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Title:
METHODS AND COMPOSITIONS FOR TREATMENT OF ATTENTION DEFICIT HYPERACTIVITY DISORDER
Document Type and Number:
WIPO Patent Application WO/2013/158837
Kind Code:
A1
Abstract:
The invention provides methods, compositions, and medical kits for treating attention deficit hyperactivity disorder. In particular, the invention provides a collection of active ingredients, such as curcumin, piperine, epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, and methods of using such active ingredients to treat attention deficit hyperactivity disorder. Medical kits for treating attention deficit hyperactivity disorder using a collection of the active ingredients are provided.

Inventors:
SCHEER DAVID I (US)
Application Number:
PCT/US2013/037105
Publication Date:
October 24, 2013
Filing Date:
April 18, 2013
Export Citation:
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Assignee:
CONCOURSE HEALTH SCIENCES LLC (US)
International Classes:
A61K31/4525
Foreign References:
US20110275591A12011-11-10
EP2258359A22010-12-08
Attorney, Agent or Firm:
DAVIS, Chad, E. et al. (Exchange PlaceBoston, MA, US)
Download PDF:
Claims:
Claims;

1. A method of treating attention deficit hyperactivity disorder in a patient, comprising

administering to a patent in need thereof a therapeutically effective amount of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt.

2. The method of claim 1, wherein a therapeutically effective amount of each of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, and lipoic acid are administered to the patient.

3. The method of claim 1 or 2, wherein said administering is oral administration.

4. The method of any one of claims 1-3, wherein the curcumin is administered at a daily

dosage of at least 4 mg/kg.

5. The method of any one of claims 1-4, wherein the piperine is administered at a daily dosage of at least 0.5 mg/kg.

6. The method of any one of claims 1-5, wherein the epigallocatechin-3-gallate is

administered at a daily dosage of at least 4 mg/kg.

7. The method of any one of claims 1-6, wherein the N-acetylcysteine is administered at a daily dosage of at least 2 mg/kg.

8. The method of any one of claims 1-7, wherein the benfotiamine is administered at a daily dosage of at least 0.5 mg/kg.

9. The method of any one of claims 1-8, wherein the lipoic acid is administered at a daily dosage of at least 1 mg/kg.

10. The method of any one of claims 1-9, wherein the epigallocatechin-3-gallate is provided in the form of an extract of green tea.

1 1. The method of any one of claims 1-10, wherein the curcumin is provided in the form of an extract of tumeric.

12. The method of any one of claims 1-11, wherein the lipoic acid is (R)-lipoic acid.

13. The method of any one of claims 1-12, wherein the method reduces the frequency with which the patient becomes distracted relative to the patient's rate of distraction without therapy.

14. The method of any one of claims 1-13, wherein the method improves the patient's ability to maintain mental focus on a task.

15. The method of any one of claims 1-14, wherein the patient is a human.

16. A pharmaceutical composition comprising:

a. a therapeutic agent present in an amount for treating attention deficit hyperactivity disorder in a patient and consisting essentially of curcumin, piperine,

epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt; and

b. optionally a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is in the form of a tablet or capsule.

18. The pharmaceutical composition of claim 16 or 17, wherein the therapeutic agent contains N-acetylcysteine.

19. The pharmaceutical composition of any one of claims 16-18, wherein the therapeutic agent contains benfotiamine.

20. The pharmaceutical composition of any one of claims 16-19, wherein the therapeutic agent contains lipoic acid.

21. The pharmaceutical composition of claim 16 or 17, wherein therapeutic agent consists essentially of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, and lipoic acid, each of which are optionally in the form of a pharmaceutically acceptable salt.

22. The pharmaceutical composition of any one of claims 16-21, wherein the epigallocatechin- 3-gallate is provided in the form of an extract of green tea.

23. The pharmaceutical composition of any one of claims 16-22, wherein the curcumin is provided in the form of an extract of tumeric.

24. The pharmaceutical composition of any one of claims 16-23, wherein the lipoic acid is (R)- lipoic acid.

25. A kit for treating attention deficit hyperactivity disorder, the kit comprising:

a. a pharmaceutical composition of any one of claims 16-24; and

b. instructions for treating attention deficit hyperactivity disorder.

Description:
METHODS AND COMPOSITIONS FOR TREATMENT OF ATTENTION DEFICIT

HYPERACTIVITY DISORDER

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 61/625,781, filed April 18, 2012, the contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention provides methods, compositions, and medical kits for treating attention deficit hyperactivity disorder. In particular, the invention provides a collection of active ingredients, such as curcumin, piperine, and epigallocatechin-3-gallate, and methods of using such active ingredients to treat attention deficit hyperactivity disorder.

BACKGROUND

[0003] Attention deficit hyperactivity disorder (ADHD) is one of the most common behavioral disorders suffered by children. Common features of patients suffering from ADHD include inattention, excessive motor activity, and impulsivity. Inattentive behavior can involve difficulty focusing on one task, failure to pay attention to details, and making careless mistakes. Excessive motor activity can include unusually frequent motion, suffering feelings of restlessness, and difficulty engaging in sedentary activities. Impulsivity can involve behavior where the patient frequently interrupts conversations or others' activities, is very impatient, has difficulty waiting for things they want, blurts out inappropriate comments, shows their emotions without restraint, and acts without regard for consequences. These behavioral conditions can place the patient at risk for poor educational achievement, underemployment, and difficulty maintaining normal social relationships.

[0004] ADHD has been reported to be highly heritable and genetics are believed to contribute to about three-quarters of patients suffering form ADHD. Most patients suffering from ADHD had their first symptoms of the disorder during childhood. A small number of ADHD cases have been reported where the disorder was acquired after conception due to brain injury caused by toxins or physical trauma. [0005] Current medical treatments for ADHD include the use of mild central nervous system stimulant drugs, such as Ritalin, Cylert, and Dexedrine. However, these medications can have multiple adverse side effects, including insomnia, loss of appetite, headaches, stomachaches, hyperactivity, drowsiness, and cardiac arrhythmia. As a result, there is a need for new therapies to treat ADHD.

[0006] The present invention addresses the need for new therapies to treat ADHD and provides other related advantages.

SUMMARY

[0007] The invention provides methods, compositions, and medical kits for treating attention deficit hyperactivity disorder. The methods involve administering, preferably for convenience as a mixture, a therapeutically effective amount of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid to a patient suffering from attention deficit hyperactivity disorder. A combination of the active ingredients curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be taken together to form a pharmaceutical composition, and each of these ingredients optionally may be in the form of a pharmaceutically acceptable salt. Medical kits for treating attention deficit hyperactivity disorder using a collection of the active ingredients are provided.

[0008] Accordingly, one aspect of the invention provides a method of treating attention deficit hyperactivity disorder in a patient. The method comprises administering to a patent in need thereof a therapeutically effective amount of a collection of active ingredients described herein (which collectively constitute a therapeutic agent), such as two or more of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid. The curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt. The particular collection of active ingredients administered to the patient may be selected in order to achieve a desired clinical benefit. For example, in certain embodiments, the method comprises administering to a patent in need thereof a therapeutically effective amount of curcumin, piperine,

epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt. Further, the curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be administered in the form of an extract of a naturally occurring composition, such as where the curcumin is provided in the form of an extract of turmeric.

[0009] Another aspect of the invention provides a pharmaceutical composition comprising a collection of active ingredients described herein and optionally a pharmaceutically acceptable carrier. The active ingredients may be taken together to form a therapeutic agent, such as a therapeutic agent comprising two or more of curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid. The curcumin, piperine, epigallocatechin-3- gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt. The particular collection of active ingredients taken together to form the therapeutic agent may be selected in order to achieve a desired clinical benefit. For example, in certain embodiments, the invention provides a pharmaceutical composition comprising (a) a therapeutic agent present in an amount for treating attention deficit hyperactivity disorder in a patient and consisting essentially of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt; and (b) optionally a pharmaceutically acceptable carrier.

[0010] Another aspect of the invention provides a kit for treating attention deficit hyperactivity disorder. The kit comprises a pharmaceutical composition described herein and instructions for treating attention deficit hyperactivity disorder.

BRIEF DESCRIPTION OF FIGURES

[0011] Figure 1 shows bar graphs of baseline cognitive test scores as a function of group prior to treatment, as explained in Example 1. Bars represent group means and error bars are standard errors of the mean.

[0012] Figure 2 shows bar graphs of the results of the Landmark Discrimination Learning Test described in Example 1. Dogs in both groups (i.e., the control group and the group that received the cocktail) underwent a systematic training protocol of learning to select one of two identical objects on the basis of the location of a landmark. Bars indicate group means and error bars standard errors of the mean. Individual data points are also shown by circles in graphs A-E DE TAILED DESCRIPTION OF THE INVENTION

[0013] The invention provides methods, compositions, and medical kits for treating attention deficit hyperactivity disorder. The methods involve administering a therapeutically effective amount of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N- acetylcysteine, benfotiamine, and lipoic acid to a patient suffering from attention deficit hyperactivity disorder. The active ingredients curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be taken together to form a pharmaceutical composition, and each these active ingredients may optionally be in the form of a

pharmaceutically acceptable salt. Also provided are medical kits for treating attention deficit hyperactivity disorder using a collection of the active ingredients described herein.

[0014] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.

Definitions

[0015] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0016] The terms "a," "an" and "the" as used herein mean "one or more" and include the plural unless the context is inappropriate

[0017] As used herein, the term "patient" refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0018] As used herein, the term "treating" includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0019] As used herein, the term "effective amount" refers to the amount of a compound sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. [0020] The phrase "therapeutically-effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.

[0021] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0022] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, "salts" of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene- 2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0023] Examples of bases include, but are not limited to, alkali metal hydroxides, alkaline earth metals hydroxides, ammonia, and compounds of formula NW , wherein W is C 1-4 alkyl, and the like. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

[0024] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,

flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a C 1-4 alkyl group), and the like.

[0025] As used herein, the term "alkyl" refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-Cioalkyl, and Ci-C 6 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2- propyl, butyl, etc.

[0026] Certain compounds may exist in particular geometric or stereoisomeric forms. In particular, it is noted that the structure of certain compounds include asymmetric carbon atoms. It is to be understood that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) and mixtures of such isomers (e.g., a mixture of enantiomers) are included within the scope of the invention, unless indicated otherwise. These compounds may be designated by the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Alkenes can include either the E- or Z-geometry, where appropriate. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.

[0027] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0028] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls. I. Therapeutic Applications

[0029] One aspect of the invention provides methods of treating attention deficit hyperactivity disorder in a patient. The method comprises administering to a patent in need thereof a therapeutically effective amount a collection of active ingredients described herein, such as two or more of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid, each of which are optionally in the form of a pharmaceutically acceptable salt.

[0030] The particular collection of active ingredients administered to the patient may be selected in order to achieve a desired clinical benefit. For example, in certain embodiments, the method comprises administering to a patent in need thereof a therapeutically effective amount of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a

pharmaceutically acceptable salt. In certain other embodiments, a therapeutically effective amount of each of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, and lipoic acid are administered to the patient. In yet other embodiments, a therapeutically effective amount of each of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid are administered to the patient. Further, the curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be administered in the form of an extract of a naturally occurring composition, such as where the curcumin is provided in the form of an extract of turmeric.

[0031] The methods are contemplated to provide various benefits to patients suffering from attention deficit hyperactivity disorder. Exemplary benefits include improving the patient's ability to maintain mental focus on a task and reducing the frequency with which the patient becomes distracted relative to the patient's rate of distraction without therapy. The patient is desirably a human, and often a male less than 19 years of age.

[0032] Further description of the active ingredients, dosages, routes of administration, and relative amount of active ingredients administered to a patient are described below. Cur cumin

[0033] Curcumin refers to the chemical compound (lis,6is)-l,7-bis (4-hydroxy-3- methoxyphenyl)-l,6-heptadiene-3,5-dione and includes (i) tautomers thereof and (ii) mixtures of (lis,6is)-l,7-bis (4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione and a tautomer thereof. The compound (lis,6is)-l,7-bis (4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5- dione has the chemical formula shown below.

The compound (lis,6is)-l,7-bis (4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione exist in equilibrium with its enol tautomer having the following chemical formula:

[0034] Curcumin may be administered at a daily dosage of, for example, at least about 4 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or 60 mg/kg. In certain embodiments, the curcumin is administered at a daily dosage of at least 4 mg/kg. In certain other embodiments, the curcumin is administered at a daily dosage in the range of from about 4 mg/kg to about 60 mg/kg, from about 4 mg/kg to about 30 mg/kg, from about 4 mg/kg to about 15 mg/kg, from about 25 mg/kg to about 60 mg/kg, from about 25 mg/kg to about 40 mg/kg, from about 30 mg/kg to about 60 mg/kg, or from about 45 mg/kg to about 60 mg/kg. The daily dosage of curcumin may be achieved by administering the patient a single pharmaceutical composition containing curcumin once per day. Alternatively, the daily dosage of curcumin may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing curcumin.

[0035] Curcumin may be administered in the form of an extract of a naturally occurring composition, such as where the curcumin is provided in the form of an extract of turmeric.

Piperine

[0036] Piperine is l-[(2£ ' ,4£)-5-(l,3-benzodioxol-5-yl)-l-oxo-2,4-pentadienyl]p iperidine and has the chemical formula shown below.

[0037] Piperine may be administered at a daily dosage of, for example, at least about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, or 5 mg/kg. In certain embodiments, piperine is administered at a daily dosage of at least 0.5 mg/kg. In certain other embodiments, piperine is administered at a daily dosage in the range of from about 0.5 mg/kg to about 5 mg/kg, from about 0.5 mg/kg to about 3 mg/kg, from about 0.5 mg/kg to about 1 mg/kg, from about 2 mg/kg to about 5 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 3 mg/kg to about 5 mg/kg, or from about 4 mg/kg to about 5 mg/kg. The daily dosage of piperine may be achieved by administering the patient a single pharmaceutical composition containing piperine once per day. Alternatively, the daily dosage of piperine may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing piperine.

[0038] Piperine may be administered in the form of an extract of a naturally occurring composition, such as where the piperine is provided in the form of an extract of black pepper.

EpigaIIocatechin-3-gaIIate

[0039] Epigallocatechin-3-gallate is [(2R,3R)-5,7-dihydroxy-2-(3,4,5- trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate and has the chemical formula shown below.

[0040] Epigallocatechin-3-gallate may be administered at a daily dosage of, for example, at least about 4 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or 60 mg/kg. In certain embodiments, the epigallocatechin-3-gallate is administered at a daily dosage of at least 4 mg/kg. In certain other embodiments, the epigallocatechin-3-gallate is administered at a daily dosage in the range of from about 4 mg/kg to about 60 mg/kg, from about 4 mg/kg to about 30 mg/kg, from about 4 mg/kg to about 15 mg/kg, from about 25 mg/kg to about 60 mg/kg, from about 25 mg kg to about 40 mg/kg, from about 30 mg/kg to about 60 mg/kg, or from about 45 mg/kg to about 60 mg/kg. The daily dosage of epigallocatechin-3 -gallate may be achieved by administering the patient a single pharmaceutical composition containing epigallocatechin-3 -gallate once per day. Alternatively, the daily dosage of epigallocatechin-3 - gallate may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing epigallocatechin-3 -gallate.

[0041] Epigallocatechin-3 -gallate may be administered in the form of an extract of a naturally occurring composition, such as where the epigallocatechin-3 -gallate is provided in the form of an extract of green tea.

N-Acetylcysteine

[0042] N- Acetylcysteine is (R)-2-acetamido-3-sulfanylpropanoic acid, which has the structure shown below.

[0043] N-Acetylcysteine may be administered at a daily dosage of, for example, at least about 2 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, or 25 mg/kg. In certain embodiments, the N-acetylcysteine is administered at a daily dosage of at least 2 mg/kg. In certain other embodiments, the N-acetylcysteine is administered at a daily dosage in the range of from about 2 mg/kg to about 25 mg/kg, from about 2 mg/kg to about 15 mg/kg, from about 2 mg/kg to about 10 mg/kg, from about 10 mg/kg to about 25 mg/kg, from about 10 mg/kg to about 15 mg/kg, from about 15 mg/kg to about 25 mg/kg, or from about 20 mg/kg to about 25 mg/kg. The daily dosage of N-acetylcysteine may be achieved by administering the patient a single pharmaceutical composition containing N-acetylcysteine once per day. Alternatively, the daily dosage of N-acetylcysteine may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing N-acetylcysteine. Benfotiamine

[0044] Benfotiamine refers to S-[(2Z)-2- {[(4-amino-2-methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate, which has the chemical structure provided below.

Benfotiamine may be provided in the form of a pharmaceutically acceptable salt, such as an alkali metal salt (e.g., a sodium or potassium salt), alkaline earth metal salt (e.g., a calcium salt), or ammonium salt.

[0045] Benfotiamine may be administered at a daily dosage of, for example, at least about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, or 5 mg/kg. In certain embodiments, the benfotiamine is administered at a daily dosage of at least 0.5 mg/kg. In certain other embodiments, the benfotiamine is administered at a daily dosage in the range of from about 0.5 mg/kg to about 5 mg/kg, from about 0.5 mg/kg to about 3 mg/kg, from about 0.5 mg/kg to about 1 mg/kg, from about 2 mg/kg to about 5 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 3 mg/kg to about 5 mg/kg, or from about 4 mg/kg to about 5 mg/kg. The daily dosage of benfotiamine may be achieved by administering the patient a single pharmaceutical composition containing benfotiamine once per day. Alternatively, the daily dosage of benfotiamine may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing benfotiamine.

Lipoic Acid

[0046] Lipoic acid is 5-(l,2-dithiolan-3-yl)pentanoic acid and includes all stereoisomeric forms and mixtures of stereoisomeric forms. The structure of lipoic acid is shown below.

In certain embodiments, the lipoic acid is (R)-lipoic acid, which has the formula:

[0047] Lipoic acid may be administered at a daily dosage of, for example, at least about 1 mg/kg, 5 mg/kg, 10 mg/kg, or 15 mg/kg. In certain embodiments, the lipoic acid is administered at a daily dosage of at least 1 mg/kg. In certain other embodiments, the lipoic acid is administered at a daily dosage in the range of from about 1 mg/kg to about 15 mg/kg, from about 1 mg/kg to about 10 mg/kg, from about 1 mg/kg to about 5 mg/kg, from about 5 mg/kg to about 15 mg/kg, or from about 10 mg/kg to about 15 mg/kg. The daily dosage of lipoic acid may be achieved by administering the patient a single pharmaceutical composition containing lipoic acid once per day. Alternatively, the daily dosage of lipoic acid may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing lipoic acid.

Administration

[0048] The active ingredients may be administered to the patient by any medically accepted route of administration. In certain embodiments, the active ingredients are administered orally. Further, the active ingredients may be administered to the patient at the same time, such as when the active ingredients are formulated into a pharmaceutical composition that is administered to the patient. Alternatively, at least a portion of the active ingredients may be administered sequentially to the patient.

Relative Amount of Active Ingredients Administered to a Patient

[0049] The amount of each active ingredient that is administered to the patient can be selected to achieve particular clinical benefits. For example, in certain embodiments, the weight percent ratio of curcumin, epigallocatechin-3-gallate, and piperine administered to a patient on a daily basis is in the range about 10-15 : 10-15 : 1. In certain embodiments, the weight percent ratio of curcumin, epigallocatechin-3-gallate, and N-acetylcysteine administered to a patient on a daily basis is in the range about 2-4 : 2-4 : 1. In certain embodiments, the weight percent ratio of curcumin, epigallocatechin-3-gallate, and lipoic acid administered to a patient on a daily basis is in the range about 3-6 : 3-6 : 1.

II. Pharmaceutical Compositions and Dosing Considerations

[0050] Another aspect of the invention provides a pharmaceutical composition comprising a collection of active ingredients described herein and optionally a pharmaceutically acceptable carrier. The active ingredients may be taken together to form a therapeutic agent, such as a therapeutic agent comprising two or more of curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid. The curcumin, piperine, epigallocatechin-3- gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt.

[0051] The particular collection of active ingredients taken together to form the therapeutic agent may be selected in order to achieve a desired clinical benefit. For example, in certain embodiments, the invention provides a pharmaceutical composition comprising (a) a therapeutic agent present in an amount for treating attention deficit hyperactivity disorder in a patient and consisting essentially of curcumin, piperine, epigallocatechin-3 -gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3 -gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt; and (b) optionally a pharmaceutically acceptable carrier. In such a pharmaceutical composition, the therapeutic agent specified above is the only agent in the pharmaceutical composition that provides a therapeutic effect in treating attention deficit hyperactivity disorder. In certain other embodiments, the aforementioned therapeutic agent contains N-acetylcysteine. In certain other embodiments, the aforementioned therapeutic agent contains benfotiamine. In certain other embodiments, the aforementioned therapeutic agent therapeutic agent contains lipoic acid. In yet other embodiments, therapeutic agent consists essentially of curcumin, piperine, epigallocatechin-3 -gallate, N-acetylcysteine, and lipoic acid, each of which are optionally in the form of a pharmaceutically acceptable salt. Further, the curcumin, piperine, epigallocatechin-3 -gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be administered in the form of an extract of a naturally occurring composition, such as where the curcumin is provided in the form of an extract of turmeric.

[0052] The pharmaceutical composition may contain an active ingredient in one of the forms (e.g., a salt form, stereoisomeric form, or extract) described in Section I above. Such forms are reiterated here. For example, in certain embodiments, the curcumin is provided in the form of an extract of tumeric. In certain other embodiments, the epigallocatechin-3 -gallate is provided in the form of an extract of green tea. In yet other embodiments, the lipoic acid is (R)-lipoic acid.

[0053] The pharmaceutical composition may contain the active ingredients in ratios that provide particular advantages for treating attention deficit hyperactivity disorder. For example, in certain embodiments, the weight percent ratio of curcumin, epigallocatechin-3 -gallate, and piperine in the pharmaceutical composition is in the range about 10-15 : 10-15 : 1. In certain embodiments, the weight percent ratio of curcumin, epigallocatechin-3-gallate, and N- acetylcysteine in the pharmaceutical composition is in the range about 2-4 : 2-4 : 1. In certain embodiments, the weight percent ratio of curcumin, epigallocatechin-3-gallate, and lipoic acid in the pharmaceutical composition is in the range about 3-6 : 3-6 : 1.

[0054] Further, the pharmaceutical composition may be characterized according to whether it contains an active ingredient at a concentration sufficient to provide one of the daily dosage amounts described in Section I. For example, in certain embodiments, the pharmaceutical composition contains curcumin at a concentration sufficient so that administration of a single unit dose provides the patient with at least about 4 mg/kg of curcumin. [0055] Exemplary pharmaceutical compositions are provided in Tables 1 and 2 below, which list the relative amounts of the active ingredients.

TABLE 1.

TABLE 2.

[0056] Another aspect of the invention provides a unit dosage pharmaceutical composition, such as a tablet or capsule. Tablets and capsules can be prepared based on procedures known in the art and as described below.

[0057] The pharmaceutical compositions desirably comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.

[0058] The phrase "pharmaceutically-acceptable carrier" means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as

pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0059] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0060] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

[0061] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. [0062] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0063] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0064] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0065] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0066] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0067] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0068] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,

subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0069] The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0070] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the salt thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0071] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0072] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.

[0073] If desired, the effective daily dose of the active ingredient may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. III. Medical Kits

[0074] Another aspect of the invention provides medical kits for treating attention deficit hyperactivity disorder. The kit comprises a pharmaceutical composition described herein (such as one of pharmaceutical compositions in Section II) and instructions for treating attention deficit hyperactivity disorder. The instructions may provide dosing procedures, including route of administration, dosing frequency, and other information desirable for safe and effective use of the medical kit.

EXAMPLES

[0075] The invention now being generally described, will be more readily understood by reference to the following example, which is included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention.

EXAMPLE 1

[0076] Administration of a Curcumin Test Cocktail to aged beagles (as a model of human aging and Alzheimer's disease) resulted in an improvement in spatial attention. Experimental procedures and results are described below.

Experimental Procedures;

I. Test Subjects and Curcumin Test Cocktail

Animals

[0077] This study included 18 beagles from Ridglan Farms, Inc. (Mount Horeb,

Wisconsin). At the start of baseline cognitive testing, the ages of the animals ranged from 98- 1 15 months (Mean=103.2 SD=5.3). Dogs were housed singly in kennel buildings with indoor/outdoor runs measuring 47"x 187.5" and were fed Teklad Pioneer Lab Diets, Madison, WI (2025 Diet). Water was available at all times. All animals were thoroughly examined prior to inclusion in the study and were determined to be in good health. Examinations included physical examination, neurological examination, and analysis of blood biochemistry values.

Curcumin Test Cocktail

[0078] The Curcumin Test Cocktail was formulated to include green tea extract (203 mg epigallocatechingallate or 36.3% by weight), piper nigrum extract (17 mg Bioperine, 95% piperine, 3.0% by weight), N-acetyl-Z-cysteine (85 mg, 15.3% by weight), curcumin (203 mg, 36.3% by weight) and (R)-lipoic acid (51 mg, 9.1% by weight). Control capsules were formulated without any of these active ingredients.

II. Establishing Two Groups of Test Subjects

[0079] Prior to administering the Curcumin Test Cocktail, all dogs were subjected to the following tests in order to establish a baseline level of cognitive function: Reward and Object Approach Learning Test, Object Discrimination Learning Test, Reversal Learning Test, and Spatial Non-Matching to Position Test. Total errors made in the tests were summed and dogs were ranked according to total error scores and placed into one of two groups (a treatment group and a control group), such that each group contained both good and poor performers.

Test procedures are described below, along with a description of the apparatus used in the tests.

Test Apparatus

[0080] The test apparatus was a 25" x 3 ' x 4' wooden box constructed from plywood coated with melamine. The box was equipped with a sliding black laminate tray containing three food wells which are covered by objects. One teaspoon (approximately 4 mL) of wet dog food was formed into a ball and placed in one food well to serve as the food reward. Vertical stainless steel bars (adjusted to provide openings appropriate for individual dog sizes) served as the front of the box. The tester sat behind a hinged door that allowed a sliding tray to be either pushed toward the dog or obscured from the dog's view. A 60W light was placed above the presentation tray to light the objects. Data acquisition was controlled using a customized program (Dogma, Metacog Testing Systems, New Westminster, B.C., Canada). This program controlled all randomization procedures and timing, indicated the location of the reward and stored all of the data in a SQL database. Each trial began when the tester pressed a key and simultaneously presented the tray to the dog, and ended when the tester recorded the dog's choice of object, thereby beginning the inter-trial interval. Each dog was given either 10 or 12 trials a day (depending on the task), with trials separated by a 30 second inter-trial interval. Dogs were tested 5 days per week.

Reward and Object Approach Learning Test

[0081] All dogs received a standard four-phase pre-training protocol. For further information, see, for example, Milgram et al. in Behav. Neurosci. (1994) 108:57-68. This procedure included a phase to expose dogs to the testing apparatus, a phase to teach dogs that a reward was always present in one of the food wells (reward approach learning), a phase that manually shaped dogs to manipulate the objects, and a phase to teach dogs to visually locate the object and approach it (object approach learning). Dogs completed all of these four phases of pre-training prior to testing for object discrimination learning.

Object Discrimination Learning Test

[0082] The first test session was used to establish object preferences. On each trial, the hinged door separating the tester and the dog was raised and the presentation tray was pushed forward. The left and right food wells were covered by the two objects. The food reward was placed in both the left and right food wells beneath each object. Dogs were required to displace an object to expose the food reward. Ten trials were given with two objects presented simultaneously (a yellow plastic Megablock and a blue plastic ball mounted on a blue plastic coaster), and with food reward beneath both objects. The objects appeared randomly five times each on the left or right side. The preferred object was whichever object was chosen more frequently (i.e., six or more times). Subsequently, the preferred object was used as the positive stimulus. After establishing object preferences, each dog was given ten daily trials with the food reward beneath the designated positive object. To prevent the dogs from using olfactory cues, the food odors were smeared over both wells. Further, a piece of food was pressed inside the negative stimulus such that the dog could smell it but not see it or eat it. A correct response was recorded when dogs approached and displaced the positive stimulus. An error was committed if dogs displaced the negative object. One correction per test session was allowed, with subsequent errors resulting in immediate withdrawal of the tray and no food reward. Dogs were trained until one of two criterion levels was met: 9/10 correct on one day or 8/10 correct on two consecutive days. A maximum of 400 trials were given if a dog could not reach criterion.

Reversal Learning Test

[0083] After dogs had reached criterion in the object discrimination task test, the reward contingencies of the positive and negative stimuli were reversed. Testing was continued on this task until the criterion described above was met. All other testing procedures were identical to those used with object discrimination learning.

Spatial Non-matching to Position Test [0084] To assess spatial acquisition and memory, a two-choice non-matching to position task was used. For further information, see, for example, Head et al. in Behav. Neurosci. (1995) 109:851-8. Animals were first shown a single, blue, plastic Megablock covering either the left or right food wells. Animals displaced the object on one side (e.g., L) to obtain the reward. After a five-second delay interval, animals were shown two, identical, blue, plastic Megablocks with the reward hidden under the object on the side not rewarded previously (e.g., R). Dogs were given 10 trials per day with a 30 second inter-trial interval and were tested until they reached criterion or 40 days (400 trials).

[0085] After learning the two-choice task, animals were placed into a three-choice spatial memory task. The three-choice delayed non-matching to position task has been described previously in, for example, Chan et al. in Behav. Neurosci. (2002) 1 16:443-54. Dogs were first shown a single, blue, plastic Megablock covering either the left, right, or center food wells. Once the dog displaced the object and obtained the reward, a five-second delay interval followed. After the delay, animals were shown two, identical, blue, plastic Megablocks, one covering the well seen previously, and the other covering one of the two remaining food wells. The correct response was to select the object covering the side not rewarded previously. Dogs were given 50 days of testing consisting of 12 trials/day, with the location of the reward appearing four times each in the 3 food wells. During the 50 days of testing, if an animal reached criterion at the five-second delay, the delay was increased to 10 seconds, followed by gradually increasing delay intervals. Two scores were calculated from this test - total number of errors made to reach criterion (or after 50 days of testing if criterion was not met) at the five- second delay, and maximal memory score, which represented the maximum delay interval animals could reach criterion at in the 50 days of testing. Following incremental delay interval increases over a 50 day period, dogs were given a variable delay procedure for 20 days. Dogs were given either a 20, 70 or 1 10 second delay in a single day of testing, with four trials at each delay interval. Accuracy scores for each delay interval were calculated as a measure of spatial working memory. Animals were tested on the spatial non-matching to position task at both baseline and after eight months of treatment.

[0086] The total errors made for reward and object approach learning, discrimination and reversal learning and acquisition of the three-choice spatial memory task were summed and dogs were ranked according to total error scores and placed into one of two groups (i.e., a control group or a group that received the Curcumin Test Cocktail). III. Administration of Curcumin Test Cocktail

[0087] One group of dogs was given the Curcumin Test Cocktail. The other group of dogs (i.e., the control group) was given a placebo. Two different colored pills were formulated to allow testing technicians to be blind with respect to treatment condition and yet also be able to administer the treatment. Dogs were given two capsules per day, one in the morning prior to cognitive testing and one in the afternoon, after cognitive testing was completed.

IV. Measuring Spatial Attention in Dogs

[0088] Spatial attention was measured using a landmark discrimination task test. For further information on the landmark discrimination task test, see, for example, Milgram et al. in Neuroscience and Biobehavioral Reviews (2002) 26:679-95 and Milgram et al. in Learning & Memory (1999) 6:54-61. The landmark discrimination learning task test was initiated two weeks after the treatment group of dogs began receiving the Curcumin Test Cocktail. The first phase, Landmark 0, involved presenting dogs with two identical objects (plastic coasters) with a landmark object (yellow peg) placed on top of the object that is associated with a food reward. The correct response was to select the object closest to the landmark. Animals were trained until criterion was met, as described above. A maximum of 40 days or 400 trials was allowed on landmark 0. In the next phase of testing, the landmark was moved at successively greater distances (5, 18, or 24 cm) away from the reward object, with animals required to meet criterion before progressing to testing with a longer landmark distance. Animals that could not reach criterion at any of the longer distances within 400 trials stopped testing on this stepwise protocol. Once all animals had been tested out to a 24 cm distance on the landmark

discrimination task or had reached the maximum number of trials for a single distance, all animals were given a variable landmark distance test. In this test, animals were given 12 trials per day, with the landmark placed either 5, 18, or 24 cm from the correct object. These three distances appeared for 4 trials per day with 12 trials per day in total, and dogs were given a total of 20 days of testing (i.e., 240 trials).

Results;

[0089] At baseline, all dogs were matched into two groups (Figure 1) and no statistical differences in age or cognition were noted prior to the start of treatment. Of the 18 dogs given baseline testing, two dogs in the placebo group and two dogs in the cocktail group would not perform consistently and could not be used in the Landmark Discrimination Learning Task test. After less than one month of treatment, one female in the placebo group required euthanasia for unmanageable pain due to arthritic elbows.

[0090] The Landmark Discrimination Learning Task test was initiated after a two-week wash in of the Curcumin Test Cocktail. Acquisition of the serial individual landmark tasks (0, 5, 18, or 24 cm) did not show significant treatment effects, although as the testing proceeded, dogs in Group 2 (those receiving the Curcumin Test Cocktail) trended towards fewer errors (Figure 2). Variable distance landmark testing was completed in six placebo-treated dogs and seven cocktail-treated dogs for a period of 20 days after the initial learning phase with either 5, 18, or 24 cm distances appearing each day, four times per day for a total of 12 trials per day. The total number of errors made during the 20 days of testing was significantly decreased in the cocktail group (t(l 1)=4.34 p=0.001; Figure 2E). Accuracy was calculated for individual distances for each dog, given that landmark testing is more difficult with increasing distance between the landmark and the object. A repeated measures general linear models analysis indicated a significant main effect of distance (F(2,18)=15.94 p<.0005) and of treatment group (F(l,9)=20.7 p=0.001). The interaction, however, was not significant indicating that overall the treated dogs performed at higher levels of accuracy but increasing distance affected performance equally across the groups (Figure 2F).

INCORPORATION BY REFERENCE

[0091] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

[0092] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.