AU2008240148B2 - Treatment of down syndrome with benzodiazepine receptor antagonists - Google Patents

Abstract

Pharmaceutical compositions and methods of treating Down Syndrome, mental retardation or both are provided. The pharmaceutical compositions comprise one or more benzodiazepine receptor antagonists, such as flumazenil.

Description

WO 2008/128116 PCT/US2008/060133 TREATMENT OF DOWN SYNDROME WITH BENZODIAZEPINE RECEPTOR ANTAGONISTS [00011 This application claims benefit of priority to United States provisional patent application serial number 60/911,254, filed April 11, 2007, which in incorporated by reference herein in its entirety. FIELD OF THE INVENTION 5 100021 This application relates to methods of treating Down Syndrome and other forms of mental retardation with a composition comprising one or more benzodiazepine receptor blocker. BACKGROUND OF THE INVENTION 100031 Down Syndrome (trisomy 21) is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. In addition to various physical characteristics, Down Syndrome is 10 often, though not always, characterized by varying degrees of cognitive impairment - impairment in memory, learning capacity or both. While advances in teaching methods and a trend toward educational mainstreaming has led to an improvement in cognitive development in those who have Down Syndrome, there remain constitutive impairments that cannot be fully addressed through pedagogic methodology alone. In particular, there is a need for improvement in the cognitive abilities 15 of Down Syndrome patients. [00041 Mental retardation is a broader classification of cognitive deficit. A common criterion for diagnosing mental retardation is a score of 70 or below on one or more accepted intelligence quotient (IQ) tests. Mental retardation affects cognitive and motor development. In regards to cognitive development, mental retardation affects learning and memory and especially manifest in slowed 20 acquisition of language skills. As is the case with Down Syndrome, advances in pedagogic methods for those suffering from mental retardation have partially addressed the problems of learning encountered by these individuals. However, there remains a need for the improvement in cognition in those suffering from mental retardation. [00051 Flumazenil is a tricyclic benzodiazepine (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H1 25 imidazo[1,5-a]benzodiazepine-3-carboxylic acid ethyl ester) that antagonizes (as a competitive inhibitor of) benzodiazepine receptors in the central nervous system. Its preparation is described in U.S. Patent No. 4,316,839. It has been administered in adults to reverse the effects of benzodiazepines in conscious sedation and general anesthesia. It has also been administered to counteract overdose of benzodiazepine agonists, such as diazepam. Its administration heretofore has 30 primarily been by intravenous injection of an initial injection of about 0.4 mg and follow up doses of 1 0.2 mg per dose up to a maximum of 1.0 mg. Oral dosing of 30 to 100 mg of flumazenil (also known as Ro 15-1788) in normal adult human subjects has been shown to act as a partial benzodiazepine agonist. (Higgitt et al., "The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measures in 5 normal subjects," Psychopharmacology, 89 (1986), 396-403.) However, flumazenil effectively antagonizes the effects of diazepam when given orally or intravenously. Id. Thus, flumazenil is often classified as a benzodiazepine receptor antagonist, although its activity is considered in some literature to be mixed (i.e. partial benzodiazenine agonist). 100061 It has recently been shown that use of GABAA antagonists in a murine model of 10 Down Syndrome (Ts65Dn mice) increase memory and declarative learning. F. Fernandez et al., "Pharmacotherapy for cognitive impairment in a mouse model of Down Syndrome," Nature Neuroscience, Advance Online Publication, (February 25, 2007). Like Down Syndrome patients Ts65Dn mice demonstrate learning and memory deficits, which are hypothetically due to selective decreases in the numbers of excitatory 15 synapses in the brain rather than gross abnormalities in neuroanatomy. (Id.) Theoretically, triplicate genes found in the Ts65Dn mice shift the optimal balance of excitation and inhibition in the dentate gyrus (and other parts of the brain, perhaps) to a state in which excessive inhibition obscures otherwise normal learning and memory. Thus, enhancement of learning and memory with a GABAA antagonist apparently arises 20 out of antagonizing the GABAA receptor, with concomitant rescue of defective cognition brought about by excessive GABA-mediated suppression of long-term potentiation in the dentate gyrus. Thus, a two-week dosing regimen of 1.0 mg/kg of picrotoxin i.p. showed a clear benefit in the rescue of cognition in Ts65Dn mice. (Id.) In a 4 week crossover study of picrotoxin and bilobalide, both GABAA antagonists demonstrated 25 statistically significant improvement in cognition. 100071 Unfortunately, many GABAA antagonists tend to cause seizure in animal models as well as humans. Thus, there is a need for a non-seizure inducing therapeutic treatment for Down Syndrome, mental retardation or other mental impairment affecting learning, especially declarative learning, memory or both. The present invention meets this need 30 and provides related advantages as well. 2 10007a] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. Summary of the invention 5 [0007b] According to a first aspect, the present invention provides a method of treating Down Syndrome or mental retardation, comprising administering to a patient suffering from Down Syndrome or mental retardation an effective amount of a composition comprising at least one active pharmaceutical ingredient selected from a benzodiazepine receptor antagonist, a partial benzodiazepine agonist, or both; wherein such 10 benzodiazepine receptor antagonist, partial benzodiazepine agonist, or both are administered for more than one day at an effective amount that provides cognition enhancing effects or temporary relief of one or more impairments of cognition. 10007c] According to a second aspect, the present invention provides a method of enhancing cognitive function in a patient suffering from mental retardation or Down 15 Syndrome, comprising administering to the patient a cognitive function enhancing amount of an active pharmaceutical ingredient comprising a benzodiazepine receptor antagonist, a partial benzodiazepine agonist or both. [0007d] According to a third aspect, the present invention provides use of a composition comprising at least one active pharmaceutical ingredient selected from a 20 benzodiazepine receptor antagonist, a partial benzodiazepine agonist, or both, in the manufacture of a medicament for treating Down Syndrome or mental retardation, wherein the medicament is for administeration for more than one day at an effective amount that provides cognition enhancing effects or temporary relief of one or more impairments of cognition. 25 [0007e] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to". 2a 100081 The foregoing and further needs are met by embodiments of the present invention, which provide a method of treating Down Syndrome or mental retardation, comprising administering to a patient suffering from Down Syndrome or mental retardation an effective amount of a composition comprising at least one active 5 pharmaceutical ingredient selected from a benzodiazepine receptor antagonist, a partial benzodiazepine agonist, or both. 2b WO 2008/128116 PCT/US2008/060133 100091 The foregoing and further needs are met by embodiments of the invention, which provide a method of enhancing cognitive function in a patient suffering from mental retardation or Down Syndrome, comprising administering to the patient a cognitive function enhancing amount of an active pharmaceutical ingredient comprising a benzodiazepine receptor antagonist, a partial 5 benzodiazepine agonist or both. [00101 The foregoing and further needs are additionally met by embodiments of the invention, which provide an oral composition for the treatment of mental retardation, Down Syndrome, memory loss or impaired learning, comprising an effective amount of an active pharmaceutical ingredient comprising a benzodiazepine antagonist, a partial benzodiazepine agonist or both. 10 [00111 The foregoing and further needs are met by embodiments of the invention, which provide a sublingual or buccal composition for the treatment of mental retardation, Down Syndrome, memory loss or impaired learning, comprising an effective amount of an active pharmaceutical ingredient comprising a benzodiazepine antagonist, a partial benzodiazepine agonist or both. [0012] Additional characteristics and advantages of the invention will be recognized upon 15 consideration of the following description and the appended claims. INCORPORATION BY REFERENCE [00131 All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. 20 BRIEF DESCRIPTION OF THE DRAWINGS [00141 The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: No Drawings 25 DETAILED DESCRIPTION OF THE INVENTION [0015J The present invention provides methods and pharmaceutical formulations for the enhancement of cognitive functioning, especially memory, learning, or both, especially in individuals suffering from Down Syndrome or mental retardation. The invention provides methods of treating impaired cognitive functioning with one or more active pharmaceutical ingredients selected from 30 chemical entities selected from benzodiazepine receptor antagonists and partial benzodiazepine agonists. Thus, the present invention seeks to improve cognitive functioning - e.g. memory and learning - in individuals whose cognitive functioning has been impaired by a mental disorder that affects their cognition. 3 WO 2008/128116 PCT/US2008/060133 [00161 Thus, in some embodiments, the invention provides a method of treating Down Syndrome or mental retardation, comprising administering to a patient suffering from Down Syndrome or mental retardation an effective amount of a composition comprising at least one active pharmaceutical ingredient selected from a benzodiazepine receptor antagonist, a partial benzodiazepine agonist, or 5 both. In some embodiments the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist. In some embodiments at least one benzodiazepine receptor antagonist is flumazenil, In some embodiments the method comprises administering to the patient about 0.05 to about 30 mg of flumazenil one to four times daily, preferably about 0.1 to about 15 mg of flumazenil one to four times daily. In some embodiments the active pharmaceutical ingredient 10 comprises at least one partial benzodiazepine agonist. In some embodiments at least one partial benzodiazepine agonist is bretazenil. In some embodiments the method comprises administering about 0.05 to about 30 mg of bretazenil one to four times daily, preferably about 0.1 to about 15 mg of bretazenil one to four times daily. In some embodiments the composition comprising the active pharmaceutical ingredient is an oral , buccal or sublingual composition. In some embodiments the 15 composition comprising the active pharmaceutical ingredient is in the form of a tablet, capsule, gel capsule, caplet or liquid solution or suspension. In some embodiments the composition comprising the active pharmaceutical ingredient is a parenteral preparation. In some embodiments the parenteral preparation is an intravenous injection. In some embodiments the effective amount of the composition comprising the active pharmaceutical ingredient is a sub-seizure inducing amount. In 20 some embodiments the effective amount of the composition is effective to produce a memory enhancing effect, a learning enhancing effect, or both. [00171 Further, in some embodiments, the invention provides a method of enhancing cognitive function in a patient suffering from mental retardation or Down Syndrome, comprising administering to the patient a cognitive function enhancing amount of an active pharmaceutical ingredient 25 comprising a benzodiazepine receptor antagonist, a partial benzodiazepine agonist or both. In some embodiments the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist. In some embodiments at least one benzodiazepine receptor antagonist is flumazenil. In some embodiments the method comprises administering to the patient about 0.05 to about 30 mg of flumazenil one to four times daily, preferably about 0.1 to about 15 mg of flumazenil one to four 30 times daily. In some embodiments active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist. In some embodiments at least one benzodiazepine agonist is bretazenil. In some embodiments the method comprises administering about 0.05 to about 30 mg of bretazenil one to four times daily, preferably about 0.1 to about 15 mg of bretazenil one to four times daily. In some embodiments at least one cognitive function that is enhanced is memory or learning. In some 35 embodiments the composition is an oral, buccal or sublingual composition. In some embodiments the composition comprising the active pharmaceutical ingredient is in the form of a tablet, capsule, gel 4 WO 2008/128116 PCT/US2008/060133 capsule, caplet, liquid solution, liquid suspension or fast-dissolve tablet. In some embodiments the composition comprising the active pharmaceutical ingredient is a parenteral preparation. In some embodiments the composition comprising the active pharmaceutical ingredient is an intravenous injection. In some embodiments the effective amount of the composition as a sub-seizure inducing 5 amount. [0018j Further, in some embodiments, the invention provides an oral composition for the treatment of mental retardation, Down Syndrome, memory loss or impaired learning, comprising an effective amount of an active pharmaceutical ingredient comprising a benzodiazepine antagonist, a partial benzodiazepine agonist or both. In some embodiments the active pharmaceutical ingredient 10 comprises at least one benzodiazepine receptor antagonist. In some embodiments at least one benzodiazepine receptor antagonist is flumazenil. In some embodiments the composition is in unit dosage form and comprises about 0.05 to about 30 mg of flumazenil, preferably about 0.1 to about 15 mg of flumazenil per dose. In some embodiments the active pharmaceutical ingredient consists essentially of a benzodiazepine antagonist. In some embodiments the benzodiazepine antagonist is 15 flumazenil. In some embodiments the composition is in unit dosage form and comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of flumazenil per dose. In some embodiments the active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist. In some embodiments at least one partial benzodiazepine agonist is bretazenil. In some embodiments the composition is in unit dosage form an comprises about 0.05 to about 30 mg, preferably about 0.1 to 20 about 15 mg of bretazenil per dose. In some embodiments the active pharmaceutical ingredient consists essentially of a partial benzodiazepine agonist. In some embodiments the partial benzodiazepine agonist is bretazenil. In some embodiments the composition is in unit dosage form an comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose. In some embodiments the form of an oral tablet, caplet, capsule, gel capsule, liquid solution, liquid 25 suspension or fast-dissolve tablet. In some embodiments the composition is in an extended release, delayed release, pulsatile or controlled release dosage form. In some embodiments the effective amount of the active pharmaceutical ingredient is a sub-seizure inducing amount. In some embodiments the effective amount of the active pharmaceutical ingredient is effective to produce a memory enhancing effect, a learning enhancing effect, or both. 30 [00191 Additionally, in some embodiments, the present invention provides a sublingual or buccal composition for the treatment of mental retardation, Down Syndrome, memory loss or impaired learning, comprising an effective amount of an active pharmaceutical ingredient comprising a benzodiazepine antagonist, a partial benzodiazepine agonist or both. In some embodiments the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist. In some 35 embodiments at least one benzodiazepine receptor antagonist is flumazenil. In some embodiments the composition is in unit dosage form and comprises about 0.05 to about 30 mg of flumazenil, 5 WO 2008/128116 PCT/US2008/060133 preferably about 0.1 to about 15 mg of flumazenil per dose. In some embodiments the active pharmaceutical ingredient consists essentially of a benzodiazepine receptor antagonist. In some embodiments the benzodiazepine receptor antagonist is flumazenil. In some embodiments the composition is in unit dosage form and comprises about 0.05 to about 30 mg, preferably about 0.1 to 5 about 15 mg of flumazenil per dose. In some embodiments the active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist. In some embodiments at least one partial benzodiazepine agonist is bretazenil. In some embodiments the composition is in unit dosage form an comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose. In some embodiments the active pharmaceutical ingredient consists essentially of a partial 10 benzodiazepine agonist. In some embodiments the partial benzodiazepine agonist is bretazenil. In some embodiments the composition is in unit dosage form an comprises about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose. In some embodiments, the buccal or sublingual composition is in the form of a fast-dissolve tablet or strip. In some embodiments, the effective amount of the active pharmaceutical ingredient is a sub-seizure inducing amount. In some 15 embodiments the effective amount of the active pharmaceutical ingredient is effective to produce a memory enhancing effect, a learning enhancing effect, or both. Active Pharmaceutical Ingredients (Active Pharmaceutical Agents) 100201 As used herein, the phrase "active pharmaceutical ingredient" (or alternatively "active pharmaceutical agent") is intended to mean a compound or combination of compounds, at least one of 20 such compounds is a benzodiazepine receptor antagonist or a partial benzodiazepine agonist as described in more detail herein. Thus, unless otherwise limited (e.g. by the delimiters "consisting of' or "consisting essentially of") recitation of an active pharmaceutical ingredient requires the presence of at least one benzodiazepine receptor antagonist or at least one partial benzodiazepine agonist, but may also include one or more additional pharmaceutical compounds that does not detract from, and in 25 some cases may enhance, the activity of the benzodiazepine receptor antagonist and/or partial benzodiazepine agonist. Thus, combinations of two or more benzodiazepine receptor antagonists, two or more partial benzodiazepine agonists, or at least one benzodiazepine receptor antagonist and at least one partial benzodiazepine agonist (including pharmaceutically acceptable salts, polymorphs, etc.) are included within the scope of the active pharmaceutical ingredient unless otherwise limited. 30 Benzodiazepine Receptor Antagonists [0021] As their name implies, benzodiazepine receptor antagonists act on the benzodiazepine receptors on GABAA chloride ion channels to block the effects of GABA. One benzodiazepine receptor antagonist, flumazenil, is used as an antidote to benzodiazepine receptor agonists, such as diazepam and midazolam, in benzodiazepine agonist overdose situations or to counteract the effects 35 of benzodiazepin receptor agonist sedation (e.g. post-operatively). 6 WO 2008/128116 PCT/US2008/060133 [0022] As discussed in more detail herein, in some embodiments the invention provides oral, buccal and sublingual dosages of benzodiazepine receptor antagonists, such as flumazenil. The oral dosage of flumazenil is expected to be about one to ten, preferably about two to seven times the usual intravenous dose owing to the oral bioavailability of flumazenil, which is approximately 20% of the 5 intravenous bioavailability. Thus, in some embodiments, the invention contemplates administering to the patient one to four doses of flumazenil per day; and those doses, for adults, are expected to be in the range of about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of flumazenil per dose. For adolescents and pre-adolescents, it is considered that the does will have to be reduced from 2 to 5 fold, depending upon the mass of the patient. 10 [00231 Although flumazenil is a preferred embodiment of the benzodiazepine receptor antagonists of the invention, the person skilled in the art will recognize that other benzodiazepine receptor antagonists, may be used in its place, with appropriate adjustments in dosage made for relative potency, bioavailability and pharmacokinetics. Partial Benzodiazepine Agonists 15 [00241 Several partial benzodiazepine agonists are known or under development. These include bretazenil (tert-butyl-(S)-8-bromo-1 1, 12, 13, 13a-tetrahydro-9-oxo-9H-imidazo[l, 5-a]pyrrolo[2, 1 c] [1, 4] benzodiazepine- 1 -carboxylate (Ro 16-6028)), abecarnil, panadiplon, and imidazenil. Partial benzodiazepine agonists (also known as partial benzodiazepine receptor agonists) partially bind to and activate GABAA chloride channels, but also partially block activation of GABAA channels, thus 20 providing some of the effects of both agonists and antagonists of benzodiazepine receptors. [00251 As discussed in more detail herein, in some embodiments the invention provides oral, buccal and sublingual dosages of partial benzodiazepine agonists, such as bretazenil. The oral dosage of bretazenil is expected to be in the range of about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg of bretazenil per dose. For adolescents and pre-adolescents, it is considered that the does will 25 have to be reduced from 2 to 5 fold, depending upon the mass of the patient. [00261 Although bretazenil is a preferred embodiment of the partial benzodiazepine agonists of the invention, the person skilled in the art will recognize that other partial benzodiazepine agonists may be used in its place. Pharmaceutically Acceptable Salts, Stereoisomers, Polymorphs and Hydrates 30 [0027] The person skilled in the art will recognize that various active pharmaceutical ingredients set forth herein are available in free base or salt forms, as enantiomerically pure stereoisomers and/or as polymorphs. Except as otherwise specified herein, recitation of a particular active pharmaceutical ingredient, without any qualification limiting the recitation to the free base or salt, enantiomer or polymorph of the active pharmaceutical ingredient, is intended to incorporate all the pharmaceutically 35 acceptable forms of the active pharmaceutical ingredient, including the free base, , pharmaceutically 7 WO 2008/128116 PCT/US2008/060133 acceptable salts, racemate, enantiomerically pure formulations, amorphous and crystalline forms of the active pharmaceutical ingredient as well as their hydrates. [00281 Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such 5 as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acid; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, 10 citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic and isethionic acids. The pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a 15 stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, PA, 1985, p. 1418). In the case of flumazenil and bretazenil, the benzodiazepine core has at least one ring amino nitrogen capable of forming a salt with an appropriate 20 acid, such as one of the acids recited above. [00291 Stercoisomers are compounds made up of the same atoms having the same bond order but having different three-dimensional arrangements of atoms which are not interchangeable. The three dimensional structures are called configurations. Two kinds of stereoisomers include enantiomers and diastereomers. Enantiomers are two stereoisomers which are non-superimposable mirror images 25 of one another. This property of enantiomers is known as chirality. The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. The choice of an appropriate chiral column, eluent, and conditions necessary to effect separation of the pair of enantiomers is well known to one of ordinary skill in the art using standard techniques (see e.g. 30 Jacques, J. et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc. 1981). Diastereomers are two stereoisomers which are not mirror images but also not superimposable. Diastereoisomers have different physical properties and can be separated from one another easily by taking advantage of these differences. 8 WO 2008/128116 PCT/US2008/060133 [00301 Different polymorphs of the compounds may also be used. Polymorphs are, by definition, crystals of the same molecule having different physical properties as a result of the order of the molecules in the crystal lattice. The polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology. The differences in physical properties exhibited by polymorphs affect 5 pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Differences in stability can result from changes in chemical reactivity (e.g. differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g. tablets crumble 10 on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g. tablets of one polymorph are more susceptible to breakdown at high humidity). Formulations 100311 The active pharmaceutical ingredients, including pharmaceutically acceptable salts and polymorphic variations thereof, can be formulated as pharmaceutical compositions. Such 15 compositions can be administered orally, buccally, sublingually, intravenously, parenterally, by inhalation spray, rectally, intradermally, transdermally, pulmonary, nasally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term "parenteral" as used herein includes 20 subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques. In some preferred embodiments the composition is administered orally, buccally or sublingually; in other preferred embodiments, the composition is administered intravenously. [00321 Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975), and Liberman, H.A. 25 and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980). [00331 The active pharmaceutical ingredients may be administered per se or in the form of a pharmaceutical composition wherein the active compound(s) is in admixture or mixture with one or more pharmaceutically acceptable ingredients, such as one or more carriers, excipients, disintegrants, glidants, diluents, delayed-release or controlled-release matrices or coatings. Pharmaceutical 30 compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. 9 WO 2008/128116 PCT/US2008/060133 [00341 Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are 5 commercially available under the trade name Eudragit* (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides. [0035] Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants. [00361 Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, 10 granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. [0037] Diluents, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium 15 sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. [00381 Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder 20 materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropyleellulose, ethyleellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, 25 aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone. [0039J Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. 30 [00401 Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp). 35 [00411 Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions. 10 WO 2008/128116 PCT/US2008/060133 [0042] Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium 5 sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol 10 monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4 oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer* 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric 15 surfactants include sodium N-dodecyl-2-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine. [00431 If desired, the tablets, beads, granules, or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives. 20 [0044] The active pharmaceutical ingredients may be complexed with other agents as part of their being pharmaceutically formulated. The pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binding agents (e.g., acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and 25 ethylcellulose); fillers (e.g., corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, or alginic acid); lubricants (e.g. magnesium stearates, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica); and disintegrators (e.g. micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid. If water-soluble, such formulated complex then may be formulated in an appropriate buffer, for 30 example, phosphate buffered saline or other physiologically compatible solutions. Alternatively, if the resulting complex has poor solubility in aqueous solvents, then it may be formulated with a non-ionic surfactant such as TWEENTm, or polyethylene glycol. Thus, the active pharmaceutical ingredients and their physiologically acceptable solvates may be formulated for administration. 11 WO 2008/128116 PCT/US2008/060133 [00451 Liquid formulations for oral administration prepared in water or other aqueous vehicles may contain various suspending agents such as methylcellulose, alginates, tragacanth, pectin, kelgin, carrageenan, acacia, polyvinylpyrrolidone, and polyvinyl alcohol. The liquid formulations may also include solutions, emulsions, syrups and elixirs containing, together with the active compound(s), 5 wetting agents, sweeteners, and coloring and flavoring agents. Various liquid and powder formulations can be prepared by conventional methods for inhalation by the patient. 100461 Delayed release and extended release compositions can be prepared. The delayed release/extended release pharmaceutical compositions can be obtained by complexing drug with a pharmaceutically acceptable ion-exchange resin and coating such complexes. The formulations are 10 coated with a substance that will act as a barrier to control the diffusion of the drug from its core complex into the gastrointestinal fluids. Optionally, the formulation is coated with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the basic environment of lower GI tract in order to obtain a final dosage form that releases less than 10% of the drug dose within the stomach. 15 [00471 In addition, combinations of immediate release compositions and delayed release/extended release compositions may be formulated together. [00481 It is anticipated that in some instances it may be advantageous to administer an active pharmaceutical ingredient of the invention as a pulsatile formulation. Such a formulation can be administered as a capsule, tablet or aqueous suspension. For example, a capsule, tablet or aqueous 20 suspension may be formulated containing two or more populations of active pharmaceutical ingredient particle - one containing active pharmaceutical ingredient in an immediate release form (e.g. uncoated or coated with an immediate release coating) and another population in which the active phannaceutical ingredient is coated with a delayed release coating and/or an enteric coating. In some embodiments, a pulsatile release of active pharmaceutical ingredient results in a longer-lasting 25 formulation, which may be administered on a twice-a-day (b.i.d.) or once-a-day (q.d.) basis. In the case of a capsule, the two populations of particles may be encased within an immediate release or delayed release capsule. In the case of a tablet (including a caplet) the two populations of particles may be compressed, optionally in admixture with an appropriate binder and/or disintegrants, to form a tablet core, which is then coated with an immediate release coating, an enteric coating or both. The 30 tablet then may be coated with a coating that enhances the swallowability of the dosage. [0049] In the case of a liquid suspension, the first population of particles may be uncoated (and indeed wholly or partially dissolved in the aqueous medium) or may be coated with an immediate release coating, an enteric coating or both. The second population of particles is coated with a delayed release coating and optionally an immediate release coating and/or an enteric coating. 35 (Enteric coatings are generally applied where the active pharmaceutical ingredient is sensitive to low pH conditions and thus would be expected to be unstable in the stomach. They may also be applied to 12 WO 2008/128116 PCT/US2008/060133 the delayed release population of particles in order to add an additional delay to the release of the active pharmaceutical ingredient within the delayed release particles. [0050] In some preferred embodiments, the active pharmaceutical ingredient will be administered as an oral liquid solution or suspension, or as a buccal or sublingual liquid, tablet or gel strip. The 5 person skilled in the art will recognize that buccal and sublingual formulations should be of the fast dissolving type in order to enhance the ease and convenience of use. Treatment of Cognitive Dysfunction [0051] The present invention provides methods of treating cognitive dysfunction, especially the treatment of impaired learning and/or memory associated with Down Syndrome (also referred to as 10 Down's Syndrome or trisomy 21) and/or mental retardation. Down Syndrome is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. In addition to various physical characteristics, Down Syndrome is often, though not always, characterized by varying degrees of cognitive impairment - e.g. impairment in memory, learning capacity or both. Mental retardation is a broader classification of cognitive deficit. A common criterion for diagnosing mental 15 retardation is a score of 70 or below on one or more accepted intelligence quotient (IQ) tests. Mental retardation affects cognitive and motor development. In regards to cognitive development, mental retardation affects learning and memory and especially manifest in slowed acquisition of language skills. [00521 Benzodiazepine receptor antagonists such as flumazenil inhibit the binding of compounds that 20 bind to the benzodiazepine receptor on GABAA chloride ion channels. The GABAA receptor is a multimeric transmembrane receptor consisting of five subunits arranged around a central ion channel. The GABAA receptors are located within neuronal membranes at a synapse. The ligand GABA (y aminobutyric acid) is the endogenous compound that causes this receptor to open. Upon binding of GABA to the GABAA receptor, the receptor changes conformation within the membrane, opening the 25 ion channel, and permitting flow of chloride ions down an electrochemical gradient into the neuron. Because the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential, activation of GABAA receptors tends to stabilize the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential. The net effect is typically inhibitory, reducing the activity of the neuron. 30 [0053] Benzodiazepine receptors are allosteric ligand binding sites on the GABAA receptor, and are thus separate from the GABA ligand binding sites. Benzodiazepine agonists, such as diazepam, lorazepam and midazolam, bind to benzodiazepine receptors and increase the activity of the chloride channel, thereby enhancing the neuronal activity inhibitory effect of GABA binding to GABAA receptors. The physiologic effect of benzodiazepine agonists is generally sedative and amnesic. In 35 contrast, benzodiazepine receptor antagonists, such as flumazenil, bind to the benzodiazepine receptor and block the effect of benzodiazepine agonists. Thus, flumazenil has been used as an antidote to 13 WO 2008/128116 PCT/US2008/060133 benzodiazepine agonist overdose or to reverse the sedative effects of benzodiazepine agonist sedatives after surgery. As GABAA antagonists such as picrotoxin rescue cognition in the Ts65Dn urine model of Down Syndrome (See Fernandez, supra), it is considered that benzodiazepine receptor antagonists also counteract the effects of GABA binding- i.e. that they have positive effects 5 on enhancing the activity of neurons involved in cognition. Thus, it is considered that an effective amount of benzodiazepine antagonist would provide cognition enhancing effects, especially to those patients who are genetically disposed to an imbalance in GABAA receptor activity. It is furthermore considered that an effective amount of a benzodiazepine antagonist would provide cognition enhancing effects in patients suffering from cognitive impairment caused by Down Syndrome or 10 mental retardation. As benzodiazepine receptor antagonists are considered to have a lower seizure inducing potential than GABAA receptor antagonists, such as picrotoxin, it is considered that an effective amount of a benzodiazepine receptor antagonist will also be less than a seizure inducing amount of the benzodiazepine receptor antagonist. [00541 Partial benzodiazepine agonists, such as bretazenil, bind to the benzodiazepine receptor and 15 provide both agonistic and antagonistic effects. Thus, bretazenil has been suggested as an alternative to benzodiazepine antagonists such as diazepam. As GABAA antagonists such as picrotoxin rescue cognition in the Ts65Dn marine model of Down Syndrome, it is considered that partial benzodiazepine agonists, which in part counteract the effects of GABA binding, would also demonstrate positive effects on enhancing the activity of neurons involved in cognition. Thus, it is 20 considered that an effective amount of a partial benzodiazepine agonist would provide cognition enhancing effects, especially to those patients who are genetically disposed to an imbalance in GABAA receptor activity. It is furthermore considered that an effective amount of a partial benzodiazepine agonist would provide cognition enhancing effects in patients suffering from cognitive impairment caused by Down Syndrome or mental retardation. As partial benzodiazepine 25 agonists are considered to have a lower seizure-inducing potential than GABAA receptor antagonists, such as picrotoxin, it is considered that an effective amount of a partial benzodiazepine agonist will also be less than a seizure inducing amount of the partial benzodiazepine agonist. [00551 As the cognitive impairment associated with Down Syndrome and mental retardation may be the result of an imbalance in GABAA functioning, it is considered that a combination of two or more 30 benzodiazepine receptor antagonists, two or more partial benzodiazepine agonists or of at least one benzodiazepine receptor antagonist and at least one partial benzodiazepine agonist may provide an optimal balance of GABAA antagonism and thus optimized improvement in memory, learning or both along. [0056] The present invention provides a method of treating a patient suffering from cognitive 35 impairment, such as a Down Syndrome patient or a patient suffering from mental retardation, comprising administering to the patient an effective amount of an active pharmaceutical ingredient 14 WO 2008/128116 PCT/US2008/060133 according to the invention. The term active pharmaceutical ingredient is described in more detail above. An "effective amount" of the active pharmaceutical ingredient is an amount of the active pharmaceutical ingredient that provides temporary relief of one or more impairments of cognition. Thus an effective amount of an active pharmaceutical ingredient is expected to provide relief of 5 impaired memory, impaired learning capacity or both. Although the relief provided is considered temporary, the person skilled in the art will recognize that even a temporary improvement in learning capacity can have a long term beneficial effect on long-term learning, as learning tends to be cumulative over time. Thus, the use of the qualifier "temporary" is not intended to exclude potential long-term improvements in cumulative learning. 10 [00571 In some embodiments, the invention provides a method of treating cognitive impairment in a patient, comprising administering an effective amount of an active pharmaceutical ingredient comprising at least one benzodiazepine receptor antagonist, at least one partial benzodiazepine agonist, or both. In some preferred embodiments, the amount of active pharmaceutical ingredient administered to the patient, while being effective to enhance cognition, is a sub-seizure inducing 15 amount. In other words, in preferred embodiments of the invention, the amount of active pharmaceutical ingredient administered to the patient is sufficient to enhance memory, learning or both, but is not sufficient to induce seizure. In some preferred embodiments, the effective amount of flumazenil will be about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg per dose, administered orally, buccally or sublingually 1 to 4 times per day. In some preferred embodiments, 20 the effective amount of bretazenil will be about 0.05 to about 30 mg, preferably about 0.1 to about 15 mg per dose, administered orally, buccally or sublingually 1 to 4 times per day. Example 1: The Effect of Flumazenil on Ts65Dn Mice [00581 The effect of a benzodiazepine receptor antagonist, flumazenil, on a murine model of Down Syndrome is investigated using Ts65Dn mice. The validity of the Ts65Dn mouse as a model of the 25 cognitive impairments associated with Down Syndrome is established by Fernandez et al., supra. 100591 A 4-week longitudinal crossover study is carried out following the method outlined by Fernandez et al., supra. Wild-type and Ts65Dn mice (3-4 months of age) are randomly assigned to groups receiving daily i.p. injections of saline or flumazenil (1.0 mg/kg), and are submitted to four weekly repetitions of object recognition testing, in which the animals are serially presented with four 30 different object sets. At the 2-week midpoint of the experimental period, wild-type and Ts65Dn mice that have been receiving saline are randomly segregated into groups that either continue to receive daily saline injections or begin to receive daily injections of flumazenil. Conversely, wild-type and Ts65Dn mice that have been chronically administered flumazenil in the first 2 weeks of testing are switched onto a saline regimen. Alongside saline and flumazenil, bilobalide (i.p. 5.0 mg/kg) may be 35 evaluated as a positive control. Bilobalide is a picrotoxin-like compound that may safely be administered for the whole 4-week experiment. 15 WO 2008/128116 PCT/US2008/060133 [0060J During the evaluation Ts65Dn and wild-type mice are tested for novel object recognition. Ts65Dn mice treated with flumazenil during the first or second 2 week period have normalized object recognition performance as do those treated with bilobalide throughout the study. [0061J Flumazenil may also be tested for its effects on declarative memory in the novel object 5 recognition test and in a modified spontaneous alternation task. Wild-type and Ts65Dn mice may be administered flumazenil (3 mg/kg in milk via voluntary oral feeding or 1 mg/kg i.p.). The wild-type and Ts65Dn mice are administered from 5 to 30 doses of milk or milk-flumazenil (or saline or flumazenil solution i.p.). The mice are then subjected to two repetitions of novel object recognition testing or three daily T-maze sessions at the tail end of the treatment regimen. It is expected that milk 10 (or saline) treated Ts65Dn mice will show an inability to object novelty in the object recognition task, whereas the flumazenil-tested Ts65Dn mice will show discrimination indices on a par with those of wild-type mice. In the spontaneous alternation task, milk fed (saline i.p.) Ts65Dn mice will show a pattern of impairment similar to untreated Ts65Dn mice, whereas flumazenil treated Ts65Dn mice will show normal levels of alternation. Comparison of treated and untreated Ts65Dn mice will 15 provide controls for any possible arm bias in the spontaneous alternation task. [00621 It is further expected that flumazenil-treated Ts65Dn mice will show long-term improvement in novel object recognition testing (up to at least 2 months after treatment) when treated with flumazenil for at least about 15 days. [00631 Since the ability of animals to learn and remember is thought to be encoded at the synaptic 20 level, and involves the ability of synapses to undergo long-term changes in synapse strength, long term potentiation (LTP) in the dentate gyrus may be evaluated. Normalized LTP in the dentate gyrus of the flumazenil treated Ts65Dn mice about 1 month after cessation of drug treatment demonstrates long-term improvement in rescue of synapse performance related to memory and learning. Example 2: The Effect of Bretazenil on Ts65Dn Mice 25 [0064] The effect of a benzodiazepine receptor antagonist, bretazenil, on a murine model of Down Syndrome is investigated using Ts65Dn mice. The validity of the Ts65Dn mouse as a model of the cognitive impairments associated with Down Syndrome is established by Fernandez et al., supra. [00651 A 4-week longitudinal crossover study is carried out following the method outlined by Fernandez et al., supra. Wild-type and Ts65Dn mice (3-4 months of age) are randomly assigned to 30 groups receiving daily i.p. injections of saline or bretazenil (1.0 mg/kg), and are submitted to four weekly repetitions of object recognition testing, in which the animals are serially presented with four different object sets. At the 2-week midpoint of the experimental period, wild-type and Ts65Dn mice that have been receiving saline are randomly segregated into groups that either continue to receive daily saline injections or begin to receive daily injections of bretazenil. Conversely, wild-type and 35 Ts65Dn mice that have been chronically administered bretazenil in the first 2 weeks of testing are switched onto a saline regimen. Alongside saline and bretazenil, bilobalide (i.p. 5.0 mg/kg) may be 16 WO 2008/128116 PCT/US2008/060133 evaluated as a positive control. Bilobalide is a picrotoxin-like compound that may safely be administered for the whole 4-week experiment. t00661 During the evaluation Ts65Dn and wild-type mice are tested for novel object recognition. Ts65Dn mice treated with bretazenil during the first or second 2 week period have normalized object 5 recognition performance as do those treated with bilobalide throughout the study. [00671 Bretazenil may also be tested for its effects on declarative memory in the novel object recognition test and in a modified spontaneous alternation task. Wild-type and Ts65Dn mice may be administered bretazenil (3 mg/kg in milk via voluntary oral feeding or 1 mg/kg i.p.). The wild-type and Ts65Dn mice are administered from 5 to 30 doses of milk or milk-flumazenil (or saline or 10 flumazenil solution i.p.). The mice are then subjected to two repetitions of novel object recognition testing or three daily T-maze sessions at the tail end of the treatment regimen. It is expected that milk (or saline) treated Ts65Dn mice will show an inability to object novelty in the object recognition task, whereas the flumazenil-tested Ts65Dn mice will show discrimination indices on a par with those of wild-type mice. In the spontaneous alternation task, milk fed (saline i.p.) Ts65Dn mice will show a 15 pattern of impairment similar to untreated Ts65Dn mice, whereas flumazenil treated Ts65Dn mice will show normal levels of alternation. Comparison of treated and untreated Ts65Dn mice will provide controls for any possible arm bias in the spontaneous alternation task. [00681 It is further expected that flumazenil-treated Ts65Dn mice will show long-term improvement in novel object recognition testing (up to at least 2 months after treatment) when treated with 20 flumazenil for at least about 15 days. 100691 Since the ability of animals to learn and remember is thought to be encoded at the synaptic level, and involves the ability of synapses to undergo long-term changes in synapse strength, long term potentiation (LTP) in the dentate gyrus may be evaluated. Normalized LTP in the dentate gyrus of the bretazenil treated Ts65Dn mice about I month after cessation of drug treatment demonstrates 25 long-term improvement in rescue of synapse performance related to memory and learning. [0070J The foregoing experiment may be repeated with one or more other benzodiazepine receptor antagonists and/or partial benzodiazepine agonists. Example 3: Effect of Flumazenil and Bretazenil on Cognition in Down Syndrome Patients [0071] Fifteen adult or adolescent Down Syndrome patients experiencing at least some level of 30 cognitive impairment participate in a double-blind, cross-over comparison of four treatments. The drugs administered are flumazenil (5 and 20 mg), bretazenil (5 and 20 mg) or placebo. Subjects are randomly assigned to treatments according to a Williams Square design (Higgitt, supra (citing Williams, "Experimental designs balanced for the estimation of residual effects of treatments, Aust. J. Sci. Res. 2:149-168 (1949))). Each subject receives a different sequence of four treatments balanced 35 for carry-over effects and separated by at least 1 week of wash-out period. At each treatment session, subjects are tested before treatment and at time points 30, 60, 90, 120, 150 and 180 min. after drug 17 WO 2008/128116 PCT/US2008/060133 administration on a set of psychophysiological measures. At pretest, 60, 120 and 180 min., paper and pencil performance measures and subjective ratings are administered. (Id. (citing Kamiol et al., "Comparative psychotropic effects of trazadone, imipramine and diazepam in normal subjects," Curr. Ther. Res. 20 (1976), 337-347. 5 [0072] Psychophysiological indices to be measured include: EEG, skin conductance, finger tremor, critical flicker fusion threshold, blood pressure and pulse rate, key tapping rate, and reaction time. Paper and pencil performance measures include: A cancellation task, digit symbol substitution and a symbol copying test. Self ratings include mood ratings, and a bodily symptom scale. [00731 EEG and evoked responses: These are recorded during the same EEG recording procedure. 10 Recordings are made from bipolar electrodes attached to the temporal and vertex sites (C, and T3 in the 10-20 system). After amplification, the EEG is fed into four parallel band-pass filters with respective upper and lower frequencies set as follows: "delta" (2.44.0 Hz), "theta" (4.0-7.5 Hz), "alpha" (7.5-13.5 Hz) and "beta" (13.5-26.0 Hz). Each filter output is sampled 32 times for 5-s periods while the subject is instructed to respond to a series of clicks presented at intervals varying 15 from 8 to 12 s. The output is rectified and averaged to yield the mean rectified voltage in each of the four wavebands. In addition, the four values are summed and each is expressed as a percentage of the total. [00741 The averaged evoked responses are obtained from the 500 ms epoch of the EEG following each of the 32 click stimuli. The averaged response is displayed on an oscilloscope screen and the 20 four peaks (P1, the first positive wave in the 30-60 ms latency range, NI, the first negative wave with a latency of 100-160 ms and N2, the second negative wave with a latency of 130-200 mg) are identified semi-automatically. The latency at each peak and peak-to-peak amplitudes are computed and recorded automatically. Reductions in amplitude and increases in latency are indicators of reduced responsiveness to stimuli and are frequently correlated with subjective decreases in alertness. 25 Conversely, increases in amplitude and/or reductions in latency are objective indicators of increased responsiveness to stimuli. [0075] Skin conductance, blood pressure and pulse rate can be measured by the method of Higgitt et al., supra. See especially page 396, which is incorporated herein by reference in its entirety. [0076] Finger tremor is measured using an accelerometer as discussed by Higgitt et al., supra. An 30 accelerometer is taped to the dorsal surface of the middle finger of the left hand just proximal to the nail bed. The hand is held out with wrist extended and lower arm supported by the arm of the chair. The signal is amplified and 16 5-s samples are frequency analyzed on line using fast Fourier transformation. [0077J Critical flicker fusion threshold is measured using a red LED at the end of a 20 cm black tube 35 according to the method of Higgitt et al, supra. Each subject view the stimulus using his or her dominant eye. The duration of the on-off cycle is changed in 0.5 Hz steps each second. Six 18 WO 2008/128116 PCT/US2008/060133 alternating ascending and descending trials are administered commencing at 20 and 50 Hz, respectively. The mean of the six limit values is used as the estimate of the threshold. [0078] Key tapping rate is measured per the method of Higgitt et al., supra. The subject is instructed to tap a one inch diameter key as fast as possible for 60 s. The mean inter-tap interval is calculated as 5 a measure of motor speed. [0079] Auditory reaction time is measured to 32 clicks of moderate intensity per Higgitt et al., supra. The mean reciprocal value is calculated. [00801 Paper-and-pencil performance measures, including a cancellation task, a digit symbol substitution test and a symbol copying test are performed essentially as described by Higgitt et al., 10 supra. In the cancellation task, subjects are instructed to cross out all the 4's in a block of numbers containing 40 target items. Time to complete the task and number of errors are recorded. [00811 The digit symbol substitution test (DSST) is a sub-test of the Wechsler Adult Intelligence Scale (WAIS), which assesses coding skills and involves the substitution of symbols for numbers. The task is presented as in the WAIS manual and the measure is the number of correct codings in a 15 90-s period. 100821 The symbol copying test measures the motor component of the DSST as the subject is instructed to copy the same symbols as are used in the DSST. The score is the number of items correctly copied in a 90-s period. Sixteen equivalent forms of the above three tests are used, one for each time of testing, to minimize practice effects. 20 [0083J Additional tests of cognitive function, such as memory and learning ability, may also be used. [00841 Self ratings of patient mood and bodily symptoms are performed essentially per Higgitt et al., supra. [00851 It is expected that flumazenil-treated Down Syndrome patients will demonstrate an improvement in one or more indicators of cognition as compared to placebo-treated patients. 25 [00861 It is expected that bretazenil-treated Down Syndrome patients will demonstrate an improvement in one or more indicators of cognition as compared to placebo-treated patients. 100871 The foregoing testing may also be applied to mentally retarded patients - e.g. patients having I.Q. scores between about 55 and 70. [0088] While preferred embodiments of the present invention have been shown and described herein, 30 it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures 35 within the scope of these claims and their equivalents be covered thereby. 19

Claims (49)

1. A method of treating Down Syndrome or mental retardation, comprising administering to a patient suffering from Down Syndrome or mental retardation an effective amount of a composition comprising at least one active pharmaceutical 5 ingredient selected from a benzodiazepine receptor antagonist, a partial benzodiazepine agonist, or both; wherein such benzodiazepine receptor antagonist, partial benzodiazepine agonist, or both are administered for more than one day at an effective amount that provides cognition enhancing effects or temporary relief of one or more impairments of cognition. 10

2. The method of claim 1, wherein the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist.

3. The method of claim 2, wherein at least one benzodiazepine receptor antagonist is flumazenil.

4. The method of claim 3, wherein the method comprises administering to the 15 patient about 0.05 to about 30 mg of flumazenil one to four times daily.

5. The method of claim 1, wherein the active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist.

6. The method of claim 5, wherein at least one partial benzodiazepine agonist is bretazenil. 20

7. The method of claim 6, wherein the method comprises administering about 0.05 to about 30 mg of bretazenil one to four times daily.

8. The method of any one of claims 1-7, wherein the composition comprising the active pharmaceutical ingredient is an oral, buccal or sublingual composition.

9. The method of claim 8, wherein the composition comprising the active 25 pharmaceutical ingredient is in the form of a tablet, capsule, gel capsule, caplet or liquid solution or suspension. 20

10. The method of any one of claims 1-7, wherein the composition comprising the active pharmaceutical ingredient is a parenteral preparation.

11. The method of claim 10, wherein the parenteral preparation is an intravenous injection. 5

12. The method of any one of claims 1-11, wherein the effective amount of the composition comprising the active pharmaceutical ingredient is a sub-seizure inducing amount.

13. The method of any one of claims 1-12, wherein the effective amount of the composition is effective to produce a memory enhancing effect, a learning enhancing 10 effect, or both.

14. A method of enhancing cognitive function in a patient suffering from mental retardation or Down Syndrome, comprising administering to the patient a cognitive function enhancing amount of an active pharmaceutical ingredient comprising a benzodiazepine receptor antagonist, a partial benzodiazepine agonist or both.

15 15. The method of claim 14, wherein the active pharmaceutical ingredient comprises at least one benzodiazepine receptor antagonist.

16. The method of claim 15, wherein at least one benzodiazepine receptor antagonist is flumazenil.

17. The method of claim 16, wherein the method comprises administering to the 20 patient about 0.05 to about 30 mg of flumazenil one to four times daily, preferably about 0.1 to about 15 mg of flumazenil one to four times daily.

18. The method of claim 14, wherein the active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist.

19. The method of claim 18, wherein at least one benzodiazepine agonist is 25 bretazenil.

20. The method of claim 19, wherein the method comprises administering about 0.05 to about 30 mg of bretazenil one to four times daily. 21

21. The method of any one of claims 14-20, wherein at least one cognitive function that is enhanced is memory or learning.

22. The method of any one of claims 14-21, wherein the composition is an oral, buccal or sublingual composition. 5

23. The method of claim 22, wherein the composition comprising the active pharmaceutical ingredient is in the form of a tablet, capsule, gel capsule, caplet, liquid solution, liquid suspension or fast-dissolve tablet.

24. The method of any one of claims 14-23, wherein the composition comprising the active pharmaceutical ingredient is a parenteral preparation. 10

25. The method of claim 24, wherein the composition comprising the active pharmaceutical ingredient is an intravenous injection.

26. The method of any one of claims 14-25, wherein the effective amount of the composition as a sub-seizure inducing amount.

27. The method of claim 4 or 17, wherein the flumazenil is administered in the 15 amount of about 0.1 to about 15mg one to four times daily.

28. The method of claim 7 or 20, wherein the bretazenil is administered in the amount of about 0.1 to about 15mg one to four times daily.

29. Use of a composition comprising at least one active pharmaceutical ingredient selected from a benzodiazepine receptor antagonist, a partial benzodiazepine agonist, or 20 both, in the manufacture of a medicament for treating Down Syndrome or mental retardation, wherein the medicament is for administration for more than one day at an effective amount that provides cognition enhancing effects or temporary relief of one or more impairments of cognition.

30. Use of claim 29, wherein the active pharmaceutical ingredient comprises at least 25 one benzodiazepine receptor antagonist.

31. Use of claim 30, wherein at least one benzodiazepine receptor antagonist is flumazenil. 22

32. Use of claim 31, wherein the medicament is in unit dosage form and comprises about 0.05 to about 30 mg of flumazenil.

33. Use of claim 29, wherein the active pharmaceutical ingredient consists essentially of a benzodiazepine receptor antagonist. 5

34. Use of claims 33, wherein the benzodiazepine receptor antagonist is flumazenil.

35. Use of claim 34, wherein the medicament is in unit dosage form and comprises about 0.05 to about 30 mg.

36. Use of claim 29, wherein the active pharmaceutical ingredient comprises at least one partial benzodiazepine agonist. 10

37. Use of claim 36, wherein at least one partial benzodiazepine agonist is bretazenil.

38. Use of claim 37, wherein the medicament is in unit dosage form and comprises about 0.05 to about 30 mg.

39. Use of claim 29, wherein the active pharmaceutical ingredient consists essentially of a partial benzodiazepine agonist. 15

40. Use of claim 39, wherein the partial benzodiazepine agonist is bretazenil.

41. Use of claim 40, wherein the medicament is in unit dosage form and comprises about 0.05 to about 30 mg.

42. Use of any one of claims 29-41 in the form of a fast-dissolve tablet or strip.

43. Use of any one of claims 29-42, wherein the effective amount of the active 20 pharmaceutical ingredient is a sub-seizure inducing amount.

44. Use of any one of claims 29-43, wherein the effective amount of the active pharmaceutical ingredient is effective to enhancing cognitive function and/or produce a memory enhancing effect, a learning enhancing effect, or any combination thereof.

45. Use of clam 32 or 35, wherein the medicament comprises about 0.1 to about 25 15mg of flumazenil per dose. 23

46. Use of claims 38 or 41, wherein the medicament comprises about 0.1 to about 15mg of bretazenil per dose.

47. Use according to any one of claims 29 to 46, wherein the medicament is in the form of an oral composition. 5

48. Use according to any one of claims 29 to 46, wherein the medicament is in the form of a sublingual or buccal composition.

49. A method according to claim 1 or 14; or use according to claim 29, substantially as herein described with reference to any one of the examples. 24