutions. Examples of formulations utilizing cyclodextrin are provided in US Appn. No. 60/953,186, filed 31 -Jul-2007, entitled: Soluble Flavonoid Methods and Pharmaceutical Compositions.

[00650| Methods for making aqueous solutions of flavonoids and cyclodextrins are provided that involve mixing the flavonoids and cyclodextrins at high pH, then subsequently reducing the pH. The methods disclosed provide a route to make high-concentration aqueous compositions comprising flavonoids and cyclodextrins, for example, comprising sulfobutylether-7-β-cyclodextrin. The compositions can be used as made, or can be further processed, for example by freeze-drying to create a powder composition. These compositions can be used as pharmaceutical compositions to be administered in a variety of ways, for example, intravenously or orally. The ability to have high concentration solutions of these compositions is useful both for the practical processing and manufacturing of pharmaceuticals based on these compositions, and for administering the compositions, where the solubility can be related to bioavailability of the compositions.

[006511 In some embodiments, the high solubility aqueous solutions of the invention are stable over time. The stability of the solutions allows them to be stored in some cases for days, weeks or months in liquid form. As used herein, stability with respect to solubility refers to stability with respect to precipitation from solution. [006521 The flavonoid-sulfoalkyl ether compositions disclosed herein are useful as compositions and method for co-administration with therapeutic agents, and analgesic agents. The compositions, for example, can be coadministered with therapeutic agents to enhance the effectiveness of the therapeutic agent. For example, a sulfobutylether-7-β-cyclodextrin-quercetin aqueous composition, or a sulfobutylether-7-β-cyclodextrin-quercetin derivative aqueous composition disclosed herein can reduce or eliminate hypogonadism. |006531 In some embodiments, a method of making aqueous flavonoid solutions is disclosed comprising mixing a cyclodextrin and the flavonoid at a pH greater than about 1 1 and subsequently lowering the pH to less than about 9. In some cases, the method allows for the preparation of aqueous solutions with high concentrations of flavonoid. In some cases, the method allows for the production of aqueous compositions with high concentrations of flavonoids.

1006541 In some embodiments, method for forming an aqueous composition is disclosed comprising a flavonoid comprising: (a) dissolving cyclodextrin in an aqueous solution; (b) adding the flavonoid to the aqueous solution; (c) raising the pH of the aqueous solution to above about pH 1 1 while mixing the cyclodextrin and flavonoid; and (d) lowering the pH of the aqueous solution to below about pH 9.

[00655| In some embodiments, the pH is raised to greater than about pH 1 1. For example, the pH can be raised to above about 1 1, 1 1.2, 1 1.4, 1 1.6, 1 1.8, 12, 12.2, 12.4, 12.6, 12.8, 13, 13.2, 13.4 or above pH 13.4. In general, the pH is raised to bring the flavonoid into solution. In some embodiments the pH is raised to bring as much of the flavonoid into solution as possible without causing significant degradation of the flavonoid. In some embodiments substantially all of the flavonoid is dissolved into solution at the high pH. 100656] In some embodiments, after raising the pH to above pH 1 1 , the pH of the solution is lowered below pH 9. In some embodiments the pH is lowered to below about 8.8, 8.6, 8.5, 8.4, 8.2, 7.8, 7.6, 7.4, 7.2, 7.0, 6.8, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, or less than pH 3. In general, after raising the pH, the pH is lowered to the level at which the aqueous composition will be used or stored. Where the composition is to be used as a pharmaceutical, the pH is lowered to a biologically acceptable pH, usually near neutral pH. In some embodiments, the pH is lowered to between 6 and 9, between 6.5 and 8.5, between about 7.2 and 8.4, between about 7.6 and 8.0, or about pH 7.8.

[00657| Some flavonoids are known to be unstable and to degrade in basic solution. For instance, Zheng, et al. J. Pharm. Sci. 94(5), 2005 teaches that while quercetin is stable below pH 3, degradation of quercetin above pH 5 became apparent (see page 1084). Thus, complexation in aqueous solutions between flavonoids and cyclodextrins has generally been carried out at or below neutral pH. For instance, Zheng et al. mix excess quercetin with various cyclodextrins in phosphate buffer at pH 3, mix the mixture for 24 hours, then filter off the undissolved material.

|00658| We have found that while flavonoids can degrade in basic solution, aqueous flavonoid-cyclodextrin compositions can be prepared with little to no degradation of the flavonoid by minimizing the the time during which the flavonoid is above pH 9. In some embodiments the time that the flavonoid is above pH 9 is less than about 60, 40, 30, 20, 15, 10, 5, 4, 3, 2, or less than about one minute. In some embodiments, the time that the flavonoid is above pH 9 is less than about 20 minutes. In some embodiments, the time that the flavonoid is above pH 9 is less than about 15 minutes. In some embodiments, the time that the flavonoid is above pH 9 is less than about 10 minutes. In some embodiments, the time that the flavonoid is above pH 9 is less than about 5 minutes. In some embodiments, the time that the flavonoid is above pH 9 is between about 30 and about 60, between about 20 and about 40, between about 15 and about 20, between about 10 and about 15, between about 5 and about 10, between about 1 and about 5, between about 1 and about 10, between about 2 and about 15, or between about 5 and about 15 minutes.

[00659| In the methods disclosed herein, the temperature at which flavonoid is above pH 9 is generally kept relatively low. In some embodiments, the temperature at which the flavonoid is above pH 9 is kept below about 50 ⁰C, below about 40 ⁰C, below about 30 ⁰C, below about 28 ⁰C, below about 26 ⁰C, below about 24 ⁰C, below about 22 ⁰C, below about 20 ⁰C, below about 18 ⁰C, below about 16 ⁰C, below about 15 ⁰C, below about 14 ⁰C, below about 12 ⁰C, or below about 10 ⁰C. In some embodiments the temperature at which the flavonoid is above pH 9 is between about 20 ⁰C and about 30 ⁰C, between about 10 ⁰C and about 40 ⁰C, between about 20 ⁰C and about 26 ⁰C, or between about 23 ⁰C and about 25 ⁰C.

(00660| Any suitable flavonoid can be used. A detailed description of flavonoids is provided herein. In some embodiments of the method, the flavonoid that is used in the method is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin or mixtures thereof. In some embodiments of the methods, the flavonoid is quercetin, kaempferol, fisetin or galangin or mixtures thereof. In some embodiments, the flavonoid is quercetin or fisetin. In some embodiments, the flavonoid is a derivative of quercetin or fisetin. [006611 Methods disclosed herein are useful for flavonoids that are insoluble in water or that are sparingly soluble in water. A flavonoid that is sparingly soluble in water has a low solubility constant or Ks. An example of a sparingly soluble flavonoid is quercetin.

|00662) Methods disclosed herein are useful for flavonoids having acidic protons. An acidic proton can be removed by base in aqueous solution. In some embodiments, the pKa of the proton is less than 10. In some embodiments the acidic proton will be an -OH group that is attached to an aromatic ring, or a phenol group. The flavonoids can have multiple aromatic -OH groups. In some embodiments, the flavoniod has 3, 4, 5, or 6 acidic protons and/or aromatic -OH groups.

[00663| While not being bound by theory, it is known that flavonoids with aromatic -OH protons that are substantially water insoluble or sparingly water soluble can be made more water soluble by raising the pH, due at least in part to the deprotonation of the acidic hydrogen(s), creating a flavonoid anion that will tend to be more soluble in water than flavonoid without the proton removed. Thus, raising the pH to above the pKa of the acidic proton on the flavonoid, can result in higher solubility of the flavonoid at the high pH. Methods disclosed herein provide that the flavonoid, at high pH, is mixed with the cyclodextrin, and then the pH of the aqueous solution is lowered. As the pH of the solution is lowered, the flavonoid becomes less soluble, but instead of precipitating out of solution, the flavonoid appears to form a complex with the cyclodextrin. This method is an effective method for rapidly obtaining a soluble flavonoid-cyclodextrin aqueous composition. Surprisingly, we have found that this method can produce a flavonoid-cyclodextrin aqueous composition in which the flavonoid is soluble at higher concentrations than obtained by conventional means such as sonicating the flavonoid and cyclodextrin below pH 8. This method can be used to obtain high aqueous concentrations of flavonoids with sulfobutylether-7-β-cyclodextrin. In some embodiments, high aqueous concentrations of quercetin or a quercetin derivative with sulfobutylether-7-β-cyclodextrin can be obtained.

[00664| The methods disclosed herein can be used with any suitable type of cyclodextrin. A more detailed description of cyclodextrins is provided below. The methods disclosed herein can be used with alpha, beta or gamma cyclodextrins. The methods disclosed herein can be used with modified cyclodextrins such as hydroxypropyl derivatives of alpha-, beta- and gamma-cyclodextrin, sulfoalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin, alkylated cyclodextrins such as the randomly methylated beta.-cyclodextrin, and various branched cyclodextrins such as glucosyl- and maltosyl-beta.-cyclodextrin. In some embodiments, the method is directed at pharmaceutical compositions, in which hydroxypropyl cyclodextrins and sulfoalkyl cyclodextrins can be useful. In some embodiments, sulfobutylether-7-β-cyclodextrin is used. [00665| In some embodiments, provided are compositions comprising a flavonoid and a sulfo-alkyl ether substituted cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 raM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM. In some embodiments, also provided are compositions comprising a flavonoid and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM.

1006661 In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 0.5 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 1 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β- cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 5 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 10 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutyiether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 20 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether- 7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 33 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 40 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 50 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 60 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 80 mM.

[00667| In some embodiments, provided are compositions comprising a flavonoid and a sulfobutylether-7-β- cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM, wherein the flavoniod is selected from the group consisting of quercetin or a quercetin derivative, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetiπ, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

(00668| In some compositions, the molar ratio of flavonoid, e.g. quercetin, to cyclodextrin, e.g. sulfobutylether- 7-β-cyclodextrin is between 1 : 1 and 1 :40. In some cases, the molar ratio of flavonoid, e.g. quercetin, to cyclodextrin, e.g. sulfobutylether-7-β-cyclodextrin is between 1 : 1 and 1 :40. In some cases, the molar ratio of flavonoid, e.g. quercetin, to cyclodextrin, e.g. sulfobutylether-7-β-cyclodextrin is between 1 : 1 and 1 :5. In some cases, the molar ratio of flavonoid, e.g. quercetin, to cyclodextrin, e.g. sulfobutylether-7-β-cyclodextrin is between 1 :2 and 1 :4. In some cases, the molar ratio of flavonoid, e.g. quercetin, to cyclodextrin, e.g. sulfobutylether-7-β-cyclodextrin is between 1 : 10 and 1 :40. In some cases, the molar ratio of flavonoid, e.g. quercetin, to cyclodextrin, e.g. sulfoburylether-7-β-cyclodextrin is between 1 : 15 and 1 :40. In some cases, the molar ratio of flavonoid, e.g. quercetin, to cyclodextrin, e.g. sulfobutylether-7-β-cyclodextrin is between 1 :3 and 1 : 12. In some cases, the molar ratio of flavonoid, e.g. quercetin, to cyclodextrin, e.g. sulfobutylether-7-β- cyclodextrin is between 1 :5 and 1 : 10.

1006691 In some embodiments, provided are methods of producing an aqueous solution of a flavonoid comprising mixing a flavonoid, a cyclodextrin, and a basic amino acid or sugar-amine at a pH of about 8.5 or greater. It has been found that the basic amino acid, such as lysine and arginine or a sugar-amine such as meglumine, can act, along with the cyclodextrin, to increase the solubility of the flavonoid in water. [00670| As used in the method, the cyclodextrin is generally present at a level between 10% w/v to 40% w/v in the aqueous solution. In some cases the cyclodextrin is present between 15% and 35%. In some cases the cyclodextrin is present between 20% and 35%. In some cases the cyclodextrin is present between 20% and 35%. In some cases the cyclodextrin is present between 25% and 35%. In some cases the cyclodextrin is present between 30% and 35%. In some cases the cyclodextrin is present at about 10%, about 12%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 38% and about 40% w/v in the aqueous solution. In some cases the cyclodextrin is present in a range of 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40% w/v in the aqueous solution. In some cases it is found that having a level of cyclodextrin greater than about 20%, greater than about 25%, or greater than about 30% w/v in the aqueous solution can be used to obtain high solubility of the flavonoid. The cyclodextrin that works in this range can be, for example, a sulfoalkyl cyclodextrins such as sulfobutylether-β-cyclodextrin.

[006711 The flavonoid used in the method of producing an aqueous solution comprising the flavonoid, cyclodextrin and amino acid or sugar-amine can be a flavonoid known and/or described herein. The flavonoid can be, for example, quercetin or a quercetin derivative, fisetin or a fisetin derivative, galangin, or kaempferol. In some cases, the method provides the flavonoid, e.g. quercetin or a quercetin derivative, or fisetin or a fisetin derivative, at a concentration in a range between 1 mg/mL and 15 mg/mL, between 3 mg/mL and 14 mg/mL, between 5 mg/mL and 13 mg/mL, between 6 mg/mL and 12 mg/mL, between 8 mg/mL and 12 mg/mL, or between 9 mg/mL and 1 1 mg/mL. In some cases, the method provides the flavonoid, e.g. quercetin or a quercetin derivative at a concentration of greater than 1 mg/mL, greater than 2 mg/mL, greater than 4 mg/mL, greater than 3 mg/mL, greater than 5 mg/mL, greater than 6 mg/mL, greater than 7 mg/mL, greater than 8 mg/mL, greater than 9 mg/mL, greater than 10 mg/mL, greater than 1 1 mg/mL, greater than 12 mg/mL, greater than 13 mg/mL, greater than 14 mg/mL, or greater than 15 mg/mL.

(00672| In some cases, the method provides the flavonoid e.g. quercetin or a quercetin derivative, or fisetin or a fisetin derivative, at a concentration of greater than about 3 mM, greater than about 6 mM, greater than about 9 mM, greater than about 12 mM, greater than about 15 mM, greater than about 18 mM, greater than about 21 mM, greater than about 24 mM, greater than about 27 mM, greater than about 30 mM, or greater than about 33 mM.

|00673) The basic amino acid can be an amino acid having a basic group (in addition to the amine of the amino acid). The basic group can be, for example, an amine group or a guanidinium group. The pKa of the basic group will generally be greater than about 9.5, greater than about 10, greater than about 10.5, greater than about

11 , or greater than about 1 1.5. The pKa of the basic group can be between about 9.5 and about 12, between about 10 and about 1 1.5, or between about 10.5 and 1 1.5. The amino acid can be a naturally occurring amino acid or a synthetic amino acid. In some cases it is desirable to use a naturally occurring basic amino acid in a pharmaceutical formulation. In some cases lysine is the amino acid. In some cases arginine is the amino acid.

In some cases, both lysine and arginine are added together.

[00674] While in most cases, an amino acid is used, in some cases another basic compound can be used in place of the amino acid. For example, in some embodiments, a polyhydroxy compound or a sugar having an amine group (a sugar-amine) can be used in place of the amino acid or in conjunction with the amino acid. In some cases, for example, meglumine (N-Methyl-d-glucamine) can be used in place of the amino acid or in conjunction with the amino acid.

[00675| The amount of the amino acid can be the amount required to bring the pH of the solution above about

8.5, above about 8.7, or above about 9.0.

[00676| In some cases, the cyclodextrin, e.g. sulfobutylether-β-cyclodextrin, is first dissolved in water, then subsequently, the flavonoid and basic amino acid or sugar-amine are mixed to form the aqueous solution.

[00677| In some cases, the flavonoid, e.g. quercetin or a quercetin derivative, will degrade in the basic medium.

Therefore, the time of mixing to form the aqueous solution will in some cases be minimized. In some cases, the mixing is done in less than about 1 hour, less than about 30 minutes, less than about 20 minutes, less than about

15 minutes, less than about 10 minutes, or less than about 5 minutes.

[00678] The temperature at which the mixing is carried out is generally near room temperature. In some cases, the temperature is between about 20⁰C and about 25°C, between about 18°C and about 28°C, between about

15°C and about 3O⁰C, between about 10⁰C and about 25°C, between about 5⁰C and about 20⁰C.

[00679] After the aqueous solution is formed, the pH of the solution can be neutralized by the addition of acid or by the addition of a buffer solution. In some cases, the acid is hydrochloric acid (HCL). The neutralized solution is generally brought to below pH 8.5. In some cases, the pH of the neutralized solution is about 8.5, about 8.4, about 8.2, about 8.0, about 7.8, about 7.6, about 7.4, about 7.2, or about 7.0.

[00680| The neutralized solution can then be dried to obtain a dry powder formulation comprising the flavonoid such as quercetin or a quercetin derivative, the cyclodextrin such as sulfobutylether-β-cyclodextrin, and the basic amino acid or sugar-amine. The dry powder can be stored, and can then be re-dissolved in water, for example to produce an intravenous solution. The dry powder can also be formulated as described below into a pharmaceutical formulation suitable for administration via various routes. The powder can be packaged into kits.

(006811 In some embodiment, the flavonoid, such as quercetin or a quercetin derivative, the cyclodextrin such as sulfobutylether-β-cyclodextrin, and the basic amino acid or sugar-amine are mixed in methanol. The methanol is then evaporated to yield a mixture which can be subsequently mixed in water to form an aqueous solution of flavonoid. While not being bound by theory, the dissolution of the flavonoid in methanol and the subsequent precipitation of the flavonoid along with the cyclodextrin such as sulfobutylether-β-cyclodextrin is believed in some cases to break up the crystallinity of the flavonoid, promoting disruption of the crystalline lattice and fostering interaction with the other components in a manner that facilitates the subsequent dissolution of the flavonoid in water or aqueous solution. In some embodiments, quercetin, for example in the form of quercetin dihydrate, Captisol, and either arginine, lysine, or meglumine are mixed with methanol, the mixture is filtered from undissolved solids, and the solution obtained from filtration is treated in order to remove the methanol to obtain a solid residue. The removal of methanol can be accomplished, for example, by treating with molecular sieves, distillation, evaporation, or lyophilization. The solid residue can be stored or used right away. The solid residue can then be dissolved in water or aqueous solution to produce an aqueous solution of quercetin.

|00682| Accordingly, one aspect is a dry powder formulation comprising the flavonoid such as quercetin or a quercetin derivative, the cyclodextrin such as sulfobutylether-β-cyclodextrin, and the basic amino acid or sugar- amine. In some cases, in the dry powder formulation, the molar ratio of the flavonoid, e.g. quercetin to the basic amino acid or sugar-amine is from about 3: 1 to about 1 :9. In some cases the molar ratio of the flavonoid, e.g. quercetin to the basic amino acid or sugar-amine is from about 1 : 1 to about 1 :5. In some cases the molar ratio of the flavonoid, e.g. quercetin to the basic amino acid or sugar-amine is about 1 :2. In some cases the molar ratio of the flavonoid, e.g. quercetin to the basic amino acid or sugar-amine is from about 1 : 1 to about 1 :5 and the molar ratio of the flavonoid to the cyclodextrin such as sulfobutylether-β-cyclodextrin is about 1 : 12 to 1 :2. [00683| In some cases the molar ratio of the flavonoid, e.g. quercetin to the basic amino acid or sugar-amine is from about 3: 1 to about 1 :9 and the molar ratio of the flavonoid to the cyclodextrin such as sulfobutylether-β- cyclodextrin is about 1 : 1 to 1 :40. In some cases the molar ratio of the flavonoid, e.g. quercetin to the basic amino acid or sugar-amine is from about 1 : 1 to about 1 :5 and the molar ratio of the flavonoid to the cyclodextrin such as sulfobutylether-β-cyclodextrin is about 1 :3 to 1 : 12. In some cases the molar ratio of the flavonoid, e.g. quercetin to the basic amino acid or sugar-amine is from about 1 : 1 to about 1 :5 and the molar ratio of the flavonoid to the cyclodextrin such as sulfobutylether-β-cyclodextrin is about 1 :5 to 1 : 10. The dry powder can be stored, and can then be re-dissolved in water, for example to produce an intravenous solution. The dry powder can also be formulated as described below into a pharmaceutical formulation suitable for administration via various routes. The powder can be packaged into kits.

[006841 In some embodiments the solutions of flavonoid produced by the above method are stable for a long period of time. In some embodiments, the flavonoid solutions at relatively high concentrations can be stable to precipitation for about 5, 10, 20, 30, 45, or 60 minutes, for about 1 , 2, 4, 8, 10, 12, 18, or 24 hours, for about 1 , 2, 3, 5, 7, or 10 days, for 1, 2, 3, 4, 6 weeks, or for 1 , 2, 3, 6, 9, or 12 months or 1, 2 3 or more years. The term "soluble" as used herein means that the flavonoid does not precipitate from the solution. In some embodiments, the soluble solution is substantially clear. In some embodiments the compositions can be stored at low temperature, e.g refrigerated, for the time periods described above without precipitation. For example, a composition with quercetin at 10 mg/ml in water with sulfobutylether-7-β-cyclodextrin is stable for more than two weeks without precipitation of the quercetin.

[00685| In some cases the method allows for the production of flavonoid-sulfoalkyl ether cyclodextrin aqueous compositions that have such a high concentrations that they tend to precipitate out of solution over time. For instance, the compositions may be clear and homogeneous for hours after their production by the methods disclosed herein, but will tend to precipitate after several hours at room temperature. These meta-stable high concentration solutions can still be useful, for instance if they are used within the time of solubility, or if they are further processed after having been produced at high concentration, for example being freeze-dried, or being diluted into formulations having long shelf life. It is known in the art how to characterize the stability of the fluids under various conditions to determine their usefulness for a given application.

[00686| The compositions can be used to make pharmaceutical formulations. In embodiments where the formulations provide a high concentration of the flavonoid in solution, these high concentration solutions can be useful for making pharmaceutical formulations. For example, in some embodiments, a composition with a high concentration of flavonoid and sulfoalkyl ether cyclodextrin can be dried, for example by freeze-drying or lyophilization in order to form a solid, powdered composition for use in a pharmaceutical formulation. The dried powder can then formulated with other components to make a pharmaceutical formulation for any suitable type of administration. For example, in some embodiments the dried powder can be mixed with other ingredients to create an oral formulation. In other embodiments, the dried powder can be made into a solid formulation that can be stored and then subsequently dissolved to produce a pharmaceutical formulation for injection.

[00687] In some embodiments, the high concentration form of flavonoid and sulfoalkyl ether cyclodextrin can be made as concentrated stock solution, and subsequently diluted for administration. It can be advantageous to have a high concentration stock solution for ease of manufacturing, storage, and handling. [00688| In some embodiments, provided are pharmaceutical compositions that are made using an aqueous composition comprising a flavonoid and a sulfo-alkyl ether substituted cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM.

[00689] In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a flavonoid and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM. In some embodiments, provided are compositions comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM. [00690| In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 0.5 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 1 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 5 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 10 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 20 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 33 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 40 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 50 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 60 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 60 mM. In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a quercetin or a quercetin derivative and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration greater than 80 mM.

|006911 In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a flavonoid and a sulfo-alkyl ether substituted cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM, wherein the flavoniod is selected from the group consisting of quercetin or a quercetin derivative, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

[00692] In some embodiments, provided are pharmaceutical compositions made from an aqueous composition comprising a flavonoid and a sulfobutylether-7-β-cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM, wherein the flavonoid is selected from the group consisting of quercetin or a quercetin derivative, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin. [00693| In some embodiments, the pharmaceutical compositions are made from an aqueous composition comprising a flavonoid and a sulfo-alkyl ether substituted cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM, wherein the administration is rectal, buccal, intranasal, transdermal, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, orally, topical, as an inhalant, or via an impregnated or coated device such as a stent. In some embodiments, the pharmaceutical compositions are for intravenous administration made from an aqueous composition comprising a flavonoid and a sulfo-alkyl ether substituted cyclodextrin and an aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM. In some embodiments, the pharmaceutical composition for intravenous administration is a solid. In some embodiments, the pharmaceutical composition for intravenous administration is made by removal of water, for example by freeze drying or lyophilization. In some embodiments the pharmaceutical composition for intravenous administration is a liquid.

[00694| The pharmaceutical formulation produced from the compositions can be processed and formulated as described herein.

[00695| Examples of additional 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, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, 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- methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[00696| Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, 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. [00697| The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

|00698| 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. [00699| In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

|00700J Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.

|007011 In embodiments where the novel formulations provide a high concentration of the flavonoid in solution, these high concentration solutions can be useful for making pharmaceutical formulations. For example, in some embodiments, a composition with a high concentration of flavonoid and sulfoalkyl ether cyclodextrin can be dried, for example by freeze-drying or lyophilization in order to form a solid, powdered composition for use in a pharmaceutical formulation. The dried powder can then formulated with other components to make a pharmaceutical formulation for any type of administration. For example, in some embodiments the dried powder can be mixed with other ingredients to create an oral formulation. Where the oral formulation is made from the aqueous composition of sulfoalkyl ether cyclodextrin-flavonoid, the oral formulation can be a solid formulation that is produced by drying the aqueous composition, for example by freeze-drying or lyophilization. Lyophilization is a freeze-drying process in which water is sublimed from the composition after it is frozen. The particular advantages of the lyophilization process are that biologicals and pharmaceuticals that are relatively unstable in aqueous solution can be dried without elevated temperatures (thereby eliminating the adverse thermal affects) and then stored in the dry state where there are few stability problems. 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.

100702 J Pharmaceutical compositions for injection Tn some embodiments, the invention provides a pharmaceutical composition for injection containing a combination of a therapeutic agent and an agent that reduces or eliminates one or more symptoms of hypogonadism induced by the therapeutic agent, and a pharmaceutical excipient suitable for injection.. In some embodiments, the invention provides a pharmaceutical composition for injection containing a combination of a therapeutic agent and a cyclodextrin-complexed agent that, e.g. reduces or eliminates one or more symptoms of hypogonadism induced by the therapeutic agent, and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[007031 In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β- cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 0.5 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative is present in a concentration of greater than 1 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 5 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutyIether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 10 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 15 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β- cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 20 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fϊsetin or fisetin derivative, a sulfobutylether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 30 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 33 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 40 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β- cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 50 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 60 mM in the composition used to make the formulation. In some embodiments, the pharmaceutical composition for injection is made using an aqueous composition comprising quercetin or a quercetin derivative, or fisetin or fisetin derivative, a sulfobutylether-7-β-cyclodextrin, and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the quercetin or a quercetin derivative, or fisetin or fisetin derivative, is present in a concentration of greater than 80 mM in the composition used to make the formulation. |00704| The forms in which the novel 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.

[00705] 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. [00706] Sterile injectable solutions are prepared by incorporating the transport protein modulator 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.

|00707| In embodiments where the novel formulations provide a high concentration of the flavonoid in solution, these high concentration solutions can be useful for making pharmaceutical formulations. For example, in some embodiments, a composition with a high concentration of flavonoid and sulfoalkyl ether cyclodextrin can be dried, for example by freeze-drying or lyophilization in order to form a solid, powdered composition for use in a pharmaceutical formulation. The dried powder can then formulated with other components to make a pharmaceutical formulation for any type of administration. For example, in some embodiments the dried powder can be made into a solid formulation that can be stored and then readily dissolved produce a pharmaceutical formulation for injection.

[00708] Where the pharmaceutical composition for injection is made from the aqueous composition of sulfoalkyl ether cyclodextrin-flavonoid, pharmaceutical composition for injection can be made into a solid formulation that is produced by drying the aqueous composition, for example by freeze drying or lyophilization. Having a dried, solid formulation can be advantageous for increasing the shelf-life. The solid formulation can then be re-dissolved into solution for injection. The dried powder can be further formulated into pharmaceutical composition for injection as described herein.

(007091 Pharmaceutical compositions for topical (e.g.. transdermal) delivery In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a combination of a therapeutic agent and an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent, and a pharmaceutical excipient suitable for transdermal delivery. In some embodiments, the agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced the therapeutic agent is a BBB transport protein modulator, e.g. a polyphenol such as a flavonol, as described elsewhere herein. In some embodiments, the pharmaceutical composition for transdermal delivery is a combination of a therapeutic agent and sulfoalkyl ether cyclodextrin-flavonoid, e.g. sulfobutylether-7-β-cyclodextrin-flavonoid, and a pharmaceutical excipient suitable for transdermal delivery. Components and amounts of agents in the compositions are as described herein.

[00710| In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery is an aqueous formulation comprising a flavonoid and a sulfo-alkyl ether substituted cyclodextrin and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 niM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM. In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery is an aqueous formulation comprising quercetin or a quercetin derivative, or fisetin or a fisetin derivative, and a sulfobutylether-7-β-cyclodextrin and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the flavonoid is present in a concentration greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM. In some embodiments, the pharmaceutical composition for transdermal delivery is made using an aqueous composition comprising a flavonoid, a sulfo-alkyl ether substituted cyclodextrin and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the flavonoid is present in a concentration of greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM. In some embodiments, the pharmaceutical composition for transdermal delivery is made using an aqueous composition comprising a flavonoid, e.g. quercetin or a quercetin derivative, or fisetin or a fisetin derivative, and a sulfobutylether-7-β-cyclodextrin and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the flavonoid is present in a concentration of greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM.

|00711 J Compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[00712] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

|00713| Another preferred formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the transport protein modulator in controlled amounts, either with or without therapeutic agent. Thus, in some embodiments the invention provides a transdermal patch incorporating a BTB transport protein modulator, e.g., a polyphenol such as a flavonoid (e.g., quercetin or a quercetin derivative). In some embodiments the invention provides a transdermal patch incorporating a BTB transport protein modulator, e.g., a polyphenol such as a flavonoid (e.g., quercetin or a quercetin derivative) in combination with a therapeutic agent, e.g. an opiate.

|00714| The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001 , 139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

IOO715| Pharmaceutical compositions for inhalation. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

(00716| Other pharmaceutical compositions Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for 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

[00717J The invention also provides kits. The kits include an agent as described herein that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. The kit may further contain a therapeutic agent that induces a hypogonadism or an impairment in a hypothalamic/pituitary/endocrine function symptom. In some embodiments, the therapeutic agent and the agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent are provided as separate compositions in separate containers within the kit. In some embodiments, the therapeutic agent and the agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by 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. In some embodiments, the kits include a container comprising pharmaceutical formulation that is made using an aqueous composition comprising a flavonoid, a sulfo-alkyl ether substituted cyclodextrin and a pharmaceutically or veterinarily acceptable aqueous carrier wherein the flavonoid is present in a concentration of greater than 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM or greater than 80 mM in the composition used to make the formulation, and instructions for using the formulation to treat a disorder. In some embodiments, the kits can include a sulfobutylether-7-β-cyclodextrin- flavonoid for example surfobutylether-7-β-cyclodexrrin-quercetin , in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like.

Methods

[00718| In another aspect, the invention provides methods, including methods of treatment, methods for reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function, methods of decreasing the concentration of a substance in a physiological compartment, and methods of enhancing a therapeutic effect of a substance. [00719] For simplicity, methods will be described in terms of reduction of one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent. |00720| 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.

[007211 The term "treating" and its grammatical equivalents as used herein includes 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.

|00722] In some embodiments, the invention provides a method of treating a condition by administering to an animal suffering from the condition an effective amount of a therapeutic agent and an amount of a BTB transport protein activator sufficient to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments, the activator reduces or eliminates a plurality of symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments the animal is a mammal, e.g., a human.

[00723] The therapeutic agent and the BTB transport protein activator 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. Thus, in some embodiments, the BTB transport protein activator and the therapeutic agent are administered in a single composition. In some embodiments, the therapeutic agent and the BTB transport protein activator are admixed in the composition. Typically, the therapeutic agent is present in the composition in an amount sufficient to produce a therapeutic effect, and the BTB transport protein activator is present in the composition in an amount sufficient to reduce one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments, the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the BTB transport protein activator is present in an amount sufficient to decrease one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by 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 one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function, compared to the effect without the BTB transport protein activator. |00724| In some embodiments, the invention provides a method of treating a condition by administering to an animal suffering from the condition an effective amount of a therapeutic agent and an amount of a BTB transport protein activator sufficient to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent, wherein the animal receiving treatment with the therapeutic agent has or its suspected to have one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments, the activator reduces or eliminates a plurality of symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent.

[00725| In some embodiments, the invention provides a method of treating a condition by administering to an animal suffering from the condition an effective amount of a therapeutic agent and an amount of a BTB transport protein activator sufficient to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent, wherein the sex of the animal receiving said therapeutic agent is determined. In some embodiments, the activator reduces or eliminates a plurality of symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent.

[00726| Administration of the therapeutic agent and the agent that reduces or eliminates at least one symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced the therapeutic agent 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.

[00727| In some embodiments, the agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent is a BTB transport protein modulator, BTB transport protein modulators are as described herein. In some embodiments, a polyphenol is used. In some embodiments, a flavonoid is used. In some embodiments, the flavonoid is quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, or epicatechin. In some embodiments, the flavonoid is quercetin, kaempferol, or galangin. In some embodiments, the flavonoid is quercetin or a quercetin derivative. Dosages are as provided for compositions. Typically, the daily dosage of the BTBtransport protein modulator will be about 0.5-100 mg/kg.

|00728| The therapeutic agent may be any therapeutic agent described herein. In some embodiments of the invention, the therapeutic agent is an agent capable of inducing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments of the invention, the therapeutic agent is an analgesic agent, such as an opiate or a non-opiate analgesic. In some embodiments, the therapeutic agent is an opiate. Examples of opiates include, but are not limited to, codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceiπe, morphine, heroin, hydromorphone, oxymorphoπe, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levoφhanol, levalloφhan, β-endoψhin, leu-enkephalin, met-enkephalin, dynoφhin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine. In some embodiments, the therapeutic agent is moφhine. In some embodiments the therapeutic agent is sufentanyl. In some embodiments, the therapeutic agent is alfentanyl. In some embodiments, the therapeutic agent is remifentanyl. In some embodiments the therapeutic agent is oxycodone.

[00729] In some embodiments of the invention, the therapeutic agent is a non-analgesic agent. In some embodiments, the agent is an anti hypertensive agent. Examples of anti hypertensive agents include, but are not limited to, diuretics, adrenergic receptor antagonists, adrenergic receptor agonist, calcium channel blockers, ace inhibitors, angiotensin ii receptor antagonists, aldosterone antagonists, vasodilators, centrally acting adrenergic drugs.

[00730| The methods of the invention may be used for treatment of any suitable condition for which a therapeutic agent that induces hypogonadism or impairment in hypothalamic/pituitary/endocrine function is administered. In certain embodiments the invention provides methods of treatment of pain with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby preventing, reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments, the invention provides methods for treatment of acute pain such as post-operative pain with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments, the invention provides methods for treatment of chronic pain with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In certain embodiments the invention provides methods of treatment of depression with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In certain embodiments the invention provides methods of treatment of conditions selected from the group consisting of cough, diarrhea, anxiety, and detoxification. In some embodiments, the animal, e.g. human, is first treated with a therapeutic agent, then, if one or more said symptoms are noted the animal is treated with one or more BTB protein transport modulator to prevent or reduce one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent.

[00731] In some embodiments, the invention provides methods to reduce or eliminate one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent used for analgesia and anesthesia

[00732| In certain embodiments the invention provides methods of treatment of hypertension with a therapeutic agent by co-administering a modulator of a BTB transport protein in combination with the therapeutic agent, thereby reducing or eliminating one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. 100733 ] The invention provides methods of treating pain.

[00734| As used herein the term "pain" may refer to all types of pain, including, but not limited to, traumatic pain, neuropathic pain, inflammatory pain, acute pain, chronic pain, organ or tissue pain, and pain associated with diseases. The International Association for the Study of Pain ("IASP") defines pain as "an unpleasant sensory and emotional experience associated with actual and potential tissue damage, or described in terms of such damage or both." Pain is classified in several manners, conventionally by location, duration, cause, frequency, and intensity.

|00735) Traumatic pain includes, but is not limited to, pain resulting from injury, post-surgical pain and inflammatory pain. Neuropathic pain may include, but is not limited to, neuropathic and idiopathic pain syndromes, and pain associated with neuropathy such as diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, fibromyalgia, gout, and other forms of neuralgia. Organ or tissue pain may include, but is not limited to, headache, ocular pain, corneal pain, bone pain, heart pain, skin/burn pain, lung pain, visceral pain (kidney, gall bladder, etc.), joint pain, dental pain, muscle pain, pelvic pain, and urogenital pain (e.g. vulvodynia and prostadynia). Pain associated with diseases may include, but is not limited to, pain associated with cancer, AIDS, arthritis, herpes and migraine. Pain may be of varying severity, i.e. mild, moderate and severe pain in acute and/or chronic modes.

[00736J Pain may be due to injury, strain or inflammation of tendons or ligaments and may be referred to as "soft tissue pain." Some of the soft tissue pain conditions which afflict humans may include, but is not limited to, tennis elbow, frozen shoulder, carpal tunnel syndrome, plantar fasciitis, and Achilles tendonitis. Tennis elbow is due to inflammation of the tendons of the hand gripping muscles where these tendons are attached to the elbow. This may result in pain at the elbow. Frozen shoulder is a stiffening of the ligaments around the shoulder joint which may come on after prolonged unaccustomed use of the arm. Carpal tunnel syndrome involves a nerve which passes through the carpal tunnel on the front of the wrist into the human hand. When this tunnel becomes inflamed it can press on the nerve causing shooting pain into the thumb and first two fingers. Plantar fasciitis involves ligaments in the sole of the foot which can get inflamed leading to pain on the bottom of the heel while walking. Achilles tendonitis involves the Achilles tendon located at the back of the human ankle and which may become inflamed and painful.

|00737| Pain may also include chronic pain, such as but not limited to, neuropathic pain, and post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post partum pain, migraine, angina pain, and genitourinary tract-related pain including cystitis, nociceptive pain or nociception.

[00738] Pain associated with inflammatory diseases includes, but is not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation including, but not limited to, transplantation of the heart, lung, liver, or kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer s disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including Type I and Type II diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorum); immune-complex vasculitis, and systemic lupus erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. Pain can be associated with a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer. Arthritis is associated with pain and can be divided into inflammatory and non-inflammatory arthritis. Osteoarthritis is a noninflammatory type of arthritis. Inflammatory arthritis can be, by way of example only, rheumatoid arthritis, gout, psoriatic arthritis, reactive arthritis, viral or post-viral arthritis, and spondylarthritis which may affect the spine as well as joints.

[00739] Any suitable type of pain, whether acute or chronic, may be treated by the methods of the invention. Thus, in some embodiments, the invention provides a method of treating an animal for pain by administering to an animal in pain an effective amount of a therapeutic agent and an amount of a BBB transport protein activator sufficient to reduce a central nervous system effect of the analgesic agent. In some embodiments the animal is a mammal, e.g., a human.

|00740| When a therapeutic agent and an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function the therapeutic agent are used in combination, any suitable ratio of the two agents, e.g., molar ratio, wt/wt ration, wt/volume ratio, or volume/volume ratio, as described herein, may be used.

[007411 The invention further provides methods of reversing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent by administering a BTB transport protein activator to an animal that has received an amount of the therapeutic agent sufficient to produce one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments, the animal, e.g. human, is found to exhibit one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function, then, the BTB transport protein modulator is administered. The BTB transport protein modulator can be administered alone or in combination with the therapeutic agent. Any suitable BTB transport protein described herein may be used. [00742| In some embodiments, the invention provides a method for reversing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent in a human by administering to the human an amount of a BTB transport protein modulator sufficient to partially or completely reverse one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent, where the human has received an amount of said therapeutic agent sufficient to produce one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In some embodiments, the human has received an overdose of the therapeutic agent producing the symptom. In some embodiments, the individual continues to experience peripheral effects of the therapeutic agent. In some embodiments, the BTB transport protein modulator is a polyphenol, such as a flavonoid. In some embodiments, the flavonoid is quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, or epicatechin. In some embodiments, the flavonoid is quercetin or a quercetin derivative. Typically, the flavonoid will be administered by injection, e.g., intravenously or intraperitoneally, in a dose sufficient to partially or completely reverse one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. Such a dose in a human can be, e.g., about 0.1-100 gm, or about 0.5-50 gm, or about 1-20 gm, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 gm. In general, the dose can be 0.01-1.5 gm/kg.

Administration

(007431 The methods involve the administration of an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent. In some embodiments, a therapeutic agent that produces a one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function is administered in combination with an agent that reduces the one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent. In some embodiments, other agents are also administered, e.g., other therapeutic agents. When two or more agents are co-administered, 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. |00744| In some embodiments, the agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent is administered in a single dose. This may be the case where the agent is introduced into an animal to quickly lower symptom induced by a therapeutic agent already present in the body. Such administration can be by any suitable route such as orally or by injection, e.g., intravenous injection, in order to introduce the agent quickly. A single dose of an agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a therapeutic agent may also be used when it is administered with the therapeutic agent (e.g., a therapeutic agent that produces a hypogonadism or an impairment in hypothalamic/pituitary/endocrine function symptom) for treatment of an acute condition. |00745] In some embodiments, the agent that reduces or eliminates one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by a substance and/or therapeutic agent 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. 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 one embodiment the therapeutic agent is an agent capable of inducing one or more symptoms of hypogonadism or impairment in hypothalamic/pituitary/endocrine function. In one embodiment the therapeutic agent is an opiate. In one embodiment the therapeutic agent is an anti-hypertensive. In another embodiment the therapeutic agent and the transport protein activator are administered together about once per day to about 6 times per day. In another embodiment the administration of the therapeutic agent and the transport protein activator 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., chronic pain in cancer patient or chronic hypertension.

[00746] Administration of the agents of the invention may continue as long as necessary. In some embodiments, an agent of the invention is administered for more than about 1 , 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, an agent of the invention is administered for less than about 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[007471 An effective amount of a transport protein modulator and an effective amount of a therapeutic agent 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. [00748| The BTB transport protein modulator 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. It is also known in the art that due to intersubject variability in therapeutic agents, such as an opiate, pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. For a flavonoid, e.g., quercetin or a quercetin derivative, 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 or a quercetin derivative is about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg. In some embodiments, the daily dose of quercetin or a quercetin derivative is 100 mg. In some embodiments, the daily dose of quercetin or a quercetin derivative is 500 mg. In some embodiments, the daily dose of quercetin or a quercetin derivative is 1000 mg. Daily doses may be administered in single or multiple doses. For instance, in some embodiments the BTB transport modulator is administered 3 times per day of an oral dose of 500 mg. In other embodiments the BTB transport modulator is administered 3 times per day of an i.v. dose of 150 mg. Daily doses of quercetin or a quercetin derivative may be administered in the same or separate composition as the therapeutic agent. In some embodiments, the BTB transport protein modulator is in the bloodstream 30 minutes prior to the therapeutic agent. This may be accomplished by administering the BTB transport modulator separately from the therapeutic agent or by administering the BTB transport modulator and therapeutic agent in the same composition that is formulated so that the BTB transport modulator reaches the bloodstream before the therapeutic agent. Daily dose range may depend on the form of flavonoid, e.g., the carbohydrate moieties attached to the flavonoid, and/or factors with which the flavonoid is administered, as described herein. The serum half-life for, e.g., quercetin or a quercetin derivative, is about 19-25 hours, so single dose accuracy is not crucial.

[00749] When a BTB transport modulator, e.g., a flavonoid such as quercetin or a quercetin derivative, is administered in a composition that comprises one or more therapeutic agents, and the therapeutic agent has a shorter half-life than BTB transport modulator (e.g., tramadol, hydrocodone, and the like have shorter half-lives than quercetin), unit dose forms of the therapeutic agent and the BTB transport modulator may be adjusted accordingly. Thus, for example, if quercetin or a quercetin derivative is given in a composition also containing, e.g., tramadol, a typical unit dose form is, e.g., 50 mg tramadol/100 mg quercetin or a quercetin derivative, or 50 mg tramadol/500 mg quercetin or a quercetin derivative. See e.g., Compositions.

|00750| When a BTB transport protein that is the target of the BTB transport modulator is present on the cells where the therapeutic agent is exerting its therapeutic effect, unit dose forms of the BTB transport modulator may be adjusted such that the symptom of hypogonadism or impairment in hypothalamic/pituitary/endocrine function induced by the therapeutic agent are reduced without a substantial reduction of the therapeutic effect.

EXAMPLES Example 1 : Morphine Clearance from Rodent Brains is Altered in the Presence of Quercetin

[00751 J Animalsi 8-9 weeks-old rats are used. General procedures for animal care and housing are in accordance with the National Research Council (NRC) Guide for the Care and Use of Laboratory Animals

(1996) and the Animal Welfare Standards incorporated in 9 CFR Part 3, 1991

[00752] Treatment: Rats are treated with Morphine alone or in combination with quercetin.

|00753] Sample Preparation: 200 μl of blank homogenized rat brain (O. lOmg/ml in water) are pipetted into a glass tube (13 X 100mm). Standard Curve and control samples are prepared as described in the tables below

Table 3: Standard Curve Samples

* 00=Sample with no drug and no internal standard. ** 0=Sample with no drug, but with internal standard Table 4: Quality Control Samples

|00754| Standards: (i) Stock Solution: (a). Morphine (C17H19NO3H2O) - USP, Lot Number : G Molecular weight of C17H19NO3 (according to Mass lynx MW calculator) is 285.3428, molecular weight of H2O (according to Mass lynx MW calculator) is 18.0153, Conversion Factor is 285.3428/ (285.3428+18.0153) =0.9406; (ii) Standard Curve and Control stock Solution: 2.13 mg morphine (0.9406)/ 10.107 ml of C H3OH, Cone. = 0.250 mg/ml (iit) Morphine-d6 (Internal Standard) - Cerilliant Corporation Round Rock, TX, Lot Number: FC021505-0 IB, Cone. = 0.100 mg/ml in methanol

[00755] Working Solutions: (i) Standard Curve and Control solution: 0.800 ml of stock solution and q.s to 10.0 ml with 50% C H3OH solution (Cone. = 20.0 μg/ml), 0.500 ml of above solution (20.0μg/ml) and q.s to 10.0 ml with 50% CH3OH solution (Cone. = 1.00 μg/ml); (ii) Morphine-d6 (Internal Standard): 0.050 ml of 100 μg/ml solution and q.s to 10.0 ml with 50% C H3OH solution (Cone. = 0.500 μg/ml)

[00756] For each standard curve and quality control samples, the appropriate volume of diluting solution is added to give a final volume of 220 μl. For clinical samples, 20 μl of diluting solution are added to give a final volume of 220 μl. 20 μl of internal standard (morphine-d6) working solution (0.500μg/ml) are added and vortexed at full speed for 10 seconds. 0.500 ml of acetonitril is added, vortex at full speed for one minute and centrifuge at 3000 rpm for 15 minutes. The supernatants are then transferred to a new tube. 20 μl of 85% CH3CN containing 1.0% formic acid and 5mM NH4FA are added. Samples are evaporated to dryness under nitrogen stream. The residue is then reconstituted with 200 μl of mobile phase and vortexed for 1 minute. Samples are transferred to autosampler vial and 5 - 10 μl is injected to the LC/MS/MS. [00757| Mass Spectrometer Parameters: (i) Duration:5.5 min; (ii) Cycle Time: 0.820 sec; (iii) # Cycles: 403, (iv) Scan Time: (a) Morphine: 200 msec, (b) Morphine-d6: 200 msec; (v) Scan Type: Positive MRM (vi) Resolution Ql : Low; (vii) Resolution Q3: Low; (viii) Intensity Threshold: 0.00 cps; () Smart Setting: off; (x) Settling Time: 0.00 msec; (xi) MR Pause: 5.00 msec; (xi) MCA: No; (xii) NEB: 8.00; (xiii) CUR: 8.00; (xiv) Temperature: 350⁰C; (xv) CAD: 4.00 (N2 = 99.999%); (xvi) Step Size: 0.00 amu; (xv)DP: 55.00; (xvi) FP: 200.00; (xvii) EP: 10.00; (xviii) CE: 35; () CXP: 12; (xx) IS: 5000; (xxi) Injection Volume: 5 - 10 μl; (xxii) Run time: (a) 5.5 min (b) morphine: 1.93min (c) morphine-d6: 1.93 min; (xxii) Mobile Phase: CH3CN: H2O: FA (85: 15 : 1.0) (v/v) with 5mM NH4FA, which is made by mixing 3400 ml of acetonitril and 600 ml of water, then adding 40.0 ml of formic acid and 10.0 ml of 2M formic acid ammonium salt; (xxiii) flow rate: 1.0 ml/min; (xxiv) Weighted Regression: 1/X 2; (xxvi) |00758| Figure 5 shows the levels of morphine on rodent brains after treatment with morphine alone or in combination with quercetin. The levels of morphine peak in the brain 10 minutes after treatment with morphine and decrease to a steady level after 30 minutes (triangles). When morphine is administered together quercetin, the levels of morphine after 10 minutes of treatment are decreased in comparison with treatment of morphine alone (squares). These results suggest that quercetin potentiates the removal of morphine from rodent brain.

Example 2: Measuring Efflux of MS04 by a Transport Modulator In Vitro

|007591 The uptake Of [³H] morphine in BB 19 cell lines is measured as described by Kusch-Poddar et al. (2005)

Brain Research 1064 (1-2): 21-31, incorporated herein by reference in its entirety.

[00760| BB 19 cells: BB 19 cells, human brain capillary endothelial cells immortalized with the E6E7 genes of human papilloma virus, are cultured as monolayer culture (cell culture medium: MEM, 0.5 mM sodium pyruvate, MEM non essential amino acids, and 50 Ag/ml gentamicin containing 10% heat inactivated fetal bovine serum (FBS, Invitrogen)). Cells are seeded onto culture surfaces precoated with 2 Ag/cm2 rat tail collagen at a density of 100,000 to 150,000 cells/cm² and cultured in an incubator at 37 -C with 5% CO2, 95% fresh air and saturated humidity. Cell culture medium is changed every 2 to 3 days. Cells attach to the cell culture surfaces within 1 day and start to grow after the second day in culture.

|00761 | Conditioned medium: BB 19 cells are seeded onto chamber slides and at the third day of culture, 10 AM dexamethasone, 0.5 AM 1,25-dihydroxyvitamin D3, 250 AM chlorophenylthio-cAMP (all Fluka Chemie

GmbH,

|00762| Buchs, Switzerland) with 35 AM RO-20-1724, or Cό-conditioned medium taken from an astrocyte culture (mixed 1 : 1 with culture medium) are added to the culture medium. 10 AM rifampicine is added to the culture medium to test the influence on P-gp and BCRP expression. From this time point on, cell culture medium including these factors are changed every day.

|00763| Uptake assay: Uptake assays are performed at 20 -C using confluent monolayers of BB 19 cells, 5 days after seeding in 24-well cell-culture plates or 96 well cell culture plates. Cells are washed using Hanks Balanced

Salt Solution supplemented with 1 mM sodium pyruvate, pH 7.4 (HBSS-P) (both Gibco). Cells are incubated for 1, 2, 5, 10, 20, 30, 60, or 120 min with 0.3 ACi/well of the extracellular marker [¹⁴C]-sucrose (Amersham) together with 0.3 ACi/well of [³H]-morphine (Du Pont, Boston, MA). Then cells are washed with HBSS-P. The cell monolayers are solubilized in 0.8% triton-X for 20 min and the solutions are transferred to scintillation vials.

Radioactivity is determined by liquid scintillation counting (Packard TriCarb 2000, Packard, Dreieich,

Germany).

|00764) BB 19 cells are treated with different concentration of morphine in the presence or absence of 100 μM of cyclosporine (see Figure 6). Figure 6 shows dose-dependent uptake of morphine in BB 19 cells (squares). No difference in the uptake of morphine is observed when cyclosporine, an inhibitor of P-gP transport, is added

(circles).

|00765| To evaluate the effect of quercetin on the uptake of morphine, cells are treated with 50 μM on morphine in the presence or absence of different concentrations of quercetin, quercetin metabolites or additional flavonoids

(Figure 7 - 10). Figure 7A shows uptake of morphine of in BB 19 cells in the presence of different concentrations of quercetin dihydrate (quercetin-DH). In the absence of quercetin-DH, 50% of the applied dose is retained. Quercetin-DH at lower concentration has no effect on the retention of morphine. Quercetin-DH at a higher concentration increases the retention of morphine, thereby decreasing its efflux. Similar results are observed in morphine efflux when cells are treated with quercetin-3-glucoside (quercetin-3G) (see Figure 7B). When BB19 cells are plated in 96 wells plates, 30% of the applied dose of morphine is retained as shown in Figure 8 A. As seen previously, quercetin-DH at lower concentration has no effect on the retention of morphine. Quercetin-DH at a higher concentration increases the retention of morphine, thereby decreasing its efflux. Figure 8B shows that quercetin-3G has no effect on morphine efflux when BB 19 cells are plated in 96 wells plates. Other flavonoids or flavonoids metabolites such as kaempferol, galangin, tamarexin and isorhamentin also showed no effect on morphine efflux in BB19 cells plated in 96 wells plates (see Figures 9 -10). Taken together these results suggest that rather than morphine, a morphine metabolite (e.g. morphine 6 glucuronide) is probably the ligand of the P-gP transporter.

Example 3: Human study of the effects of Quercetin Dihydrate and MS04 on Testosterone Levels

|00766] An empirical trial is conducted on the effects of quercetin dihydrate on Morphine treatment and testosterone levels. Parenteral morphine HD (0.1 mg/kg) and LD (0.05 mg/kg) are tested with 4 doses parenteral activator (0, 20 mg, 50 mg, or 200 mg) on 25 male subjects.

[00767| Subject Selection: To minimize the potential teratogenic effects of quercetin, only male subjects are eligible to participate. 25 males subjects aged 18-65 years of age are selected. The main inclusion criteria are: (i) no history of significant cardiac, respiratory, hepatic, renal or neurological disease; (ii) general good health; (iii) able to comprehend and sign the informed consent and (iv) BMl within 19-32. The main exclusion criteria are: (i) known allergy to morphine, Captisol, and/or quercetin dihydrate; (ii) vegetarians; (iii) consumption of supplements containing quercetin 2 weeks before randomization; (iv) History or presence of clinically significant cardiac, respiratory, hepatic, renal or neurological disease; (v). Abnormal 12-lead ECG, including bundle branch block, sinus pauses >2 seconds, second or third degree heart block, QTc >450 msec, or other abnormalities judged clinically significant by the Investigator, a. Heart block controlled by a cardiac pacemaker is allowed; (vi) history of cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer resolved by excision); (vii) positive for Hepatitis B antibody indicative of present or past infection, a. positive test consistent with prior vaccination is allowed; (viii) positive for Hepatitis C antibody; (ix) Positive HIV test; (x) estimated GFR < 90 ml/min (calculated by the Cockroft-Gault formula); (xi) Hepatic tests > 2 x ULN, as confirmed in a repeat test, a. Isolated increase in one or more of hepatic enzymes is allowed per Investigator's discretion; (xii) history of alcohol or drug addiction within the past 5 years; (xiii) positive urine test for the drugs of abuse not due to diet; (xiv) positive blood alcohol test on dosing days prior to dosing; (xv) consumption of caffeine, tea, chocolate, and other products containing methylxanthines within 24 hours of randomization and each dosing day (Days 1 and 8 in Part 1 and Days 1, 8, 15, and 21 in Part 2); (xvi) Donation of blood within 8 weeks prior to dosing; (xvii) taking part in a study with an investigational drug in the month prior to study Day 1.

1007681 Subjects are prohibited from consuming the following medications 24 hours before any study visit or within 5 half-lives whichever is longer, and during the study except as noted: (i) any preparation of opioid agonists such as morphine, oxycodone, hydrocodone, tramadol, codeine etc.; (ii) mixed agonist/antagonist opioid preparations such as pentazocine, nalbuphine, butorphanol, or buprenorphine; (iii) drugs that may cause respiratory depression such as sedatives, antihistamines, or psychotropic drugs taken less than 24 hours prior to each visit or within 5 half-lives, whichever is longer; (iv) other analgesic preparations such as NSAlDs, Cox-2 inhibitors, or acetaminophen; (v) alcohol taken within 24 hours before study visit; (vi) barbiturates and benzodiazepines; (vii) other hypnotics and sedatives; (viii) MAO inhibitors; (ix) β-blockers; (x) other known P450 inducers or inhibitors |00769| Drugs

[00770| Quercetin dihydrate: quercetin dihydrate is micronized and comes in the form of a yellow powder. The appropriate amount of drug substance, calculated on an anhydrous basis and corrected for 100% potency based on the Certificate of Analysis, and Captisol (beta-cyclodextrinsulfobutyl ether, sodium salt = solubilizing agent) are reconstituted in Sterile Water for Injection (WFI) with the addition of sodium hydroxide and hydrochloric acid to adjust the solution to about pH 7.6 and 8.4. The reconstituted solution is aseptically transferred to an IV bag containing sterile saline to prepare the infusion solutions for patient administration. Placebo- quercetin dihydrate consists of Captisol reconstituted in WFI and added to a sterile saline IV bag. The infusion times are 20 minutes.

[007711 Morphine: Commercially available preparations of morphine sulfate for IV infusion are used. Doses are expressed in terms of morphine sulfate and are prepared as per the standard of care at the site. Morphine is infused over 5 minutes.

|00772] Treatment: The subjects are randomly assigned, in groups of 5, to 5 treatment groups to receive treatment according to Table 3, in separate treatment periods. Quercetin dihydrate is dosed 60 minutes prior to morphine. Morphine infusions are given approximately every 10 minutes (-10 min - 0 on Figures 1 1 - 13). The subjects are treated in four weekly repeat exposures. There is a washout of 7 days between treatment periods. [00773| The Table, below, provides exemplary dosing schemes for quercetin dihydrate and Morphine. Table 3: Dosing scheme for quercetin dihydrate and Morphine

Quercetin dihydrate -0 - vehicle

MO.05 - morphine 0.05 mg/kg Quercetin dihydrate -20 - 20 mg MO.10 - morphine 0.10 mg/kg Quercetin dihydrate -50 - 50 mg

Quercetin dihydrate - 200 mg [00774] Measurement of Testosterone: A blood sample is collected before and after the treatment with morphine. Testosterone levels in the blood are measured using liquid chromatography tandem mass spectrometry (LC-MS/MS). a. Reagents

|00775| HPLC-grade ethyl acetate, hexane, methanol, water, and sodium hydroxide are purchased from Fisher Scientific (Waltham, MA). Testosterone (>99% pure Sigma Aldrich, St. Louis, MO) and 1 ,2 deuterated (D2> testosterone (>98% pure, Cambridge Isotope Laboratories, Inc., Andover, MA) are used as the internal standard for testosterone quantitation so that the isotopic peak of testosterone from Cl 3 natural abundance does not interfere with the molecular ion of the recovery standard. Batches of steroid free serum (MP Biomedicals, Solon, OH) are charcoal treated and verified to have non-detectable testosterone by LC-MS/MS prior to use. Stock testosterone (69.3 nmol/L or 2000 ng/dL) solutions are prepared in ethanol and diluted with methanol to a final concentration of D2- testosterone at 10.4 nmol/L. Three sample pools for precision studies are prepared by spiking steroid free serum with testosterone spanning the low, middle, and high end of the calibration curve. b. Specimen Preparation before LC-MS/MS assay

[00776| Recovery (internal) standards are prepared by pipetting 25 μL of the internal standard solutions containing D2- testosterone (0.26 pmol, 75 pg), into separate 13 x 100mm glass tubes and dried under nitrogen. Aliquots (10OuL) of blank, standards, quality controls, and samples are then pipetted into the glass tubes containing the recovery standards and extracted with 2 mL ethyl acetate: hexanes (3:2 volume: volume). The samples are vortexed for two minutes, allowed to stand for ten minutes and the organic layer removed to another glass tube. The extraction procedure is repeated once and the organic phase is pooled. The acidic contaminants in the extract are removed by adding 350 μL of 0.1 moI/L sodium hydroxide to the extract, mixing the samples for 2 minutes, standing for 15 minutes, and the organic layer is transferred to another glass tube before drying. The dried sample extracts are reconstituted with lOOμL of 25% methanol (75% water, 0.1% formic acid) and transferred into 1.5mL vials fitted with a 300μL inserts for LC-MS/MS analysis. During the development of the method, solid phase extraction is initially tested. This is time-consuming, by using about 15 ml of solvent, and recovery of T is about 50% compared to the simple liquid:/liquid extraction method described above.

C. LC-MS/MS

[00777| Testosterone analysis is conducted using a Shimadzu HPLC system (Columbia, MD) attached to an Applied Biosystems AP1-5000 LC-MS/MS (Foster City, CA). A Thermo Hypersil GOLD (100mm x lmm, 3um) column (Waltham, MA) is used with a gradient profile at an optimal flow rate of 0.045mL/min for the detection of testosterone (mobile phase solvents MeOH and 2% MeOH, 0.1% formic acid and 98% H2O). Testosterone is analyzed using the turbo ion spray source in the positive mode. The parent/product ions for testosterone and D2Testosterone are monitored at 289.2/109.0 m/z and 291.2/1 10.9 m/z. d. Preparation of Calibration Standards

[00778) The concentrations of the standards in steroid free serum are 0.035, 0.069, 0.173, 0.347, 0.867, 1.734, 10.40, 34.67 and 69.34 nmol/L (1, 2, 5, 10, 25, 50,300, 1000 and 2000 ng/dL) for testosterone. The calibration curve is analyzed by Analyst® software (Concord, Ontario, Canada) using the known standard concentrations versus the ratio of analyte peak area to internal standard peak area. e. LC-MS/MS Assay Validation [00779| The LC-MS/MS method is validated according to the guidelines and best practices for chromatographic assays set forth by the Food and Drug Administration.

|00780| Results: Figure 11 shows the changes in total circulating testosterone after treatment with morphine alone or in combination with quercetin dihydrate. The solid gray line represents the changes in total testosterone after treatment with morphine at a dose of 0.1 mg/kg. The dotted gray line represents the changes in total testosterone after treatment with morphine at a dose of 0.05 mg/kg. The solid red line represents the changes in total testosterone after treatment with morphine at a dose of 0.1 mg/kg in combination with quercetin dihydrate at a dose of 50. Total testosterone levels are highest in the morning and drop over the course of the day (diurnal variation). At either dose of morphine the levels of total testosterone decrease 90 minutes after treatment as indicated by the solid and dotted gray lines. Low dose morphine shows partial recovery at the 6 hour time point. Quercetin dihydrate at 50 mg (solid red line) and 20 mg (data not shown) produce significant sparing of total circulating testosterone at both post-morphine time points.

[00781 ] Figure 12 shows the changes in free circulating testosterone after treatment with morphine alone or in combination with quercetin dihydrate. The solid gray line represents the changes in free testosterone after treatment with morphine at a dose of 0.1 mg/kg. The dotted gray line represents the changes in free testosterone after treatment with morphine at a dose of 0.05 mg/kg. The solid red line represents the changes in free testosterone after treatment with morphine at a dose of 0.1 mg/kg in combination with quercetin dihydrate at a dose of 50. Free testosterone levels are highest in the morning and dropped over the course of the day (diurnal variation). At either dose of morphine the levels of free testosterone decrease 90 minutes after treatment as indicated by the solid and dotted gray lines. Low dose morphine shows partial recovery at the 6 hour time point. Quercetin dihydrate at 50 mg (solid red line) and 20 mg (data not shown) produce significant sparing of free circulating testosterone at both post-morphine time points.

[00782] Figure 13 shows the changes in free androgen index after treatment with morphine alone or in combination with quercetin dihydrate. The solid gray line represents the changes in free androgen index after treatment with morphine at a dose of 0.1 mg/kg. The dotted gray line represents the changes in free androgen index after treatment with morphine at a dose of 0.05 mg/kg. The solid red line represents the changes in free androgen index after treatment with morphine at a dose of 0.1 mg/kg in combination with quercetin dihydrate at a dose of 50. Free androgen index levels are highest in the morning and dropped over the course of the day (diurnal variation). At either dose of morphine the levels of free androgen index decrease 90 minutes after treatment as indicated by the solid and dotted gray lines. Low dose morphine showed partial recovery at the 6 hour time point. Quercetin dihydrate at 50 mg (solid red line) and 20 mg (data not shown) produce significant sparing of free androgen index at both post-morphine time points.

[00783| The results of free androgen index are consistent with other testosterone indices and it suggests a possible gonadal benefit.

[00784| All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from 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. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A composition comprising a therapeutic agent capable of inducing one or more symptoms of hypogonadism and a BTB transport protein modulator, wherein the therapeutic agent is present in an amount sufficient to produce a therapeutic effect, and wherein the BTB transport protein modulator is present in an amount sufficient to reduce one or more symptoms of hypogonadism induced by said therapeutic agent.

2. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier.

3. The composition of claim 1 wherein said therapeutic agent is selected from the group consisting of an anti hypertensive and an opiate.

4. The composition of claim 1 wherein said therapeutic agent is an opiate.

5. The composition of claim 4 wherein said opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu- enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine.

6. The composition of claim 5 wherein said opiate is morphine.

7. The composition of claim 1 wherein the BTB transport protein is a BBB transport protein.

8. The composition of claim 1 wherein the BTB transport protein is an ABC transport protein.

9. The composition of claim 8 wherein the ABC transport protein is a P-gP.

10. The composition of claim 1 wherein said BTB transport protein modulator is a flavonoid or flavonoid derivative.

1 1. The composition of claim 10 wherein said flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

12. The composition of claim 1 1 wherein said flavonoid or flavonoid derivative is quercetin or a quercetin derivative.

13. The composition of claim 12, wherein said quercetin or quercetin derivative is 5,7-dideoxyquercetin.

14. The composition of claim 12, wherein said quercetin or quercetin derivative is phosphorylated.

15. The composition of claim 14, wherein said phosphorylated quercetin is 3'-quercetin phosphate, 4'- quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof.

16. The composition of claim 14, wherein said phosphorylated quercetin is 3-quercetin phosphate.

17. The composition of claim 14, wherein said phosphorylated quercetin is 4'-quercetin phosphate.

18. The composition of claim 14, wherein said phosphorylated quercetin is a mixture of 3 '-quercetin phosphate and 4'-quercetin phosphate.

19. The composition of claim 18, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate.

20. The composition of claim 18, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate.

21. The composition of claim 10, wherein said flavonoid or flavonoid derivative is fisetin or a fisetin derivative.

22. The composition of claim 21 , wherein said fisetin or fisetin derivative is phosphorylated.

23. The composition of claim 22, wherein said phosphorylated fisetin is 3'-fisetin phosphate, 4'-fisetin phosphate, 3-fiscetin phosphate, or a combination thereof..

24. The composition of claim 1 , further comprising an oligosaccharide.

25. The composition of claim 24, wherein said oligosaccharide is a cyclic oligosaccharide.

26. The composition of claim 25, wherein said oligosaccharide is a cyclodextrin.

27. The composition of claim 26, wherein said cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin.

28. The composition of claim 26, wherein said cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof.

29. The composition of claim 1 , wherein said therapeutic agent is morphine and said flavonoid or flavonoid derivative is quercetin a quercetin derivative, fisetin or a fisetin derivative.

30. The composition of claim 29, wherein said quercetin derivative is quercetin phosphate.

31. The composition of claim 29, wherein said fisetin derivative is fisetin phosphate.

32. The composition of claim 29 wherein morphine and quercetin or fisetin are present in a molar ratio of about 0.001 :1 to 10: 1.

33. The composition of claim 29 wherein morphine is present at about 1 - 500 mg and quercetin or fisetin is present at about 10- 1000 mg.

34. The composition of claim 29 wherein morphine is present at about 10 - 200 mg and quercetin or fisetin is present at about 50-500 mg.

35. The composition of claim 29 wherein morphine is present at about 50 mg and quercetin or fisetin is present at about 500 mg.

36. The composition of claim 1 wherein said therapeutic agent is sufentanyl and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, fisetin or fisetin phosphate.

37. The composition of claim 1 wherein said therapeutic agent is alfentanyl and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, or fisetin phosphate.

38. The composition of claim 1 wherein said therapeutic agent is remifentanyl and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, fisetin or fisetin phosphate.

39. The composition of claim 1 wherein a symptom of hypogonadism induced by said therapeutic agent is decreased by an average of at least about 5% compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal.

40. The composition of claim 1 wherein said symptom is a result of impairment of secretion of one or more hypothalamic-releasing hormones.

41. The composition of claim 1 wherein said symptom is selected from the group consisting of premature menopause, decrease of energy, fatigue, muscle mass decline, increase visceral fat, decreased positive mood factors and an increased negative mood factors, depression, decrease in fertility, decrease in libido and sexual function, increased risk for osteoporosis, increased pain sensitization, hematological abnormalities, decrease in cognitive skills, sleep disturbances, vasomotor instability, increase CAD risk, changes in secondary sex characteristic and decrease in circulating sex hormones.

42. The composition of claim 41 wherein said symptom is a decrease in circulating sex hormones.

43. The composition of claim 42 wherein the amount of said BTB transport modulator is sufficient to prevent, reduce, or eliminate said decrease in circulating sex hormones.

44. The composition of claim 42 wherein said symptom is a decrease in circulating testosterone.

45. A kit comprising the composition of claim 1 and instructions for use of the composition.

46. A method of decreasing or preventing the appearance of one or more symptoms of hypogonadism induced by a therapeutic agent comprising administering to a subject receiving said therapeutic agent an amount of a BTB transport protein modulator sufficient to prevent, reduce or eliminate said one or more symptoms of hypogonadism.

47. The method of claim 46 wherein said subject is suffering from or is suspected to suffer from one or more symptoms of hypogonadism induced or capable of being induced by treatment with said therapeutic agent

48. The method of claim 46 wherein said BTB transport protein modulator is a BTB protein transport activator.

49. The method of claim 46 wherein said symptom is selected from the group consisting of premature menopause, decrease of energy, fatigue, muscle mass decline, increase visceral fat, decreased positive mood factors and an increased negative mood factors, depression, decrease in fertility, decrease in libido and sexual function, increased risk for osteoporosis, increased pain sensitization, hematological abnormalities, decrease in cognitive skills, sleep disturbances, vasomotor instability, increase CAD risk, changes in secondary sex characteristic and decrease in circulating sex hormones.

50. The method of claim 49 wherein said symptom is a decrease in circulating sex hormones.

51. The method of claim 50 wherein said symptom is a decrease in circulating testosterone.

52. The method of claim 46 wherein the BTB transport protein is a BBB transport protein.

53. The method of claim 46 wherein said BTB transport protein is an ABC transport protein.

54. The method of claim 53 wherein said ABC transport protein is P-gP.

55. The method of claim 46 wherein said BTB transport protein modulator is a flavonoid or flavonoid derivative.

56. The method of claim 55 wherein said flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

57. The method of claim 56 wherein said flavonoid or flavonoid derivative is quercetin or a quercetin derivative.

58. The composition of claim 57, wherein said quercetin or quercetin derivative is 5,7-dideoxyquercetin.

59. The composition of claim 57, wherein said quercetin or quercetin derivative is phosphorylated.

60. The composition of claim 59, wherein said phosphorylated quercetin is 3'-quercetin phosphate, 4'- quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof.

61. The composition of claim 59, wherein said phosphorylated quercetin is 3 '-quercetin phosphate.

62. The composition of claim 59, wherein said phosphorylated quercetin is 4'-quercetin phosphate.

63. The composition of claim 59, wherein said phosphorylated quercetin is a mixture of 3 '-quercetin phosphate and 4'-quercetin phosphate.

64. The composition of claim 63, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate.

65. The composition of claim 63, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate.

66. The composition of claim 55, wherein said flavonoid or flavonoid derivative is fisetin or a fisetin derivative.

67. The composition of claim 66, wherein said fisetin or fisetin derivative is phosphorylated.

68. The composition of claim 67, wherein said phosphorylated fisetin is 3 '-fisetin phosphate, 4 '-fisetin phosphate, 3-fiscetin phosphate, or a combination thereof..

69. The composition of claim 46, further comprising an oligosaccharide.

70. The composition of claim 69, wherein said oligosaccharide is a cyclic oligosaccharide.

71. The composition of claim 69, wherein said oligosaccharide is a cyclodextrin.

72. The composition of claim 71, wherein said cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin.

73. The composition of claim 71, wherein said cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof.

74. The method of claim 46 wherein said therapeutic agent is selected from the group consisting of an anti hypertensive and an opiate.

75. The method of claim 74 wherein said therapeutic agent is an opiate.

76. The method of claim 75 wherein said opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu- enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine.

77. The method of claim 76 wherein said opiate is morphine.

78. The method of claim 76 wherein said opiate is sufentanyl.

79. The method of claim 76 wherein said opiate is alfentanyl.

80. The method of claim 76 wherein said opiate is remifentanyl.

81. The method of claim 46 wherein said administration comprises single or multiple doses of said therapeutic agent and single or multiple doses of said BTB transport protein modulator.

82. The method of claim 46 wherein said administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form, concurrent administration in separate dosage forms, or separate administration.

83. The method of claim 82 wherein said administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form.

84. The method of claim 46 wherein the molar ratio of the amount of the therapeutic agent administered and the amount of BTB transport protein modulator administered is about 0.001 : 1 to about 10: 1.

85. The method of claim 46 wherein the therapeutic agent is administered in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is administered in an amount sufficient to decrease a symptom of hypogonadism induced by the therapeutic agent by an average of at least about 5%, compared to the symptom without the BTB transport protein modulator.

86. A composition comprising a therapeutic agent capable of inducing a decrease in circulating sex hormone levels and a BTB transport protein modulator, wherein the therapeutic agent is present in an amount sufficient to produce a therapeutic effect, and wherein the BTB transport protein activator is present in an amount sufficient to prevent or reduce a therapeutic agent-induced decrease in circulating sex hormone levels.

87. The composition of claim 86 wherein the decrease in circulating sex hormone is selected from the group consisting of decrease in circulating androgens, decrease in circulating estrogens, and decrease in circulating progestagens.

88. The composition of claim 87 wherein the decrease in circulating sex hormone is decrease in circulating androgens.

89. The composition of claim 88 wherein the decrease in circulating androgens is selected from the group consisting decrease in circulating testosterone, decrease in circulating androstenedione, decrease in circulating dihydrotestosterone, decrease in circulating dehydroepiandrosterone, and decrease in circulating anabolic steroids.

90. The composition of claim 89 wherein the decrease in circulating androgens is impairment in testosterone.

91. A pharmaceutical composition comprising the composition of claim 86 and a pharmaceutically acceptable carrier.

92. The composition of claim 86 wherein said therapeutic agent is selected from the group consisting of an anti hypertensive and an opiate.

93. The composition of claim 92 wherein said therapeutic agent is an opiate.

94. The composition of claim 93 wherein said opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu- enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine.

95. The composition of claim 94 wherein said opiate is morphine.

96. The composition of claim 86 wherein the BTB transport protein is a BBB transport protein.

97. The composition of claim 86 wherein the BTB transport protein is an ABC transport protein.

98. The composition of claim 97 wherein the ABC transport protein is a P-gP.

99. The composition of claim 86 wherein said BTB transport protein modulator is a flavonoid or flavonoid derivative.

100. The composition of claim 99 wherein said flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

101. The composition of claim 100 wherein said flavonoid or flavonoid derivative is quercetin or a quercetin derivative.

102. The composition of claim 101, wherein said quercetin or quercetin derivative is 5,7-dideoxyquercetin.

103. The composition of claim 101, wherein said quercetin or quercetin derivative is phosphorylated.

104. The composition of claim 103, wherein said phosphorylated quercetin is 3 '-quercetin phosphate, 4'- quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof.

105. The composition of claim 103, wherein said phosphorylated quercetin is 3 '-quercetin phosphate.

106. The composition of claim 103, wherein said phosphorylated quercetin is 4'-quercetin phosphate.

107. The composition of claim 103, wherein said phosphorylated quercetin is a mixture of 3 '-quercetin phosphate and 4'-quercetin phosphate.

108. The composition of claim 107, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate.

109. The composition of claim 107, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate.

1 10. The composition of claim 99, wherein said flavonoid or flavonoid derivative is fisetin or a fisetin derivative.

1 1 1. The composition of claim 1 10, wherein said fisetin or fisetin derivative is phosphorylated.

1 12. The composition of claim 1 1 1 , wherein said phosphorylated fisetin is 3 '-fisetin phosphate, 4'-fisetin phosphate, 3-fϊscetin phosphate, or a combination thereof.

113. The composition of claim 86, further comprising an oligosaccharide.

1 14. The composition of claim 1 13, wherein said oligosaccharide is a cyclic oligosaccharide.

1 15. The composition of claim 1 13, wherein said oligosaccharide is a cyclodextrin.

1 16. The composition of claim 115, wherein said cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin.

1 17. The composition of claim 115, wherein said cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof.

1 18. The composition of claim 86 wherein said therapeutic agent is morphine and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, fisetin or fisetin fisetin phosphate.

1 19. The composition of claim 1 18 wherein morphine and quercetin are present in a molar ratio of about 0.001: 1 to 10: 1.

120. The composition of claim 1 18 wherein morphine is present at about 1- 500 mg and quercetin is present at about 10-1000 mg.

121. The composition of claim 120 wherein said morphine is present at about 10 - 200 mg and quercetin is present at about 50-500 mg.

122. The composition of claim 121 wherein morphine is present at about 50 mg and quercetin is present at about 500 mg.

123. The composition of claim 86 wherein said therapeutic agent is sufentanyl and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, fisetin or fisetin phosphate.

124. The composition of claim 861 wherein said therapeutic agent is alfentanyl and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, fisetin or fisetin phosphate.

125. The composition of claim 86 wherein said therapeutic agent is remifentanyl and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, fisetin or fisetin phosphate.

126. The composition of claim 86 wherein said impairment in sex hormone secretion induced by said therapeutic agent is decreased at least about 5% compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal.

127. A kit comprising the composition of claim 86 and instructions for use of the composition

128. A method of preventing or reducing a therapeutic agent-induced decrease in circulate sex hormone levels comprising: providing a subject receiving treatment with said therapeutic agent with a known or suspected decrease in circulating sex hormone levels administering to said subject an amount of a BTB transport protein modulator sufficient to prevent, reduce or eliminate said therapeutic agent-induced decrease in circulating sex hormone levels in combination with said therapeutic agent.

129. The method of claim 128 wherein the decrease in circulating sex hormone levels is selected from the group consisting of decrease in circulating androgen levels, decrease in circulating estrogen levels, and decrease in circulating progestagen levels.

130. The method of claim 129 wherein the decrease in circulating sex hormone levels is impairment in androgen levels.

131. The method of claim 130 wherein the decrease in circulating androgen levels is selected from the group consisting of decrease in circulating testosterone decrease in circulating, decrease in circulating androstenedione levels, decrease in circulating dihydrotestosterone levels, decrease in circulating dehydroepiandrosterone levels, decrease in circulating anabolic steroids levels.

132. The method of claim 131 wherein the decrease in circulating androgen levels is decrease in circulating testosterone levels.

133. The method of claim 128 wherein the BTB transport protein is a BBB transport protein.

134. The method of claim 128 wherein said BTB transport protein modulator is a BTB protein transport activator.

135. The method of claim 128 wherein said BTB transport protein is an ABC transport protein.

136. The method of claim 135 wherein said ABC transport protein is P-gP.

137. The method of claim 128 wherein said BTB transport protein modulator is a flavonoid or flavonoid derivative.

138. The method of claim 137 wherein said flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

139. The method of claim 138 wherein said flavonoid or flavonoid derivative is quercetin or a quercetin derivative.

140. The composition of claim 139, wherein said quercetin or quercetin derivative is 5,7-dideoxyquercetin.

141. The composition of claim 139, wherein said quercetin or quercetin derivative is phosphorylated.

142. The composition of claim 141 , wherein said phosphorylated quercetin is 3'-quercetin phosphate, 4'- quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof.

143. The composition of claim 141 , wherein said phosphorylated quercetin is 3'-quercetin phosphate.

144. The composition of claim 141 , wherein said phosphorylated quercetin is 4'-quercetin phosphate.

145. The composition of claim 141 , wherein said phosphorylated quercetin is a mixture of 3'-quercetin phosphate and 4'-quercetin phosphate.

146. The composition of claim 145, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1 % or at least 99.9% of 3 '-quercetin phosphate.

147. The composition of claim 145, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate.

148. The composition of claim 137, wherein said flavonoid or flavonoid derivative is fisetin or a fisetin derivative.

149. The composition of claim 148, wherein said fisetin or fisetin derivative is phosphorylated.

150. The composition of claim 149, wherein said phosphorylated fisetin is 3'-fisetin phosphate, 4'-fisetin phosphate, 3-fiscetin phosphate, or a combination thereof..

151. The composition of claim 128, further comprising an oligosaccharide.

152. The composition of claim 151 , wherein said oligosaccharide is a cyclic oligosaccharide.

153. The composition of claim 151 , wherein said oligosaccharide is a cyclodextrin.

154. The composition of claim 153, wherein said cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin.

155. The composition of claim 153, wherein said cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof.

156. The method of claim 128 wherein said therapeutic agent is selected from the group consisting of an anti hypertensive and an opiate.

157. The method of claim 156 wherein said therapeutic agent is an opiate.

158. The method of claim 157 wherein said opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu- enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine.

159. The method of claim 158 wherein said opiate is morphine.

160. The method of claim 158 wherein said opiate is sufentanyl.

161. The method of claim 158 wherein said opiate is alfentanyl.

162. The method of claim 158 wherein said opiate is remifentanyl.

163. The method of claim 128 wherein said administration comprises single or multiple doses of said therapeutic agent and single or multiple doses of said BTB transport protein modulator.

164. The method of claim 128 wherein said administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form, concurrent administration in separate dosage forms, or separate administration.

165. The method of claim 164 wherein said administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form.

166. The method of claim 128 wherein the molar ratio of the amount of the therapeutic agent administered and the amount of BTB transport protein modulator administered is about 0.001 : 1 to about 10: 1.

167. The method of claim 128 wherein the therapeutic agent is administered in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is administered in an amount sufficient to decrease an impairment in sex hormone secretion induced by the therapeutic agent by an average of at least about 5%, compared to the impairment without the BTB transport protein modulator.

168. A method of preventing or reducing a therapeutic agent-induced decrease in circulating androgen levels comprising determining the sex of a subject receiving treatment with said therapeutic agent administering to the subject an amount of a BTB transport protein modulator sufficient to prevent, reduce or eliminate said therapeutic agent-induced decrease in circulating androgen levels in combination with said therapeutic agent.

169. The method of claim 168 wherein the decrease circulating androgen levels is selected from the group consisting of impairment in testosterone secretion, impairment in androstenedione secretion, impairment in dihydrotestosterone secretion, impairment in dehydroepiandrosterone secretion, impairment in anabolic steroids secretion.

170. The method of claim 169 wherein the decrease circulating androgen levels is impairment in testosterone secretion.

171. The method of claim 168 wherein the BTB transport protein is a BBB transport protein.

172. The method of claim 168 wherein said BTB transport protein modulator is a BTB protein transport activator.

173. The method of claim 168 wherein said BTB transport protein is an ABC transport protein.

174. The method of claim 173 wherein said ABC transport protein is P-gP.

175. The method of claim 168 wherein said BTB transport protein modulator is a flavonoid or flavonoid derivative.

176. The method of claim 175 wherein said flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

177. The method of claim 176 wherein said flavonoid or flavonoid derivative is quercetin or a quercetin derivative.

178. The composition of claim 177, wherein said quercetin or quercetin derivative is 5,7-dideoxyquercetin.

179. The composition of claim 177, wherein said quercetin or quercetin derivative is phosphorylated.

180. The composition of claim 179, wherein said phosphorylated quercetin is 3'-quercetin phosphate, 4'- quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof.

181. The composition of claim 179, wherein said phosphorylated quercetin is 3 '-quercetin phosphate.

182. The composition of claim 179, wherein said phosphorylated quercetin is 4'-quercetin phosphate.

183. The composition of claim 179, wherein said phosphorylated quercetin is a mixture of 3 '-quercetin phosphate and 4'-quercetin phosphate.

184. The composition of claim 183, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate.

185. The composition of claim 183, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate.

186. The composition of claim 175, wherein said flavonoid or flavonoid derivative is fisetin or a fisetin derivative.

187. The composition of claim 186, wherein said fisetin or fisetin derivative is phosphorylated.

188. The composition of claim 187, wherein said phosphorylated fisetin is 3'-fisetin phosphate, 4'-fisetin phosphate, 3-fiscetin phosphate, or a combination thereof.

189. The composition of claim 168, further comprising an oligosaccharide.

190. The composition of claim 189, wherein said oligosaccharide is a cyclic oligosaccharide.

191. The composition of claim 189, wherein said oligosaccharide is a cyclodextrin.

192. The composition of claim 191 , wherein said cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin.

193. The composition of claim 191 , wherein said cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof.

194. The method of claim 168 wherein said therapeutic agent is selected from the group consisting of an anti hypertensive and an opiate.

195. The method of claim 194wherein said therapeutic agent is an opiate.

196. The method of claim 195 wherein said opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu- enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine.

197. The method of claim 196 wherein said opiate is morphine.

198. The method of claim 196 wherein said opiate is sufentanyl.

199. The method of claim 196 wherein said opiate is alfentanyl.

200. The method of claim 196 wherein said opiate is remifentanyl.

201. The method of claim 168 wherein said administration comprises single or multiple doses of said therapeutic agent and single or multiple doses of said BTB transport protein modulator.

202. The method of claim 168 wherein said administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form, concurrent administration in separate dosage forms, or separate administration.

203. The method of claim 202 wherein said administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form.

204. The method of claim 168 wherein the molar ratio of the amount of the therapeutic agent administered and the amount of BTB transport protein modulator administered is about 0.001 : 1 to about 10: 1.

205. The method of claim 168 wherein the therapeutic agent is administered in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is administered in an amount sufficient to reduce a decrease in circulating androgen levels induced by the therapeutic agent by an average of at least about 5%, compared to the impairment without the BTB transport protein modulator.

206. A composition comprising a therapeutic agent capable of inducing one or more symptoms of impairment in hypothalamic/pituitary/endocrine function and a BTB transport protein modulator, wherein the therapeutic agent is present in an amount sufficient to produce a therapeutic effect, and wherein the BTB transport protein modulator is present in an amount sufficient to reduce one or more symptoms of a therapeutic agent-induced impairment in hypothalamic/pituitary/endocrine function.

207. The composition of claim 206 wherein said symptom is at least partially a result of impairment of secretion of one or more hypothalamic-releasing hormones.

208. The composition of claim 207 wherein said hypothalamic-releasing hormone is selected from the group consisting of corticotropin-releasing hormone (CRH), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, and thyrotropin-releasing hormone (TRH).

209. The composition of claim 206 wherein said symptom is at least partially a result of impairment in hypothalamic response to one or more stimuli.

210. The composition of claim 209 wherein said stimulus is selected from the group consisting of light, olfactory stimuli, steroids, neurally transmitted information, autonomic inputs, blood-borne stimuli, stress, changes in temperature and an invading microorganism.

211. The composition of claim 206 wherein said symptom is at least partially a result of impairment in pituitary response to one or more hypothalamic-releasing hormones.

212. The composition of claim 21 1 wherein said symptom is at least partially a result of impairment of secretion of one or more pituitary hormones.

213. The composition of claim 206 wherein said symptom is at least partially a result of impairment in a response of one or more endocrine glands to one or more pituitary hormones.

214. The composition of claim 212 or 213 wherein said pituitary hormone is selected from the group consisting of ACTH, TSH, prolactin, growth hormone, endorphins, FSH, LH, oxytocin, and antidiuretic hormone (ADH).

215. The composition of claim 206 wherein said therapeutic agent is selected from the group consisting of an anti-hypertensive and an opiate.

216. The composition of claim 215 wherein said therapeutic agent is an opiate.

217. The composition of claim 216 wherein said opiate is selected from the group consisting of codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu- enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine.

218. The composition of claim 217 wherein said opiate is morphine.

219. The composition of claim 206 wherein the BTB transport protein is a BBB transport protein.

220. The composition of claim 206 wherein the BTB transport protein is an ABC transport protein.

221. The composition of claim 220 wherein the ABC transport protein is P-gP.

222. The composition of claim 206 wherein said BTB transport protein modulator is a flavonoid or flavonoid derivative.

223. The composition of claim 222 wherein said flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

224. The composition of claim 223 wherein said flavonoid or flavonoid derivative is quercetin or a quercetin derivative.

225. The composition of claim 224, wherein said quercetin or quercetin derivative is 5,7-dideoxyquercetin.

226. The composition of claim 224, wherein said modified quercetin or quercetin derivative is phosphorylated.

227. The composition of claim 226, wherein said phosphorylated quercetin is 3'-quercetin phosphate, 4'- quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof.

228. The composition of claim 226, wherein said phosphorylated quercetin is 3 '-quercetin phosphate.

229. The composition of claim 226, wherein said phosphorylated quercetin is 4'-quercetin phosphate.

230. The composition of claim 226, wherein said phosphorylated quercetin is a mixture of 3 '-quercetin phosphate and 4'-quercetin phosphate.

231. The composition of claim 230, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate.

232. The composition of claim 230, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4 '-quercetin phosphate.

233. The composition of claim 222, wherein said flavonoid or flavonoid derivative is fisetin or a fisetin derivative.

234. The composition of claim 233, wherein said fisetin or fisetin derivative is phosphorylated.

235. The composition of claim 234, wherein said phosphorylated fisetin is 3'-fisetin phosphate, 4'-fisetin phosphate, 3-fiscetin phosphate, or a combination thereof..

236. The composition of claim 206, further comprising an oligosaccharide.

237. The composition of claim 236, wherein said oligosaccharide is a cyclic oligosaccharide.

238. The composition of claim 2361, wherein said oligosaccharide is a cyclodextrin.

239. The composition of claim 238, wherein said cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfobutyl-ether susbstituted cyclodextrin.

240. The composition of claim 238, wherein said cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodexrrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof,

241. The composition of claim 206 wherein said therapeutic agent is sufentanyl and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, fisetin or fisetin phosphate.

242. The composition of claim 206 wherein said therapeutic agent is alfentanyl and said flavonoid or flavonoid derivative is quercetin, quercetin phosphate, fisetin or fisetin phosphate.

243. The composition of claim 206 wherein said therapeutic agent is remifentanyl and said flavonoid or flavonoid derivative is quercetin quercetin phosphate, fisetin or fisetin phosphate.

244. The composition of claim 206 wherein a symptom of a therapeutic agent-induced impairment in hypothalamic/pituitary/endocrine function is decreased at least about 5% compared to the symptom without the BTB transport protein modulator, when the composition is administered to an animal.

245. A kit comprising the composition of claim 206 and instructions for use of the composition.

246. A method of decreasing or preventing the appearance of one or more symptoms of impairment in hypothalamic/pituitary endocrine function induced by a therapeutic agent comprising administering_a subject receiving or who is going to receive treatment with said therapeutic agent an amount of a BTB transport protein modulator sufficient to reduce said impairment in hypothalamic function in combination with said therapeutic agent.

247. The method of claim 246 wherein said subject has or is suspected to have impairment in a hypothalamic/pituitary/endocrine function.

248. The method of claim 246 wherein said symptom is at least partially a result of impairment of secretion of one or more hypothalamic-releasing hormone.

249. The method of claim 248 wherein said hypothalamic-releasing hormone is selected from the group consisting of corticotropin-releasing hormone (CRH), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, and thyrotropin-releasing hormone (TRH).

250. The method of claim 246 wherein said symptom is at least partially a result of impairment in hypothalamic response to one or more stimuli.

251. The method of claim 250 wherein said stimuli is selected from the group consisting of light, olfactory stimuli, steroids, neurally transmitted information, autonomic inputs, blood-borne stimuli, stress, changes in temperature and an invading microorganism.

252. The method of claim 246 wherein said symptom is at least partially a result of impairment in pituitary response to one or more hypothalamic-releasing hormone.

253. The method of claim 252 wherein said symptom is at least partially a result of impairment of secretion of one or more pituitary hormones.

254. The method of claim 246 wherein said symptom is at least partially a result of impairment in a response of one or more endocrine glands to one or more pituitary hormones.

255. The method of claim 253 or 254 wherein said pituitary hormone is selected from the group consisting of ACTH, TSH, prolactin, growth hormone, endorphins, FSH, LH, Oxytocin, and antidiuretic hormone (ADH).

256. The method of claim 246 wherein the BTB transport protein is a BBB transport protein.

257. The method of claim 246 wherein said BTB transport protein is an ABC transport protein.

258. The method of claim 257 wherein said ABC transport protein is P-gP.

259. The method of claim 246 wherein said BTB transport protein modulator is a flavonoid or flavonoid derivative.

260. The method of claim 259 wherein said flavonoid or flavonoid derivative is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

261. The method of claim 260 wherein said flavonoid or flavonoid derivative is quercetin or a quercetin derivative.

262. The composition of claim 261, wherein said quercetin or quercetin derivative is 5,7-dideoxyquercetin.

263. The composition of claim 261 , wherein said modified quercetin or quercetin derivative is phosphorylated.

264. The composition of claim 263, wherein said phosphorylated quercetin is 3'-quercetin phosphate, 4'- quercetin phosphate, 5,7-dideoxyquercetin phosphate, or a combination thereof.

265. The composition of claim 263, wherein said phosphorylated quercetin is 3'-quercetin phosphate.

266. The composition of claim 263, wherein said phosphorylated quercetin is 4'-quercetin phosphate.

267. The composition of claim 263, wherein said phosphorylated quercetin is a mixture of 3 '-quercetin phosphate and 4'-quercetin phosphate.

268. The composition of claim 267, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 3 '-quercetin phosphate.

269. The composition of claim 267, wherein said phosphorylated quercetin mixture comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.1% or at least 99.9% of 4'-quercetin phosphate.

270. The composition of claim 259, wherein said flavonoid or flavonoid derivative is fisetin or a fisetin derivative.

271. The composition of claim 270, wherein said fisetin or fisetin derivative is phosphorylate.

272. The composition of claim 271 , wherein said phosphorylated fisetin is 3'-fisetin phosphate, 4'-fisetin phosphate, 3-fiscetin phosphate, or a combination thereof..

273. The composition of claim 246, further comprising an oligosaccharide.

274. The composition of claim 273, wherein said oligosaccharide is a cyclic oligosaccharide.

275. The composition of claim 273, wherein said oligosaccharide is a cyclodextrin.

276. The composition of claim 275, wherein said cyclodextrin is a sulfo-alkyl ether substituted cyclodextrin or a sulfoburyl-ether susbstituted cyclodextrin.

277. The composition of claim 275, wherein said cyclodextrin is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether- β-cyclodextrin, sulfobutylether-7- β-cyclodextrin, Captisol or combinations thereof.

278. The method of claim 246 wherein said therapeutic agent is selected from the group consisting of an anti-hypertensive and an opiate.

279. The method of claim 246 wherein said therapeutic agent is an opiate.

280. The method of claim 279 wherein said opiate is selected from the group consisting codeine, dihydrocodeine, thebaine, papaverine, noscapine, narceine, morphine, heroin, hydromorphone, oxymorphone, oxycodone, hydrocodone, nalbuphine, buprenorphine, nalorphine, methadone, propoxyphene, dextropropoxyphene, meperidine, fentanyl, diphenoxylate, butorphanol, pentazocine, cyclazocine, pethidine, ethorphine, buprenorphine, levorphanol, levallorphan, β-endorphin, leu- enkephalin, met-enkephalin, dynorphin, meptazinol, sufentanyl, alfentanyl, remifentanyl and pholcodine.

281. The method of claim 280 wherein said opiate is morphine.

282. The method of claim 280 wherein said opiate is sufentanyl.

283. The method of claim 280 wherein said opiate is alfentanyl.

284. The method of claim 280 wherein said opiate is remifentanyl.

285. The method of claim 246 wherein said administration comprises single or multiple doses of said therapeutic agent and single or multiple doses of said BTB transport protein modulator.

286. The method of claim 246 wherein said administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form, concurrent administration in separate dosage forms, or separate administration.

287. The method of claim 286 wherein said administration comprising co-administration of said therapeutic agent and said BTB transport protein modulator in the same dosage form.

288. The method of claim 246 wherein the molar ratio of the amount of the therapeutic agent administered and the amount of BTB transport protein modulator administered is about 0.001 : 1 to about 10: 1.

289. The method of claim 246 wherein the therapeutic agent is administered in an amount sufficient to exert a therapeutic effect and the BTB transport protein modulator is administered in an amount sufficient to decrease or prevent the appearance of one or more symptoms of impairment in hypothalamic/pituitary endocrine function induced by the therapeutic agent by an average of at least about 5%, compared to the symptom without the BTB transport protein modulator.