US 2010.0056444A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0056444 A1 Jacobson et al. (43) Pub. Date: Mar. 4, 2010

(54) TREATMENT OF ALZHEIMER'S DISEASE A6II 3/472 (2006.01) USING COMPOUNDS THAT REDUCE THE A63L/45 (2006.01) ACTIVITY OF NON SELECTIVE CA A6II 3/44 (2006.01) ACTIVATED ATP- SENSTIVE CATION A63L/366 (2006.01) CHANNELS REGULATED BY SUR1 A63L/352 (2006.01) RECEPTORS A6II 3L/27 (2006.01) A6II 3/196 (2006.01) (76) Inventors: Sven Martin Jacobson, New York, A 6LX 3L/I75 (2006.01) NY (US); Robert Ang, Cupertino, A6II 3/165. (2006.01) CA (US) A6II 3/13 (2006.01) A6IP 25/28 (2006.01) Correspondence Address: (52) U.S. Cl...... 514/12: 514/23: 514/178; 514/182: Goodwin Procter LLP 514/215: 514/217.1.1 : 514/297: 514/309 Attn: Patent Administrator s • us s s 135 Commonwealth Drive 514/319; 514/331; 514/352: 514/450; 514/453; Menlo Park, CA 94025-1105 (US) 514/456; 514/490; 514/567; 5...... (21) Appl. No.: 12/444,908 (57) ABSTRACT (22) PCT Filed: Oct. 11, 2007 NSC antagonists are disclosed as useful in the treatment of dementia, in delaying the onset of dementia, and in the pre (86). PCT No.: PCT/US2007/081128 vention of dementia. Dementia so treated may be, for example, Alzheimer's Disease (AD). NSC antagonists for S371 (c)(1), treating dementia Such as AD may be administered alone, a) (2), (4) Date: Apr. 9, 2009 in combination with other drugs used for treating dementia, b) in combination with drugs that stabilize or increase blood Related U.S. Application Data plasma glucose levels, or with botha) and b). Pharmaceutical compositions, dosage forms, and methods for using the same (60) sial application No. 60/851,412, filed on Oct. are disclosed, which include NSC antagonists, NSC antago s nists combined with dementia drugs, NSC antagonists com O O bined with glucose-level stabilizing or enhancing drugs, or Publication Classification combinations of these. Dosage forms may be designed to (51) Int. Cl. provide stable plasma levels for extended periods of time. A6 IK 38/26 (2006.01) Exemplary pharmaceutical compositions include composi A6 IK3I/7004 (2006.01) tions including glibenclamide and memantine; glibenclamide A6 IK3I/S65 (2006.01) and donepezil; tolbutamide and memantine; tolbutamide and A6 IK3I/55 (2006.01) donepezil; and these compositions further including gluca A6 IK 3/435 (2006.01) gon and/or glucose. US 2010/0056444 A1 Mar. 4, 2010

TREATMENT OF ALZHEMERS DISEASE ies. Many of these histopathologic findings are associated USING COMPOUNDS THAT REDUCE THE with neuronal cell death which occurs insidiously many years ACTIVITY OF NON SELECTIVE CA before symptoms manifest. ACTIVATED ATP- SENSITIVE CATION CHANNELS REGULATED BY SUR1 SUMMARY RECEPTORS 0006. Applicants disclose herein the use of sulfonylurea receptor antagonists and of blockers of non-selective chan BACKGROUND nels (the NC channel, the TRPM4 channel, and the TRPM5 channel) to treat dementia. The use of Sulfonylureas, 0001. This application is a national phase application active metabolites of Sulfonylureas, Sulfonylurea mimetics, claiming priority under 35 U.S.C. S 120 from PCT/US07/ or any drug or chemical compound effective to antagonize a sulfonylurea receptor 1 (SUR1 receptor) or to block or reduce 08.1128 filed on Oct. 11, 2007, and claims the benefit, under the physiological activity of channels associated with SUR1 35 U.S.C. S 119(e), of U.S. Provisional Application 60/851, receptors, for ameliorating dementia, for ameliorating the 412 filed Oct. 12, 2006, the entire disclosures of which appli effects of dementia, for treating dementia, for reducing the cations are hereby incorporated by reference in their entire effects of dementia, or for preventing or delaying the onset of ties. dementia is disclosed herein. Sulfonylureas, Sulfonylurea 0002 Sulfonylurea drugs and related drugs are believed to mimetics, or any drug or chemical compound selective for act on the type 1 sulfonylurea receptor (SUR1 receptor) and SUR1 receptors that antagonize SUR1 receptors, or are effec the type 2 sulfonylurea receptor (SUR2). Sulfonylurea drugs tive to block or reduce the physiological activity of channels have been shown to be effective in treating stroke and spinal associated with SUR1 receptors, including antagonists and cord injury due to the drug acting on a non selective cation blockers of the NC channel and antagonists and block channel which has type 1 sulfonylurea receptor (SUR1) bind ers of the TRPM4 channel and the TRPM5 channel, are ing sites and thus binds to Sulfonylureas. This channel is a collectively termed herein “NSC antagonists’ referring to the non-selective Ca"-activated ATP-sensitive cation channel common action of antagonizing the activity of the non-selec termed the "NC channel' (see, e.g., Chen and Simard, tive channels the NC channel (regulated by SUR1 Journal of Neuroscience 21:6512-6521 (2001); and Chen et receptors) and the TRPM4 channel and the TRPM5 channel. al., Journal of Neuroscience 23:8568-8577 (2003), each A particular form of dementia treated by the methods, com hereby incorporated by reference) and is believed to include positions, and formulations disclosed herein is Alzheimer's a regulatory Sub-unit including a SUR1 receptor, and a pore Disease (AD). 0007 Thus, the use of NSC antagonists for treating AD, Subunit that has similar properties to, and may be comprised reducing the effects of AD, or delaying or preventing the of a TRPM4 channel (see, e.g., Simard et al., Biochimica et onset of AD is disclosed herein. Thus, methods, pharmaceu Biophysica Acta, 1772(8):947-957 (2007), hereby incorpo tical compositions and formulations for the treatment, pallia rated by reference). There is also some ex-vivo evidence that tion, amelioration, slowing the progression of, or prevention certain Sulfonylureas may have an effect in treating Parkin of AD are disclosed herein. son's disease, and the K channel has been implicated in 0008 Embodiments of the invention disclosed herein this regard. include the use of a NSC antagonist in the manufacture of a 0003. There have been numerous studies as to the associa medicament for the treatment of dementia, including wherein tion between Alzheimer's disease (AD) and Type 2 Diabetes. the dementia is Alzheimer's Disease (AD). For example, a Type 2 Diabetes has been found to be both negatively and NSC antagonist for use in the manufacture of a medicament positively associated with AD. Thus, according to the scien for the treatment of dementia, may be selected from glib tific literature, the relationship, if any, between Type 2 Dia enclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxy betes and AD remains unknown. glibenclamide, tolbutamide, chlorpropamide, tolaZamide, 0004 Dementia is a term describing loss of mental func repaglinide, nateglinide, meglitinide, midaglizole, tolaza tion in a patient. As used herein, the term “dementia' refers to mide, gliquidone, LY397364, LY389382, glyclazide, glime broadly to a psychiatric or medical condition characterized by piride, estrogen, estradiol, estrone, estriol, genistein, diethys cognitive deficits that may include impairments in memory, tilbestrol, coumestrol, Zearalenone, non-steroidal estrogens, reasoning, planning, and judgment. Senile dementia is a phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, dementia having an onset at an advanced age. One form of niflumic acid, rimonabant, SKF 9635, and combinations dementia that is more frequent in aged than in younger indi thereof. viduals is multi-infarct dementia, characterized by brain dam 0009. In embodiments of the invention disclosed herein, a age resulting from multiple infarcts, or strokes. Other forms NSC antagonist is used together with an other compound in of brain injury, brain trauma, inflammation, or other insult to the manufacture of a medicament for the treatment of demen the brain may lead to or exacerbate dementia. Anotherform of tia, Such as, e.g., AD, wherein the other compound is a com dementia, Alzheimer's Disease (AD), is a particularly preva pound used in the treatment of dementia. For example, an lent form of dementia, and is more frequently found in aged other compound used in the treatment of dementia may be than in younger individuals. selected from memantine, donepezil, galantamine, rivastig 0005 AD is the most common form of dementia among mine, tacrine, and combinations thereof. older people, and initially involves the parts of the brain that 0010. In further embodiments of the invention disclosed control thought, memory, and language. There are classic herein, the NSC antagonist used in the manufacture of a histolopathologic findings in AD Such as neurofibrillary medicament for the treatment of dementia, Such as, e.g., AD. tangles, neuritic (senile) plaques, Hirano bodies, granulo may comprises a combination of compounds comprisinga) at vacuolar bodies of Simchowicz, Pick bodies and Lewy bod least one compound selected from: glibenclamide, 4-trans US 2010/0056444 A1 Mar. 4, 2010 hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolb rpropamide, tolaZamide, repaglinide, nateglinide, utamide, chlorpropamide, tolaZamide, repaglinide, nateglin meglitinide, midaglizole, tolaZamide, gliquidone, ide, meglitinide, midaglizole, tolaZamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethyStilbestrol, estradiol, estrone, estriol, genistein, diethyStilbestrol, coumestrol, Zearalenone, non-steroidal estrogens, and phy coumestrol, Zearalenone, non-steroidal estrogens, and phy toestrogens; and b) at least one compound selected from: toestrogens; and b) at least one compound selected from: pinkolant, flufenamic acid, mefanamic acid, niflumic acid, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635. rimonabant, SKF 9635. 0015. In still further embodiments, a pharmaceutical com 0011. In yet further embodiments, the NSC antagonist position may comprise a pharmaceutical composition of any used in the manufacture of medicaments having features of of the above, and further comprising a compound effective to the invention is selected from: glibenclamide, 4-trans-hy increase blood plasma glucose levels; for example, a com droxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolbuta pound effective to increase blood plasma glucose levels may mide, chlorpropamide, tolaZamide, repaglinide, nateglinide, be selected from glucose and glucagon. meglitinide, midaglizole, tolaZamide, gliquidone, 0016 Embodiments of the invention disclosed herein LY397364, LY389382, glyclazide, and glimepiride. In still include pharmaceutical dosage forms comprising any of the further embodiments, the NSC antagonist used in the manu above-described pharmaceutical compositions. For example, facture of medicaments having features of the invention is a pharmaceutical dosage form having features of the inven glibenclamide. In yet further embodiments, the NSC antago tion may be selected from a pill, a tablet, an oral formulation, nist used in the manufacture of medicaments having features an intravenous formulation, an intra-arterial formulation, an of the invention is selected from pinkolant, flufenamic acid, intramuscular formulation, a Subcutaneous formulation, a mefanamic acid, niflumic acid, rimonabant, and SKF9635. In peritoneal formulation, an inhalational formulation, a rectal a further embodiment, the NSC antagonist used in the manu formulation, a vaginal formulation, a topical formulation, a facture of medicaments having features of the invention is gel, an ointment, and a transdermal patch. pinkolant. 0017. In embodiments, a pharmaceutical dosage form 0012. Further embodiments of the invention disclosed having features of the invention includes a pharmaceutical herein include a pharmaceutical composition comprising a dosage form wherein the NSC antagonist comprises a com NSC antagonist; an other compound used in the treatment of bination of compounds comprising a) at least one compound dementia; and a pharmaceutically acceptable carrier. For selected from: glibenclamide, 4-trans-hydroxy-glibencla example, a NSC antagonist Suitable for Such a pharmaceutical mide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlorpro composition may be selected from glibenclamide, 4-trans pamide, tolaZamide, repaglinide, nateglinide, meglitinide, hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolb midaglizole, tolazamide, gliquidone, LY397364, LY389382, utamide, chlorpropamide, tolaZamide, repaglinide, nateglin glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, ide, meglitinide, midaglizole, tolaZamide, gliquidone, genistein, diethystilbestrol, coumestrol. Zearalenone, non LY397364, LY389382, glyclazide, glimepiride, estrogen, steroidal estrogens, and phytoestrogens; and b) at least one estradiol, estrone, estriol, genistein, diethyStilbestrol, compound selected from: pinkolant, flufenamic acid, mefa coumestrol, Zearalenone, non-steroidal estrogens, phy namic acid, niflumic acid, rimonabant, SKF 9635. toestrogens, pinkolant, flufenamic acid, mefanamic acid, 0018. Also disclosed herein is a method of treating demen niflumic acid, rimonabant, SKF 9635, and combinations tia, such as, e.g., AD, comprising administering a NSC thereof. For example, an other compound used in the treat antagonist to a patient in need of Such treatment. As disclosed ment of dementia Suitable for inclusion in a Such pharmaceu herein, a method of treating dementia, Such as, e.g., AD, may tical composition may be selected from memantine, done include administering a NSC antagonist and an other com pezil, galantamine, rivastigmine, tacrine, and combinations pound used in the treatment of dementia, to a patient in need thereof. of such treatment. A NSC antagonist suitable for the practice 0013 Further embodiments of pharmaceutical composi of the method disclosed herein may be, for example, selected tions having features of the invention include pharmaceutical from glibenclamide, 4-trans-hydroxy-glibenclamide, 3-cis compositions comprising glibenclamide; a compound hydroxy-glibenclamide, tolbutamide, chlorpropamide, selected from memantine, donepezil, galantamine, rivastig tolaZamide, repaglinide, nateglinide, meglitinide, midagli mine, tacrine, and combinations thereof, and a pharmaceuti Zole, tolazamide, gliquidone, LY397364, LY389382, glycla cally acceptable carrier. In further embodiments, a pharma Zide, glimepiride, estrogen, estradiol, estrone, estriol, ceutical composition comprises tolbutamide; a compound genistein, diethystilbestrol, coumestrol. Zearalenone, non selected from memantine, donepezil, galantamine, rivastig steroidal estrogens, phytoestrogens, pinkolant, flufenamic mine, tacrine, and combinations thereof, and a pharmaceuti acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, cally acceptable carrier. In yet further embodiments, a phar and combinations thereof. An other compound used in the maceutical composition comprises chlorpropamide; a treatment of dementia, Such as, e.g., AD, may be selected compound selected from memantine, donepezil, galan from memantine, donepezil, galantamine, rivastigmine, tamine, rivastigmine, tacrine, and combinations thereof, and tacrine, and combinations thereof. a pharmaceutically acceptable carrier. 0019. Also disclosed herein is a method of preventing or 0014. In further embodiments, the pharmaceutical com delaying the onset of dementia, such as, e.g., AD, comprising positions having features of the invention include pharmaceu administering a NSC antagonist to a patient in need of Such tical compositions wherein the NSC antagonist comprises a treatment. In embodiments, a method of preventing or delay combination of compounds comprising a) at least one com ing the onset of dementia, such as, e.g., AD, may comprise pound selected from: glibenclamide, 4-trans-hydroxy-glib administering a NSC antagonist and an other compound used enclamide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlo in the treatment of dementia, to a patient in need of Such US 2010/0056444 A1 Mar. 4, 2010

treatment. For example, a NSC antagonist suitable for the blockade of the channels associated with SUR1 by NSC practice of Such methods may be selected from glibencla antagonists is effective to prevent neuronal from occurring, mide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glib delay, or ameliorate cell death associated with dementia, Such enclamide, tolbutamide, chlorpropamide, tolaZamide, repa as AD. glinide, nateglinide, meglitinide, midaglizole, tolaZamide, 0024. The channels known as the “TRPM4 channel and gliduidone, LY397364, LY389382, glyclazide, glimepiride, as the “TRPM5 channel are non-selective channels sharing estrogen, estradiol, estrone, estriol, genistein, diethystil many of the characteristics of the NC channel, and are bestrol, coumestrol. Zearalenone, non-steroidal estrogens, postulated by some to be the pore-forming subunit of the phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, SUR1-regulated NC channel (see, e.g., Simard et al., niflumic acid, rimonabant, SKF 9635, and combinations Biochimica et Biophysica Acta, 1772(8):947-957 (2007)). thereof. For example, an other compound used in the treat Blockers of the TRPM4 channel include pinkolant (R.S)-(3. ment of dementia, Such as , e.g., AD, may be selected from 4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N- memantine, donepezil, galantamine, rivastigmine, tacrine, di 2-(2,3,4-trimethoxyphenyl)ethyl-acetamide)); fenama and combinations thereof. tes, including flufenamic acid, mefanamic acid, and niflumic 0020 Instill further embodiments, a method of preventing acid; rimonabant (SR141716A; (5-(4-Chlorophenyl)-1-(2,4- or delaying the onset of dementia, Such as, e.g., AD, may dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole further comprise administration of a compound effective to 3-carboxamide); SKF 9635 (1-(beta-3 (4-methoxy-phenyl) increase blood plasma glucose levels; a compound effective propoxyl-4-methoxyphenyethyl)-1H-imidazole to increase blood plasma glucose levels may be, for example, hydrochloride); and other compounds. As used herein, the selected from glucose and glucagon. terms “NSC antagonist' and “NSC antagonists’ include 0021. In embodiments of the methods disclosed herein, blockers of the TRPM4 channel, including those listed above. the NSC antagonist comprises a combination of compounds In embodiments of the invention, the blockade of the TRPM4 comprising a) at least one compound selected from: glib channels by NSC antagonists is effective to reduce the enclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxy amount of neuronal cell death associated with dementia, Such glibenclamide, tolbutamide, chlorpropamide, tolaZamide, as AD. In embodiments of the invention, the blockade of repaglinide, nateglinide, meglitinide, midaglizole, tolaza TRPM4 channels by NSC antagonists is effective to prevent mide, gliquidone, LY397364, LY389382, glyclazide, glime from occurring, delay, or ameliorate neuronal cell death asso piride, estrogen, estradiol, estrone, estriol, genistein, diethys ciated with dementia, Such as AD. tilbestrol, coumestrol, Zearalenone, non-steroidal estrogens, 0025 Thus, the present invention provides compounds, and phytoestrogens; and b) at least one compound selected pharmaceutical compositions, methods of treatment, and kits from: pinkolant, flufenamic acid, mefanamic acid, niflumic comprising NSC antagonists for treating dementia, Such as acid, rimonabant, SKF 9635. AD. Such treatment may provide preventative treatment for 0022. Also disclosed herein are kits, including a kitcom persons not presently Suffering from dementia, such as AD, or prising a pharmaceutically acceptable formulation of a NSC for persons thought to be at risk for developing dementia, antagonist, and a pharmaceutically acceptable formulation of Such as AD, and may provide therapeutic treatment for per an AD drug; and a kit comprising a pharmaceutically accept Sons Suffering from dementia, Such as AD, or from a dement able formulation of a NSC antagonist, a pharmaceutically ing condition related to AD. acceptable formulation of an AD drug, and a pharmaceuti 0026. In one example, a person at risk for developing AD cally acceptable formulation of a compound effective to would take a NSC antagonist Such as glibenclamide in order increase blood plasma glucose levels. to prevent or delay the onset of the disease. The drug may be taken orally or transdermally, although it will be understood DETAILED DESCRIPTION that any suitable mode of delivery (e.g. Subcutaneously, intra 0023 The term “Sulfonylureas” as used in the following venously (IV), intramuscularly, etc.) may be used in the prac disclosure includes Sulfonylureas, Sulfonylurea mimetics, tice of the invention. and any other drug or chemical compound that is effective to 0027. In another example, a person developing or having block or reduce the activity of channels associated with developed AD would take a NSC antagonist such as glib SUR1. In embodiments, the channels associated with SUR1 enclamide in order to treat the disease. The drug may be include the NC channel (see, e.g., U.S. Patent Applica administered orally, topically (e.g., via transdermal patch, or tion Publications 20030215889, “Non-selective cation chan via ointment) but any suitable mode of delivery (e.g. Subcu nel in neural cells and methods for treating brain Swelling': taneously, intravenously (IV), intramuscularly, etc.) may be 20050181980, “Novel non-selective cation channel in neural used in the practice of the invention. cells and method for treating brain swelling’: 20060100183. 0028. In another example, a person having developed AD “Therapeutic agents targeting the NC channel and may take a NSC antagonist Such as glibenclamide in order to methods of use thereof; and 20060276411. “Novel non treat the disease and signs and symptoms of AD would be selective cation channel in neuronal cells and methods for monitored during treatment. The drug dosage may be treating brain swelling all of which applications are hereby adjusted upwards or downwards depending on clinical incorporated by reference in their entireties) and K chan response to the drug. The drug may be administered orally or nels. In embodiments of the invention, the Sulfonylureas, topically (e.g., via transdermal patch or via ointment), but any Sulfonylurea mimetics, or other drugs are NSC antagonists Suitable mode of delivery (e.g. Subcutaneously, IV, intramus effective to block the channels associated with SUR1. In cularly, etc.) may be used in the practice of the invention. embodiments of the invention, the blockade of the channels 0029. In another example, a person developing or having associated with SUR1 by NSC antagonists is effective to developed AD and who has concurrent diabetes may take a reduce the amount of neuronal cell death associated with NSC antagonist such as glibenclamide in order to treat both dementia, such as AD. In embodiments of the invention, the the AD and diabetes. The drug may be administered orally or US 2010/0056444 A1 Mar. 4, 2010

topically (e.g. via transdermal patch, or ointment), but any is used to administer the NSC antagonist, or combination of Suitable mode of delivery (e.g. Subcutaneously, intravenously drugs including a NSC antagonist, the dosing regimen may (IV), intramuscularly, etc.) may be used in the practice of the include placement of the patch at a Suitable place on the skin invention. This dosage would need to be high enough to cause of a subject and allowing the patch to remain in that position therapeutic effect for both AD and diabetes. for a day, for multiple days, or for a week or multiple weeks, 0030 The dose may be low enough to cause therapeutic or for a month, or for two or more months. effect without causing hypoglycemia, although higher doses could be used if co-treated with an agent that would prevent Administration hypoglycemia Such as glucose or glucagon. Given this, while 0035. The manner in which the compounds are adminis doses of 2.5 mg to 20 mg per day would be permissible, lower tered can vary. The compounds can be administered topically doses in the range 0.01 mg/day through to 2.5 mg per day (e.g., in lotion form); orally (e.g., in liquid form within a would be preferable. Higher doses might be useful as “rescue Solvent Such as an aqueous or non-aqueous liquid, or within a treatments', or at the beginning of treatment, or intermittently Solid carrier); intravenously (e.g., within a dextrose or saline to speed recovery. Solution); as an infusion or injection (e.g., as a suspension or 0031 Administration of NSC antagonists for ameliorat as an emulsion in a pharmaceutically acceptable liquid or ing, treating, delaying, or preventing dementia, Such as AD, mixture of liquids); intrathecally; intracerebro-ventricularly; includes administration of a single NSC antagonist; admin ortransdermally (e.g., using a transdermal patch). Although it istration of two, or of more than two, NSC antagonists: is possible to administer the compounds in the form of a bulk administration of one or more NSC antagonists with other active chemical, it is preferred to present each compound in drugs, where such other drugs may include drugs used to the form of a pharmaceutical composition or formulation for ameliorate, treat, delay, or prevent dementia Such as AD; efficient and effective administration. Exemplary methods for administration of one or more NSC antagonists with other administering Such compounds will be apparent to the skilled drugs, where such other drugs may include drugs used to artisan. For example, the compounds can be administered in correct or stabilize blood glucose levels; and other forms of the form of a tablet, a hard gelatin capsule or as a time-release administration in conjunction with other drugs or treatments. capsule. As another example, the compounds can be delivered 0032. In embodiments in which administration of NSC transdermally using the types of patch technologies available antagonists forameliorating, treating, delaying, or preventing from Novartis and Alza Corporation (now part of Johnson and dementia, Such as AD, includes the administration of more Johnson). The administration of the pharmaceutical compo than one NSC antagonist, suitable combinations of NSC sitions of the present invention can be intermittent, or at a antagonists may be provided where a) at least one NSC gradual, continuous, constant or controlled rate. In addition, antagonist compound is selected from: glibenclamide, the time of day and the number of times per day that the 4-trans-hydroxy-glibenclamide, 3-cis-hydroxy-glibencla pharmaceutical formulation is administered can vary. Admin mide, tolbutamide, chlorpropamide, tolaZamide, repaglinide, istration preferably is such that the active ingredients of the nateglinide, meglitinide, midaglizole, tolaZamide, gliqui pharmaceutical formulation interact with receptor sites done, LY397364, LY389382, glyclazide, glimepiride, estro within the body of the subject that effect the functioning of the gen, estradiol, estrone, estriol, genistein, diethyStilbestrol, central nervous system (CNS). More specifically, in treating a coumestrol, Zearalenone, non-steroidal estrogens, and phy CNS disorder administration preferably is such so as to opti toestrogens; and b) at least one NSC antagonist compound is mize the effect upon those relevant receptor subtypes which selected from: pinkolant, flufenamic acid, mefanamic acid, have an effect upon the functioning of the CNS, while mini niflumic acid, rimonabant, SKF 9635. mizing the effects upon muscle-type receptor Subtypes. This 0033 ANSCantagonist, such as, e.g., glibenclamide, may may include the use of slow release capsules and pills to be administered in conjunction (either separately or together) provide blood plasma levels of the agent that are substantially with other compounds useful for treating AD or for amelio constant over time, or relatively less varying over time than rating the symptoms of AD, including, e.g., drugs such as would be the case with other modes of administration, rather memantine (Namenda R., 1-amino-3,5-dimethyl-adaman than peaks and troughs associated with fast and regular-re tane), donepezil (Aricept(R), 2-(1-benzyl-4-piperidyl)me lease capsules and pills. Other suitable methods for adminis thyl-5,6-dimethoxy-2,3-dihydroinden-1-one), galantamine tering the compounds of the present invention are described (Nivalin R; (4aS,6R,8aS)-4a,5.9,10,11,12-hexahydro-3- in U.S. Pat. No. 5,604.231 to Smith et al. methoxy-11-methyl-6H-benzofuro3a,3,2-ef 2)benza 0036 Typical dosages for systemic administration of NSC Zepin-6-ol), rivastigmine (Exelon(R): (S) N-Ethyl-N-me antagonists may range from about 0.1 to about 1000 milli thyl-3-1-(dimethylamino)ethyl-phenyl carbamate grams per kg weight of Subject per administration. A typical hydrogen-(2R,3R)-tartrate), tacrine (Cognex R; 1,2,3,4-tet dosage may be one 0.4-3000 mg tablet taken once a day, or rahydroacridin-9-amine); or other drug or drugs useful in the one time-release capsule or tablet taken once a day and con treatment, prevention, palliation, or amelioration of demen taining a proportionally higher content of active ingredient. tia, Such as AD. The time-release effect may be obtained by capsule materials 0034. The length of treatment may extend for days, that dissolve at different pH values, by capsules that release months or for years, and may comprise treatment with a NSC slowly by osmotic pressure, or by any other known means of antagonist, or may comprise co-treatment with a SUR1 controlled release (see, e.g., osmotic drug delivery advice as antagonist and with other drugs. In embodiments with other shown, e.g., in U.S. Pat. No. 5.312,390; slow-release compo drugs, such other drugs may be drugs used in treating demen sitions as discussed, e.g., in U.S. Pat. No. 5.41 1,737). tia. In preferred embodiments with other drugs, such other drugs are drugs used in treating AD. Suitable dosing regimens Sulfonylurea Receptor 1 Antagonists are NSC Antagonists include single doses per day and include multiple times per 0037 Sulfonylureas and compounds that act at, and day, daily, or less frequent doses. Where a transdermal patch antagonize the activation or activity of Sulfonylurea recep US 2010/0056444 A1 Mar. 4, 2010

tors such as SUR1, are useful as NSC antagonists. Glibencla may be designed to provide stable plasma levels for extended mide is an exemplary NSC antagonist, and is named hereinas periods of time. Thus, Suitable pharmaceutical dosage forms an example of one of the NSC antagonists that are suitable for include forms for injection; oral forms; topical forms; tablets, the practice of the embodiments of the invention disclosed pills, capsules, gels, and so forth; Sustained release forms, herein. Glibenclamide is also known as glybenclamide, gly enteric-coated forms, implantable forms including depot and buride, glybenzcyclamide, and by other names. The chemical pump forms, and other pharmaceutical forms. name (IUPAC name) of glibenclamide is 5-chloro-N-2-4- 0041. By a “therapeutically effective amount” or simply (cyclohexylcarbamoylsulfamoyl) phenylethyl-2-methoxy “effective amount of an active compound. Such as glibencla benzamide. Equivalent chemical names for glibenclamide mide or tolbutamide, is meant a Sufficient amount of the include, e.g., 5-chloro-N-2-4-cyclohexylamino)carbo compound to treat, prevent or alleviate AD or a condition nylaminosulfonylphenylethyl-2-methoxy-benzamide related to AD. It will be understood, however, that the total (as reported in the Merck Index (12" Edition, Merck daily usage of the active compounds and compositions of the Research Laboratories, 1996, page 762), and 1p-25-chloro present invention will be decided by the attending physician O-anisamido)ethylphenylsulfonyl-3-cyclohexyl-3-urea. within the scope of Sound medical judgment. The specific 0038. It will be understood that any NSC antagonist is therapeutically effective dose level for any particular patient suitable for the practice of the embodiments of the invention will depend upon a variety of factors including the disorder disclosed herein, and that naming glibenclamide is not meant being treated and the severity of the disease; activity of the to be limiting. Other suitable NSC antagonists include, in specific compound employed; the specific composition addition to, glibenclamide: glibenclamide's active metabo employed; the age, body weight, general health, sex and diet lites, such as (for example) 4-trans-hydroxy-glibenclamide of the patient; the time of administration, route of adminis and 3-cis-hydroxy-glibenclamide; tolbutamide (orinase(R): tration, and rate of excretion of the specific compound 3-butyl-1-(4-methylphenyl)sulfonyl-urea); chlorpropamide employed; the duration of the treatment; drugs used in com (N-(4-chlorophenyl)sulfonylmethanamide; also given as bination or coinciding with the specific compound employed; 1-(p-chlorophenyl)sulfonyl-3-propylurea); glipizide and like factors well known in the medical arts. (1-cyclohexyl-3p-2(5-methylpyrazine carboxamido) 0042. Toxicity and therapeutic efficacy of such com ethylphenylsulfonylurea); or tolazamide(benzenesulfona pounds can be determined by standard pharmaceutical pro mide-N-(hexahydro-1H-azepin-1yl)aminocarbonyl-4- cedures in cell assays or experimental animals, e.g., for deter methyl), repaglinide, nateglinide (N-trans-4- mining the LDs (the dose lethal to 50% of the population) isopropylcyclohexanecarbonyl)-D-phenylalanine), and the EDs (the dose therapeutically effective in 50% of the meglitinide, midaglizole, tolaZamide, gliquidone, population). The dose ratio between toxic and therapeutic LY397364, LY389382, glyclazide, glimepiride, estrogen, effects is the therapeutic index and it can be expressed as the estrogen related-compounds (estradiol, estrone, estriol, ratio LDso/EDso. Compounds which exhibit largetherapeutic genistein, non-steroidal estrogen (e.g., diethystilbestrol), indices are preferred. While compounds that exhibit toxic phytoestrogen (e.g., coumestrol), Zearalenone, etc.), and side effects may be used, care should be taken to design a combinations thereof. Examples of suitable NSC antagonists delivery system that targets such compounds to the site of further include, but are not limited to, compounds known to affected tissue in order to minimize potential damage and, inhibit or block K. channels (which include, without limi thereby, reduce side effects. tation, tolbutamide, glibenclamide, and other compounds 0043 Data obtained from cell culture assays and animal named above, as well as MgADP, and other compounds). studies can be used informulating a range of dosage for use in 0039 NSC antagonists include compounds that block or humans. The dosage of Such compounds lies preferably reduce the physiological activity of the TRPM4 channel. within a range of circulating concentrations that include the NSC antagonists which are blockers of the TRPM4 channel EDs with little or no toxicity. The dosage may vary within include pinkolant (R.S)-(3,4-dihydro-6,7-dimethoxy-iso this range depending upon the dosage form employed and the quinoline-1-yl)-2-phenyl-N,N-di2-(2,3,4-trimethoxyphe route of administration utilized. For any compound used in nyl)ethyl-acetamide)); fenamates, including flufenamic the method of the invention, the therapeutically effective dose acid, mefanamic acid, and niflumic acid; rimonabant can be estimated initially from cell based assays. A dose may (SR141716A (5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)- be formulated in animal models to achieve a circulating 4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide); plasma concentration range that includes the ICs (i.e., the SKF 9635 (1-(beta-3 (4-methoxy-phenyl)propoxyl-4- concentration of the test compound which achieves a half methoxyphenyethyl)-1H-imidazole hydrochloride); and maximal inhibition of symptoms) as determined in cell cul other compounds. ture. Such information can be used to more accurately deter mine useful doses in humans. Levels in plasma may be Dose Determinations measured, for example, by high performance liquid chroma 0040 Any suitable medicament, pharmaceutical formula tography. tion, and dosage form may be used in the practice of the 0044) The total daily dose of the active compounds of the invention. A Suitable medicament, pharmaceutical formula present invention administered to a Subject in single or in tion, and dosage form is effective to deliver or provide a divided doses can be in amounts, for example, from 0.01 to 25 therapeutically effective amount of the drug or drug combi mg or more usually from 0.1 to 15 mg. It will be understood nation to the patient. For example, Suitable pharmaceutical that dosages will vary between the different NSC antagonists. dosage forms include a pill, a tablet, an oral formulation, a However, in general, in embodiments, dosages may be gel, an ointment, a transdermal patch, an intravenous solu between about 0.4 mg to about 3000 mg. In preferred embodi tion, a formulation for intramuscular administration, a formu ments, for example, glibenclamide dosages may be between lation for peritoneal administration, and a formulation for about 0.4 mg to about 10 mg. Single dose compositions may Subcutaneous administration. Pharmaceutical dosage forms contain such amounts or Submultiples thereof to make up the US 2010/0056444 A1 Mar. 4, 2010

daily dose. In general, treatment regimens according to the about 5-8 mg per day, or other amount as determined by the present invention comprise administration to a human or weight, age, sex, liver and kidney status, or other character other mammal in need of such treatment from about 0.01 mg istic of the patient. Dosage forms, such as pills including a to about 5 mg per day, or up to about 1000 mg of the active NSC antagonist as an active ingredient, along with other Substance(s) of this invention per day in multiple doses or in ingredients such as pharmaceutically acceptable excipients, a single dose of from 0.01 mg, 0.1 mg, 1 mg, 2.5 mg, 5 mg, 10 may include, for example, about 10 mg. or about 5 mg, or mg, 100 mg, 500 mg or 1000 mg. about 2.5 mg, or about 1 mg. or about 0.5 mg, or about 0.1 mg 0045 An effective amount of a NSC antagonist or related of glibenclamide. compounds thereof as a treatment varies depending upon the Subject that is treated and the particular mode of administra 0048. It is believed that suitable glibenclamide doses use tion. In one embodiment of the invention the dose range of the ful for treating AD will typically result in blood plasma con NSC antagonist or related-compounds thereof will be about centrations of about 2-6 ng/ml or higher. Thus, in embodi 0.01 ug/kg body weight to about 20,000 ug/kg body weight. ments, treatments will result in suitable blood plasma All concentrations and treatment levels are expressed as concentrations of about 5 ng/ml, or of about 4 ng/ml, or of “body weight” or simply “kg in this application are also about 3 ng/ml, or of about 2 ng/ml, or of about 1 ng/ml, or considered to cover the analogous “total body weight” con higher blood plasma concentrations. centrations. However, those of skill will recognize the utility 0049. In alternative embodiments, for example, a suitable of a variety of dosage range, for example, 0.01 g/kg body dose of oral or intravenous (IV) glibenclamide for the treat weight to 20,000 ug/kg body weight, 0.02 g/kg body weight ment of AD may be about 0.01 mg to about 10 mg per day; a to 15,000 ug/kg body weight, 0.03 ug/kg body weight to suitable dose of oral or IV tolbutamide for the treatment of 10,000 ug/kg body weight, 0.04 ug/kg body weight to 5,000 AD may be about to 0.001 mg to about 3,000 mg per day; a ug/kg body weight, 0.05 g/kg body weight to 2,500 ug/kg suitable dose of oral gliclazide for the treatment of AD may be body weight, 0.06 g/kg body weight to 1,000 ug/kg body about 0.1 mg to about 100 mg per day; weight, 0.07 g/kg body weight to 500 ug/kg body weight, 0.08 ug/kg body weight to 400 g/kg body weight, 0.09 ug/kg 0050. In certain situations, it may be important to maintain body weight to 200 ug/kg body weight or 0.1 ug/kg body a fairly low dose of the active agent in the blood stream of the weight to 100 ug/kg body weight. Further, those of skill will patient. Such a fairly low dose may include a dose that is less recognize that a variety of different dosage levels will be of than its use in other indications. For example, the typical use, for example, 0.0001 ug/kg, 0.0002 ug/kg, 0.0003 ug/kg, anti-diabetic dose of oral glibenclamide is about 2.5 mg to 0.0004 ug/kg, 0.005 ug/kg, 0.0007 ug/kg, 0.001 ug/kg, 0.1 about 15 mg per day; the typical anti-diabetic dose of oral or g/kg, 1.0 Lig/kg, 1.5ug/kg, 2.0 Lig/kg, 5.0 Lig/kg, 10.0 g/kg. IV tolbutamide is about to 500 mg to about 3000 mg per day: 15.0 ug/kg, 30.0 ug/kg, 50 g/kg, 75 g/kg, 80 g/kg, 90 the typical anti-diabetic dose for oral gliclazide is about 30 Lig/kg, 100 g/kg, 120 g/kg, 140||g/kg, 150 ug/kg, 160 g/kg, mg to about 120 mg per day; however, in embodiments, 180 g/kg, 200 ug/kg, 225 ug/kg, 250 ug/kg, 275 g/kg, 300 smaller doses may be used in treatment of AD. Where smaller ug/kg, 325 ug/kg, 350 g/kg, 375 g/kg, 400 ug/kg, 450 doses are used, such smaller doses may be, for example, less ug/kg, 500 ug/kg, 550 g/kg, 600 g/kg, 700 lug/kg, 750 than about 2.5 mg/day of glibenclamide, less than about 500 g/kg, 800 g/kg, 900 g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 12 mg per day of tolbutamide, less than about 30 mg per day of mg/kg, 15 mg/kg, 20 mg/kg, and/or 30 mg/kg. Of course, all oral gliclazide, or other doses. Such smaller doses may be of these dosages are exemplary, and any dosage in-between used, for example, where multiple doses are administered these points is also expected to be of use in the invention. Any during the course of a single day, effective to reduce the of the above dosage ranges or dosage levels may be employed variability in the plasma levels of the drug over time. for a NSC antagonist or related-compounds thereof. 0051. In particular, it is believed that preferred dosages of 0046 For example, in certain embodiments, the amount of glibenclamide for use according to the present invention pro the NSC antagonist administered to the subject is in the range vide between about 0.4 mg to about 10 mg glibenclamide per of about 0.0001 ug/kg/day to about 20 mg/kg/day, about 0.01 day; preferred dosages oftolbutamide for use according to the ug/kg/day to about 100 ug/kg/day, or about 100 ug/kg/day to present invention provide between about 50 mg to about 1000 about 20 mg/kg/day. Still further, the NSC antagonist may be mg tolbutamide per day; and preferred dosages of gliclaZide administered to the subject in the from of a treatment in which for use according to the present invention provide between the treatment may comprise the amount of the NSC antago about 5 mg to about 20 mg gliclaZamide per day. nist or the dose of the NSC antagonist that is administered per 0052. In certain situations, it may be important to maintain day (1, 2, 3, 4, etc.), week (1, 2, 3, 4, 5, etc.), month (1, 2, 3, a fairly high dose of the active agent in the blood stream of the 4, 5, etc.), etc. Treatments may be administered such that the patient, particularly early in the treatment. Such a fairly high amount of NSC antagonist administered to the subject is in dose may include a dose that is several times greater than its the range of about 0.0001 ug/kg/treatment to about 20 mg/kg/ use in other indications. For example, the typical anti-diabetic treatment, about 0.01 ug/kg/treatment to about 100 g/kg/ dose of oral glibenclamide is about 2.5 mg to about 15 mg per treatment, or about 100 ug/kg/treatment to about 20 mg/kg/ day; the typical anti-diabetic dose of oral tolbutamide is about treatment. to 0.5gm to about 3.0 gm per day; the typical anti-diabetic 0047. In embodiments, a NSC antagonist dosage may be dose for oral gliclazide is about 30 mg to about 120 mg per between about 0.01 mg to about 15 mg. In preferred embodi day; however, larger doses may be required in Some cases. ments, a dosage may be between about 0.4 mg to about 10 mg 0053 For example, in one embodiment of the present per day. For example, a Suitable daily dose of glibenclamide invention directed to a method of preventing or treating AD in may be less than about 10 mg per day; in particular embodi a Subject by administering to the Subject a formulation con ments, a suitable daily dose of glibenclamide may be about taining an effective amount of a NSC antagonist and a phar 0.4 mg/day to about 10 mg/day, or about 4-9 mg per day, or maceutically acceptable carrier, such formulations may con US 2010/0056444 A1 Mar. 4, 2010 tain, for example, from about 0.01 to about 3000 milligrams istration of NSC antagonists in conjunction with AD drugs of tolbutamide or from about 0.05 to about 50 milligrams of includes, without limitation: simultaneous or concomitant glibenclamide. administration of a NSC antagonist with an AD drug; admin 0054. In regards to oral glibenclamide for AD in non dia istration of a NSC antagonist followed by administration of betics, doses may be in the range 0.1 mg/day to 10 mg/day or an AD drug; and administration of an AD drug followed by even as high as 15-20 mg/day, and would be divided into low administration of a NSC antagonist. Simultaneous or con dose pills given as few as 1 doses a day, and as many as 4-6 comitant administration includes administration of both doses. Dose regimens are designed so as to maintain the drugs, or of both types of drugs, within a few minutes or plasma concentrations of glibenclamide, or of any other NSC within a few tens of minutes of each other. antagonist, steady over time, and so as to, as much as possible, 0060 Accordingly, compositions and pharmaceutical for avoid or minimize large peaks and Valleys or plasma concen mulations of the present invention include combined dosage tration over time. Administration more than twice a day is forms including as active ingredients a NSC antagonist and often associated with low compliance, thus it is considered another drug. The other drug is preferably a drug that is used that in practice maximal numbers or doses per day may be in the treatment of AD, or a drug that is useful in the treatment about 4-6 doses per day. of AD. In embodiments, the other drug may be memantine, or 0055. A preferred method of administration includes donepezil, or galantamine, or rivastigmine, or tacrine, or any transdermal administration of NSC antagonist, such as by use combination thereof. Combined pills having features of the of a transdermal patch. For example, transdermal glibencla invention include pills providing suitable amounts of NSC mide patches as presently used for treatment of diabetes may antagonist, as discussed above. Thus, for example, where the be used in the methods disclosed herein, as adapted to provide NSC antagonist is glibenclamide, a combined dosage form proper dosage levels of NSC antagonist, such as glibencla may include in a single pill, tablet, capsule, or other dosage mide, for treatment, palliation, amelioration, or prevention of form, for example, glibenclamide with memantine; glib AD enclamide with donepezil; glibenclamide with galantamine; 0056. A NSC antagonist may be administered intrave glibenclamide with rivastigmine; or glibenclamide with nously. For example, where glibenclamide is administered to tacrine. Similarly, where the NSC antagonist is tolbutamide, a patient for the treatment of AD, smaller amounts of glib a combined dosage form may include in a single pill, tablet, enclamide may be required to obtain a blood plasma level of capsule, or other dosage form, for example, tolbutamide with about 6 ng/ml, so that, for example, as little as about 0.5 memantine; tolbutamide with donepezil; glibenclamide with mg/day glibenclamide may be administered intravenously. galantamine; tolbutamide with rivastigmine; or tolbutamide 0057. A suitable amount of NSC antagonist may also bean with tacrine. It will be understood that a combined dosage amount that maintains a reasonable level of blood glucose in form may include in a single pill, tablet, capsule, or other the patient, for example, the amount of the antagonist main dosage form having features of the invention any combination tains a blood glucose level of at least 60 mg/dl. More prefer of a NSC antagonist and a drug used in, or useful for, treating ably, the blood glucose level is maintained in the range of AD, and may include more than one NSC antagonist, more about 60 mg/dl to about 150 mg/dl. Thus, the amount of NSC than one drug used in, or useful for, treating AD; and may antagonist may be provided so as to prevents the Subject from include more than one of both a NSC antagonist and more becoming hypoglycemic. If glucose levels are not normal, than one drug used in, or useful for, treating AD. then one of skill in the art would administer either insulin or 0061 For example, a single pill, tablet, capsule, or other glucose, depending upon if the patient is hypoglycemic or dosage form having features of the invention may include hyperglycemic. about 0.4-5 mg glibenclamide with about 5-10 mg meman 0058 Glucose may be administered with a NSC antago tine. Other examples, listed to provide examples but not to nist in embodiments of the present methods of preventing or limit the single pill, tablet, capsule, or other dosage forms treating AD in a subject. Thus, in embodiments of the meth disclosed herein, include about 1-5 mg glibenclamide with ods disclosed herein, the methods include co-administration about 5-10 mg donepezil; about 1-5 mg glibenclamide with of a NSC antagonist with glucose, or with a related carbohy about 1-5 mg rivastigmine; about 1-5 mg glibenclamide with drate, or both, effective to maintain appropriate levels of about 4-12 mg galantamine; about 1-5 mg glibenclamide with serum glucose. Appropriate serum levels of blood glucose are about 10-40 mg tacrine; and other combinations. within the range of about 60 mg/dl to about 150 mg/dl. Thus, 0062. A transdermal patch having features of the invention glucose, or a related carbohydrate, or both, may be adminis may combine active ingredients a NSC antagonist and tered, alone or in combination, to maintain the serum glucose another drug. The other drug is preferably a drug that is used within this range or within. in the treatment of AD, or a drug that is useful in the treatment 0059 A NSC antagonist such as glibenclamide may be of AD. In embodiments, the other drug may be memantine, or administered in conjunction (either separately or together) donepezil, or galantamine, or rivastigmine, or tacrine, or any with drugs used for treating AD patients such as, e.g., meman combination thereof. Combined transdermal patches having tine (Namenda R., 1-amino-3,5-dimethyl-adamantane), done features of the invention include pills providing suitable pezil (Aricept(R): 2-(1-benzyl-4-piperidyl)methyl-5,6- amounts of NSC antagonist, as discussed above. Thus, for dimethoxy-2,3-dihydroinden-1-one), galantamine example, where the NSC antagonist is glibenclamide, a com (Nivalin R; (4aS,6R,8aS)-4a,5.9,10,11,12-hexahydro-3- bined transdermal patch may include, for example, glibencla methoxy-11-methyl-6H-benzofuro3a,3,2-ef 2)benza mide with memantine; glibenclamide with donepezil; glib Zepin-6-ol), rivastigmine (Exelon(R): (S)-N-Ethyl-N-methyl enclamide with galantamine; glibenclamide with 3-1-(dimethylamino)ethyl-phenyl carbamate hydrogen rivastigmine; or glibenclamide with tacrine. Similarly, where (2R,3R)-tartrate), or other drugs useful in the treatment, the NSC antagonist is tolbutamide, a combined transdermal prevention, palliation, or amelioration of AD. Such drugs patch may include, for example, tolbutamide with meman used for treating AD patients are termed “AD drugs.” Admin tine; tolbutamide with donepezil; glibenclamide with galan US 2010/0056444 A1 Mar. 4, 2010

tamine; tolbutamide with rivastigmine; or tolbutamide with range, or before administration of a NSC antagonist with an tacrine. It will be understood that a transdermal patch having other dementia drug and with a substance effective to main features of the invention may include any combination of a tain blood plasma glucose levels within an acceptable physi NSC antagonistanda drug used in, or useful for, treating AD, ological range. and may include more than one NSC antagonist; more than 0067. In further embodiments, blood glucose level moni one drug used in, or useful for, treating AD; and may include toring may be performed during administration of a NSC more than one of both a NSC antagonist and more than one antagonist, or during administration of a NSC antagonist with drug used in, or useful for, treating AD. an other dementia drug, or during administration of a Sub stance effective to maintain blood plasma glucose levels Methods within an acceptable physiological range, or during adminis 0063. Applicants disclose herein that the onset of demen tration of a NSC antagonist with an other dementia drug and tia may be prevented or delayed, and that dementia may be with a Substance effective to maintain blood plasma glucose treated, or its symptoms relieved, by administration of an levels within an acceptable physiological range. effective amount of a NSC antagonist to a patient at risk of 0068 Blood glucose level monitoring may be performed developing dementia, or suffering from the onset of dementia, after administration of a NSC antagonist, or after administra or suffering from dementia. The dementia may be AD. The tion of a NSC antagonist with an other dementia drug, or after NSC antagonist may be, for example, glibenclamide, glib administration of a substance effective to maintain blood enclamide's active metabolites (e.g., 4-trans-hydroxy-glib plasma glucose levels within an acceptable physiological enclamide and 3-cis-hydroxy-glibenclamide), tolbutamide, range, or after administration of a NSC antagonist with an chlorpropamide, tolaZamide, repaglinide, nateglinide, megli other dementia drug and with a substance effective to main tinide, midaglizole, tolazamide, gliquidone, LY397364, tain blood plasma glucose levels within an acceptable physi LY389382, glyclazide, glimepiride, estrogen, estradiol, ological range. estrone, estriol, genistein, diethystilbestrol, coumestrol, 0069. In further embodiments, blood glucose level moni Zearalenone, non-steroidal estrogens, phytoestrogens, or a toring may be performed at any time with respect to the combination thereof. In embodiments, the NSC antagonist is administration of a NSC antagonist, or the administration of selected from glibenclamide, tolbutamide, chlorpropamide, a NSC antagonist with an other dementia drug, or the admin tolaZamide, repaglinide, nateglinide, meglitinide, midagli istration of a Substance effective to maintain blood plasma Zole, tolazamide, gliquidone, LY397364, LY389382, glycla glucose levels within an acceptable physiological range, or Zide, glimepiride, and combinations thereof. the administration of a NSC antagonist with an other demen 0064. Applicants further disclose herein that the onset of tia drug and with a substance effective to maintain blood dementia may be prevented or delayed, and that dementia plasma glucose levels within an acceptable physiological may be treated, or its symptoms relieved, by administration of range. an effective amount of a NSC antagonist in combination with 0070 Blood plasma concentrations of glibenclamide of as an other drug that is used to treat dementia, to a patient at risk low as 2-6 ng/ml are effective to statistically significant of developing dementia, or Suffering from the onset of reductions in blood plasma glucose levels in some patients. dementia, or Suffering from dementia. The dementia may be Thus in an embodiment, blood plasma levels of glibencla AD. The NSC antagonist may be glibenclamide, tolbutamide, mide are maintained at about 2-6 ng/ml or more. In further chlorpropamide, tolaZamide, repaglinide, nateglinide, megli embodiments, glucose is provided in order to maintain blood tinide, midaglizole, tolazamide, gliquidone, LY397364, glucose levels within the desirable range (typically above LY389382, glyclazide, glimepiride, estrogen, estradiol, about 60 mg/dl., or between about 60 mg/dl to about 150 estrone, estriol, genistein, diethystilbestrol, coumestrol, mg/dl). Glucose may be administered at the same time as the Zearalenone, non-steroidal estrogens, phytoestrogens, or a glibenclamide; may be administered at different times (e.g., combination thereof. In embodiments, the NSC antagonist is before or after glibenclamide administration); and glucose selected from glibenclamide, tolbutamide, chlorpropamide, may be administered by another route of administration (or tolaZamide, repaglinide, nateglinide, meglitinide, midagli separate pill) in order to keep blood plasma glucose levels Zole, tolazamide, gliquidone, LY397364, LY389382, glycla within the desirable range. In embodiments of the methods of Zide, glimepiride, and combinations thereof. The other drug the invention, glucose levels may be monitored. For example, that is used to treat dementia may be, for example, selected a glucose monitoring system may be used monitor glucose from memantine, donepezil, galantamine, rivastigmine, levels and to aid in determining the properamounts of glucose tacrine, and combinations thereof. to be administered in order to adjust glucose administration 0065. In further embodiments of the methods disclosed specifically for that particular patient. Such a glucose moni herein, a substance is administered to the patient effective to toring system may be one-time glucose monitoring system; maintain blood plasma glucose levels within an acceptable may be an intermittent glucose monitoring system; and may physiological concentration range. In some embodiments, the be a continuous glucose monitoring system. Substance is glucose. In some embodiments, the Substance is (0071. Formulations and Administration glucagon. In some embodiments, both glucose and glucagon 0072 The NSC antagonist compounds for use in the com are administered. positions, formulations, methods, and kits of the present 0.066. In further embodiments of the methods disclosed invention may be administered alone or in combination or in herein, blood plasma glucose levels are monitored. Blood concurrent therapy with other agents which affect the central glucose level monitoring may be performed before adminis or peripheral nervous system, particularly selected areas of tration of a NSC antagonist, or before administration of a the brain. Compositions and formulations suitable for the NSC antagonist with an other dementia drug, or before practice of the invention include pharmaceutical dosage administration of a substance effective to maintain blood forms that are suitable for administration by one or more of plasma glucose levels within an acceptable physiological any Suitable route of administration, and include a pill, a US 2010/0056444 A1 Mar. 4, 2010

tablet, an oral formulation, an intravenous formulation, an physical characteristics to the tablet. Such pharmaceutical intra-arterial formulation, an intramuscular formulation, a excipients may be selected from diluents, binders, glidants, Subcutaneous formulation, a peritoneal formulation, an inha lubricants, disintegrants, colors, flavors, Sweetening agents, lational formulation, a rectal formulation, a vaginal formula polymers, waxes or other solubility-retarding materials. tion, a topical formulation, a gel, an ointment, and a transder 0079 Compositions for intravenous administration will mal patch. generally comprise intravenous fluids, i.e., Sterile Solutions of 0073. In compositions, formulations, methods and kits of simple chemicals such as Sugars, amino acids or electrolytes, the invention, NSC antagonist compounds can be incorpo which can be easily carried by the circulatory system and rated into a pharmaceutically acceptable formulation for assimilated. Such fluids are prepared with water for injection administration. Those of skill in the art can readily determine USP. Suitable dosage levels when the invention compounds are so 0080 Dosage forms for parenteral administration will used. In embodiments of the invention, compositions and generally comprise fluids, particularly intravenous fluids, i.e., formulations comprising at least one NSC antagonist com sterile solutions of simple chemicals such as Sugars, amino pound, and a pharmaceutically acceptable carrier are contem acids or electrolytes, which can be easily carried by the cir plated. culatory system and assimilated. Such fluids are typically 0074 As employed herein, the phrase “suitable dosage prepared with water for injection USP. Fluids used commonly levels' refers to levels of compound sufficient to provide for intravenous (IV) use are disclosed in Remington, The circulating concentrations high enough to prevent or treat Science and Practice of Pharmacy full citation previously dementia, such as AD, in a patient. In embodiments of the provided, and include: alcohol, e.g., 5% alcohol (e.g., in invention, such dosages are effective to block the NC dextrose and water (“D/W) or D/W in normal saline solution channel in vivo. (“NSS”), including in 5% dextrose and water (“D5/W), or 0075 Pharmaceutical dosage forms include a NSC D5/W in NSS); synthetic amino acid such as Aminosyn, antagonists or a pharmaceutically acceptable salt, Solvate, or FreAmine, Travasol, e.g., 3.5 or 7: 8.5: 3.5, 5.5 or 8.5% Solvate of a salt thereof, and one or more pharmaceutical respectively; ammonium chloride e.g., 2.14%; dextran 40, in excipients. As is known in the art, pharmaceutical excipients NSS e.g., 10% or in D5/W e.g., 10%; dextran 70, in NSS e.g., are secondary ingredients which function to enable or 6% or in D5/W e.g., 6%; dextrose (glucose, D5/W) e.g., enhance the delivery of a drug or medicine in a variety of 2.5-50%; dextrose and sodium chloride e.g., 5-20% dextrose dosage forms (e.g.: oral forms such as tablets, capsules, and and 0.22-0.9% NaCl; lactated Ringer's (Hartmann's) e.g., liquids; topical forms such as dermal, opthalmic, and otic NaCl 0.6%, KC1 0.03%, CaCl.sub.2 0.02%; lactate 0.3%: forms; Suppositories; injectables; respiratory forms and the mannitol e.g., 5%, optionally in combination with dextrose like). Pharmaceutical excipients include inert or inactive e.g., 10% or NaCl e.g., 15 or 20%; multiple electrolyte solu ingredients, synergists or chemicals that Substantively con tions with varying combinations of electrolytes, dextrose, tribute to the medicinal effects of the active ingredient. For fructose, invert sugar Ringer's e.g., NaCl 0.86%. KCl 0.03%, example, pharmaceutical excipients may function to improve CaCl.sub.2 0.033%; sodium bicarbonate e.g., 5%; sodium flow characteristics, product uniformity, stability, taste, or chloride e.g., 0.45, 0.9, 3, or 5%; sodium lactate e.g., /6 M; appearance, to ease handling and administration of dose, for and sterile water for injection The pH of such IV fluids may convenience of use, or to control bioavailability. While phar vary, and will typically be from 3.5 to 8 as known in the art. maceutical excipients are commonly described as being inert I0081 Injectable preparations, for example, sterile inject or inactive, it is appreciated in the art that there is a relation able aqueous or oleaginous Suspensions may be formulated ship between the properties of the pharmaceutical excipients according to the known art using Suitable dispersing or wet and the dosage forms containing them. ting agents and Suspending agents. The sterile injectable 0076 Pharmaceutical excipients suitable for use as carri preparation may also be a sterile injectable solution, Suspen ers or diluents are well known in the art, and may be used in sion or emulsion in a nontoxic parenterally acceptable diluent a variety of formulations. See, e.g., Remington's Pharmaceu or solvent, for example, as a solution in 1,3-butanediol. tical Sciences, 18th Edition, A. R. Gennaro, Editor, Mack Among the acceptable vehicles and solvents that may be Publishing Company (1990); Remington: The Science and employed are water, Ringer's solution, U.S.P. and isotonic Practice of Pharmacy, 20th Edition, A. R. Gennaro, Editor, sodium chloride solution. In addition, sterile, fixed oils are Lippincott Williams & Wilkins (2000); Handbook of Phar conventionally employed as a solvent or Suspending medium. maceutical Excipients, 3rd Edition, A. H. Kibbe, Editor, For this purpose any bland fixed oil can be employed includ American Pharmaceutical Association, and Pharmaceutical ing synthetic mono- or diglycerides. In addition, fatty acids Press (2000); and Handbook of Pharmaceutical Additives, Such as oleic acid are used in the preparation of injectables. compiled by Michael and Irene Ash, Gower (1995), each of I0082. The injectable formulation can be sterilized, for which is incorporated herein by reference for all purposes. example, by filtration through a bacteria-retaining filter, or by 0077 Liquid dosage forms for oral administration may incorporating sterilizing agents in the form of sterile solid include pharmaceutically acceptable emulsions, microemul compositions, which can be dissolved or dispersed in sterile sions, solutions, Suspensions, syrups and elixirs containing water or other sterile injectable medium just prior to use. inert diluents commonly used in the art, such as water, iso I0083. In order to prolong the effect of a drug, it is often tonic solutions, or saline. Such compositions may also com desirable to slow the absorption of a drug from subcutaneous prise adjuvants, such as wetting agents; emulsifying and Sus or intramuscular injection. The most common way to accom pending agents: Sweetening, flavoring and perfuming agents. plish this is to inject a Suspension of crystalline or amorphous 0078 Oral solid dosage forms such as tablets will typi material with poor water solubility. The rate of absorption of cally comprise one or more pharmaceutical excipients, which the drug becomes dependent on the rate of dissolution of the may for example help impart satisfactory processing and drug, which is, in turn, dependent on the physical State of the compression characteristics, or provide additional desirable drug, for example, the crystal size and the crystalline form. US 2010/0056444 A1 Mar. 4, 2010

Another approach to delaying absorption of a drug is to to preserve the active ingredient and provide for a homog administer the drug as a solution or Suspension in oil. Inject enous mixture. The ointments, pastes, creams and gels may able depot forms can also be made by forming microcapsule contain, in addition to an active compound of this invention, matrices of drugs and biodegradable polymers, such as poly excipients such as animal and vegetable fats, oils, waxes, lactide-polyglycoside. Depending on the ratio of drug to paraffins, starch, tragacanth, cellulose derivatives, polyethyl polymer and the composition of the polymer, the rate of drug ene glycols, silicones, bentonites, silicic acid, talc and Zinc release can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. The oxide, or mixtures thereof. depot injectables can also be made by entrapping the drug in 0090 Transdermal administration of the present invention liposomes or microemulsions, which are compatible with may also comprise the use of a "patch'. For example, the body tissues. patch may supply one or more active Substances at a prede 0084 Suppositories for rectal administration of the drug termined rate and in a continuous manner over a fixed period can be prepared by mixing the drug with a suitable non of time. Transdermal patches have the added advantage of irritating excipient, such as cocoa butter and polyethylene providing controlled delivery of active compound to the body. glycol which are solid at ordinary temperature but liquid at Such dosage forms can be made by dissolving or dispersing the rectal temperature and will, therefore, melt in the rectum the compound in the proper medium. Absorption enhancers and release the drug. can also be used to increase the flux of the compound across 0085 Solid dosage forms for oral administration may the skin. The rate can be controlled by either providing a rate include capsules, tablets, pills, powders, gelcaps and gran controlling membrane or by dispersing the compound in a ules. In Such solid dosage forms the active compound may be polymer matrix or gel. In addition, a patch may include pen admixed with at least one inert diluent Such as Sucrose, lac etration enhancers. Suitable penetration enhancers include tose or starch. Such dosage forms may also comprise, as is glycerin, alcohols, alkyl methylsulfoxides, pyrrolidones and normal practice, additional Substances other than inert dilu luarocapram. ents, e.g., tableting lubricants and other tableting aids such as 0091 Exemplary pharmaceutically acceptable carriers magnesium Stearate and microcrystalline cellulose. In the include carriers Suitable for oral, intravenous, Subcutaneous, case of capsules, tablets and pills, the dosage forms may also intramuscular, intracutaneous, and the like administration. comprise buffering agents. Tablets and pills can additionally Administration in the form of creams, lotions, tablets, dis be prepared with enteric coatings and other release-control persible powders, granules, syrups, elixirs, sterile aqueous or ling coatings. non-aqueous solutions, Suspensions or emulsions, and the I0086 Solid compositions of a similar type may also be like, is contemplated. employed as fillers in Soft and hard-filled gelatin capsules 0092. For the preparation of oral liquids, suitable carriers using such excipients as lactose or milk Sugar as well as high include emulsions, solutions, Suspensions, syrups, and the molecular weight polyethylene glycols and the like. like, optionally containing additives such as wetting agents, 0087. The active compounds can also be in micro-encap emulsifying and Suspending agents, Sweetening, flavoring sulated form with one or more excipients as noted above. The and perfuming agents, and the like. Solid dosage forms of tablets, capsules, pills, and granules can 0093. For the preparation of fluids for parenteral adminis be prepared with coatings and shells such as enteric coatings tration, Suitable carriers include sterile aqueous or non-aque and other coatings well known in the pharmaceutical formu ous solutions, Suspensions, or emulsions. Examples of non lating art. They may optionally contain opacifying agents and aqueous solvents or vehicles are propylene glycol, can also be of a composition that they release the active polyethylene glycol, vegetable oils, such as olive oil and corn ingredient(s) only, or preferably, in a certain part of the intes oil, gelatin, and injectable organic esters such as ethyl oleate. tinal tract, optionally in a delayed manner. Examples of Such dosage forms may also contain adjuvants such as pre embedding compositions which can be used include poly serving, wetting, emulsifying, and dispersing agents. They meric Substances and waxes. may be sterilized, for example, by filtration through a bacte 0088 Dosage forms for topical or transdermal administra ria-retaining filter, by incorporating sterilizing agents into the tion of a compound of this invention further include oint compositions, by irradiating the compositions, or by heating ments, pastes, creams, lotions, gels, powders, Solutions, the compositions. They can also be manufactured in the form sprays, inhalants or patches. of sterile water, or some other sterile injectable medium 0089 Pharmaceutical compositions for topical adminis immediately before use. The active compound is admixed tration may include the active compound formulated for a under Sterile conditions with a pharmaceutically acceptable medicated application Such as an ointment, paste, cream or carrier and any needed preservatives or buffers as may be powder. Ointments include all oleaginous, adsorption, emul required. sion and water-solubly based compositions for topical appli 0094. In certain embodiments, the pharmaceutical com cation, while creams and lotions are those compositions that positions may be delivered by eye drops, intranasal sprays, include an emulsion base only. Topically administered medi inhalation, and/or other aerosol delivery vehicles. Methods cations may contain a penetration enhancer to facilitate for delivering compositions directly to the lungs via nasal absorption of the active ingredients through the skin. Suitable aerosol sprays has been described e.g., in U.S. Pat. Nos. penetration enhancers include glycerin, alcohols, alkyl 5,756.353 and 5,804.212 (each specifically incorporated methyl sulfoxides, pyrrolidones and luarocapram. Possible herein by reference in its entirety). Likewise, the delivery of bases for compositions for topical application include poly drugs using intranasal microparticle resins (Takenaga et al., ethylene glycol, lanolin, cold cream and petrolatum as well as 1998) and lysophosphatidyl-glycerol compounds (U.S. Pat. any other Suitable absorption, emulsion or water-soluble oint No. 5,725,871, specifically incorporated herein by reference ment base. Topical preparations may also include emulsifiers, in its entirety) are also well-known in the pharmaceutical arts. gelling agents, and antimicrobial preservatives as necessary Likewise, transmucosal drug delivery in the form of a poly US 2010/0056444 A1 Mar. 4, 2010

tetrafluoroetheylene support matrix is described in U.S. Pat. 0101. In addition to the NSC antagonist or related-com No. 5,780.045 (specifically incorporated herein by reference pounds thereof, the kits may also include a second active in its entirety). ingredient. Examples of the second active ingredient include 0095. The term aerosol refers to a colloidal system of Substances to prevent hypoglycemia (e.g., glucose, glucagon, finely divided solid of liquid particles dispersed in a liquefied glucose solutions such as 5% dextrose in water (D5W), and or pressurized gas propellant. The typical aerosol of the other Substances), and steroids (e.g., methylprednisolone), present invention for inhalation will consist of a suspension of etc. These second active ingredients may be combined in the active ingredients in liquid propellant or a mixture of liquid same vial as the NSC antagonist or related-compounds propellant and a suitable solvent. Suitable propellants include thereof or they may be contained in a separate vial. hydrocarbons and hydrocarbon ethers. Suitable containers 0102 All patents and publications discussed herein are will vary according to the pressure requirements of the pro hereby incorporated by reference in their entireties. pellant. Administration of the aerosol will vary according to Examples Subject's age, weight and the severity and response of the symptoms. 0103) The following exemplary descriptions illustrate 0096. Therapeutic kits of the present invention are kits ways to implement the methods and treatments disclosed comprising an antagonist or a related-compound thereof. herein. Thus, the kit may comprise an NSC antagonist or related 0104. A 56-year old man with a family history of AD in his compound thereof to block and/or inhibit the NC chan grandfather, father and elder sibling presents to a neurologist nel or to block or inhibit a TRPM4 channel. Such kits will concerned about his risk of AD. Upon examination he is generally contain, in Suitable container means, a pharmaceu found to be cognitively normal, with no clinical signs of tically acceptable formulation of NSC antagonist or related neurological disease. The patient is begun on a low dose of compound thereof, may contain, in Suitable container means, daily glibenclamide of 0.5 mg per day for transdermal admin a pharmaceutically acceptable formulation of an AD drug or istration, to be taken on a chronic basis as a prophylactic related-compound thereof, and may include a compound treatment. effective to raise or to maintain, at suitable levels, blood 0105. A 56-year old man with a family history of AD in his plasma glucose concentrations. The kit may have a single grandfather, father and elder sibling presents to a neurologist concerned about his risk of AD. Upon examination he is container means, and/or it may have distinct container means found to be cognitively normal, with no clinical signs of for each compound. neurological disease. The patient is begun on a low dose of 0097. A pharmaceutically acceptable formulation is a daily glibenclamide of 0.5 mg per day for oral administration, composition, including at least one active ingredient, and to be taken on a chronic basis as a prophylactic treatment. including one or more otheringredients, such as, for example, 0106 The daughter of an 83-year old female notices her diluents, solutions, buffers, carriers, excipients, binders, mother exhibiting episodes of forgetfulness, and a situation in extenders, osmoticants, and other compounds and ingredients which the mother is unable to locate her car in a shopping as are Suitable for dissolving, storing, and/or delivering an centerparking lot. The elderly patient is brought to a geriatri active pharmaceutical agent. cian, where mini-mental state examination reveals short-term 0098 Kits comprising pharmaceutical compositions and/ memory loss and mild cognitive impairment. A diagnosis of or formulations suitable for preventing AD, or for treating AD is made as other causes are ruled out. The patient begins AD, may include instructions for administration of the phar a course of daily glibenclamide of 1.0 mg per day adminis maceutical compositions and/or formulations, and may tered via monthly depot intramuscular injection. Depot injec include containers Suitable for holding the pharmaceutical tion is chosen in order to optimize patient compliance. Neu compositions and/or formulations. Such containers of Such rological testing detects a stabilization of symptoms due to kits may be suitable for organizing pills, vials, or other unit the treatment. dosage forms for daily, weekly or other dosage regimens. 0107. A 68-year old type 2 diabetic male presents to his 0099 Kits may comprise a pharmaceutically acceptable family physician with complaints of forgetfulness and formulation of a NSC antagonist, and a pharmaceutically increasing confusion. He is being treated with metforminand acceptable formulation of an AD drug. IN embodiments, a kit diet controls for his Type 2 diabetes. The patient is diagnosed may comprise a pharmaceutically acceptable formulation of a with AD upon referral to a geriatrician and upon clinical, NSC antagonist, a pharmaceutically acceptable formulation laboratory and imaging investigations. The patient begins a of an AD drug, and a pharmaceutically acceptable formula daily dose of glibenclamide at 10 mg per day, and his daily tion of a compound effective to increase blood plasma glu metformin is ceased. The patient demonstrates stable blood cose levels. A compound effective to increase blood plasma glucose measurements and Hb A1C levels, and the patient glucose levels may be, for example, glucagon, or glucose, or notes that his episodes of forgetfulness are waning with this both, or other compound. treatment regimen. 0100 When the components of the kit are provided in one 1-41. (canceled) and/or more liquid solutions, the liquid Solution is an aqueous 42. A method of treating dementia, comprising administer Solution, with a sterile aqueous solution being particularly ing an NSC antagonist to a patient in need of Such treatment, preferred. The NSC antagonist or related-compounds thereof wherein said NSC antagonist comprises an antagonist of may also be formulated into a syringeable composition. In activity of the NC channel, the TRPM4 channel, or the which case, the container means may itself be a syringe, TRPM5 channel. pipette, and/or other Such like apparatus, from which the 43. The method of claim 42, wherein said dementia is formulation may be applied to an infected area of the body, Alzheimer's Disease (AD). injected into an animal, and/or even applied to and/or mixed 44. The method of claim 42, wherein said NSC antagonist with the other components of the kit. is selected from glibenclamide, 4-trans-hydroxy-glibencla US 2010/0056444 A1 Mar. 4, 2010 mide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlorpro from memantine, donepezil, galantamine, rivastigmine, pamide, tolaZamide, repaglinide, nateglinide, meglitinide, tacrine, and combinations thereof. midaglizole, tolazamide, gliquidone, LY397364, LY389382, 52. The pharmaceutical composition of claim 49 compris glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, ing glibenclamide; a compound selected from memantine, genistein, diethystilbestrol, coumestrol. Zearalenone, non donepezil, galantamine, rivastigmine, tacrine, and combina steroidal estrogens, phytoestrogens, pinkolant, flufenamic tions thereof, and a pharmaceutically acceptable carrier. acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, 53. The pharmaceutical composition of claim 49 compris and combinations thereof. ing tolbutamide; a compound selected from memantine, 45. The method of claim 42, further comprising adminis donepezil, galantamine, rivastigmine, tacrine, and combina tration of an other compound, wherein said other compound tions thereof, and a pharmaceutically acceptable carrier. is a compound used in the treatment of dementia. 54. The pharmaceutical composition of claim 49 compris 46. The method of claim 45, wherein said dementia is ing chlorpropamide; a compound selected from memantine, Alzheimer's Disease (AD). donepezil, galantamine, rivastigmine, tacrine, and combina 47. The method of claim 45, wherein said NSC antagonist tions thereof, and a pharmaceutically acceptable carrier. is selected from glibenclamide, 4-trans-hydroxy-glibencla 55. The pharmaceutical composition of claim 49, further mide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlorpro comprising a compound effective to increase blood plasma pamide, tolaZamide, repaglinide, nateglinide, meglitinide, glucose levels. midaglizole, tolazamide, gliquidone, LY397364, LY389382, 56. The pharmaceutical composition of claim 55, wherein glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, said compound effective to increase blood plasma glucose genistein, diethystilbestrol, coumestrol. Zearalenone, non levels is selected from glucose and glucagon. steroidal estrogens, phytoestrogens, pinkolant, flufenamic 57. The method of claim 42, wherein treating dementia acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, comprises preventing or delaying the onset of AD. and combinations thereof. 58. The method of claim 45, wherein treating dementia 48. The method of claim 45, wherein said other compound comprises preventing or delaying the onset of AD. used in the treatment of dementia is selected from memantine, 59. The method of claim 57, wherein said NSC antagonist donepezil, galantamine, rivastigmine, tacrine, and combina is selected from glibenclamide, 4-trans-hydroxy-glibencla tions thereof. mide, 3-cis-hydroxy-glibenclamide, tolbutamide, chlorpro 49. A pharmaceutical composition comprising a NSC pamide, tolaZamide, repaglinide, nateglinide, meglitinide, antagonist; a compound used in the treatment of dementia; midaglizole, tolazamide, gliquidone, LY397364, LY389382, and a pharmaceutically acceptable carrier. glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, 50. The pharmaceutical composition of claim 49, wherein genistein, diethystilbestrol, coumestrol. Zearalenone, non said NSC antagonist is selected from glibenclamide, 4-trans steroidal estrogens, phytoestrogens, pinkolant, flufenamic hydroxy-glibenclamide, 3-cis-hydroxy-glibenclamide, tolb acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, utamide, chlorpropamide, tolaZamide, repaglinide, nateglin and combinations thereof. ide, meglitinide, midaglizole, tolaZamide, gliquidone, 60. The method of claim 58, wherein said other compound LY397364, LY389382, glyclazide, glimepiride, estrogen, used in the treatment of dementia is selected from memantine, estradiol, estrone, estriol, genistein, diethyStilbestrol, donepezil, galantamine, rivastigmine, tacrine, and combina coumestrol, Zearalenone, non-steroidal estrogens, phy tions thereof. toestrogens, pinkolant, flufenamic acid, mefanamic acid, 61. The method of claim 57, further comprising adminis niflumic acid, rimonabant, SKF 9635, and combinations tration of a compound effective to increase blood plasma thereof. glucose levels. 51. The pharmaceutical composition of claim 49, wherein said compound used in the treatment of dementia is selected