Pharmaceutical compositions for the prevention and treatment of central nervous system disorders

A pharmaceutical composition incorporates a pharmaceutically effective amount of at least two components, one of those components being a nicotinic compound capable of interacting with nicotinic cholinergic receptors (e.g., a nicotinic agonist, such as E-metanicotine) and one of those components being an acetylcholinesterase inhibitor (e.g., tacrine). The pharmaceutical composition is useful for treating CNS disorders, such as Alzheimer's disease.

BACKGROUND OF THE INVENTION
 The present invention relates to pharmaceutical compositions, and
 particularly pharmaceutical compositions incorporating compounds that are
 capable of affecting acetylcholine levels. More particularly, the present
 invention relates to pharmaceutical compositions incorporating at least
 one component capable of inhibiting acetylcholinesterase and at least one
 compound capable of interacting with (e.g., activating) nicotinic
 cholinergic receptors (e.g., at least one agonist of specific nicotinic
 receptor subtypes). The present invention also relates to methods for
 treating a wide variety of conditions and disorders, and particularly
 conditions and disorders associated with dysfunction of the central and
 autonomic nervous systems.
 Central nervous system (CNS) disorders are a type of neurological disorder.
 CNS disorders can be drug induced; can be attributed to genetic
 predisposition, infection or trauma; or can be of unknown etiology. CNS
 disorders comprise neuropsychiatric disorders, neurological diseases and
 mental illnesses; and include neurodegenerative diseases, behavioral
 disorders, cognitive disorders and cognitive affective disorders. There
 are several CNS disorders whose clinical manifestations have been
 attributed to CNS dysfunction (i.e., disorders resulting from
 inappropriate levels of neurotransmitter release, inappropriate properties
 of neurotransmitter receptors, and/or inappropriate interaction between
 neurotransmitters and neurotransmitter receptors). Several CNS disorders
 can be attributed to a cholinergic deficiency, a dopaminergic deficiency,
 an adrenergic deficiency and/or a serotonergic deficiency. CNS disorders
 of relatively common occurrence include presenile dementia (early onset
 Alzheimer's disease), senile dementia (dementia of the Alzheimer's type),
 Parkinsonism including Parkinson's disease, Lewy body diseasse (LBD),
 supranuclear palsy (SNP), Huntington's chorea, tardive dyskinesia,
 hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia,
 schizophrenia and Tourette's syndrome.
 Nicotine has been proposed to have a number of pharmacological effects.
 See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994).
 Certain of those effects may be related to effects upon neurotransmitter
 release. See for example, Sjak-shie et al., Brain Res. 624:295 (1993),
 where neuroprotective effects of nicotine are proposed. Release of
 acetylcholine and dopamine by neurons upon administration of nicotine has
 been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et
 al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313
 (1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release of
 norepinephrine by neurons upon administration of nicotine has been
 reported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release of
 serotonin by neurons upon administration of nicotine has been reported by
 Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release of
 glutamate by neurons upon administration of nicotine has been reported by
 Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotine
 reportedly potentiates the pharmacological behavior of certain
 pharmaceutical compositions used for the treatment of certain disorders.
 See, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303 (1993); Harsing
 et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings from Intl.
 Symp. Nic. S40 (1994). Furthermore, various other beneficial
 pharmacological effects of nicotine have been proposed. See, Decina et
 al., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry
 21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984); Onaivi
 et al., Life Sci. 54(3):193 (1994); Tripathi et al., JPET 221: 91-96
 (1982) and Hamon, Trends in Pharmacol. Res. 15:36.
 Various nicotinic compounds have been reported as being useful for treating
 a variety of conditions and disorders, including various CNS disorders.
 See, for example, Williams et al. DN&P 7(4):205-227 (1994), Americ et al.,
 CNS Drug Rev. 1(1):1-26 (1995), Americ et al., Exp. Opin. Invest. Drugs
 5(1):79-100 (1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et
 al., JPET 279:1422 (1996), Damaj et al., Neuroscience (1997), Lin et al.,
 J. Med. Chem. 40: 385-390 (1997), Holladay et al., J. Med. Chem 40(28):
 4169-4194 (1997), Bannon et al., Science 279: 77-80 (1998), PCT WO
 94/08992, PCT WO 96/31475, and U.S. Pat. No. 5,583,140 to Bencherif et
 al., U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No. 5,604,231 to
 Smith et al. and U.S. Pat. No. 5,616,716 to Dull et al.
 Various acetylcholinesterase (AChE) inhibitors have been reported as being
 useful for treating a variety of conditions and disorders, including
 various CNS disorders. AChE inhibitors limit the activity of the enzyme,
 acetylcholinesterase, which hydrolyzes the endogenous neurotransmitter
 acetylcholine (ACh); and as such, AChE inhibitors reportedly preserve
 existing ACh levels in patients treated therewith, and the resulting
 increase in extracellular ACh within the CNS reportedly restores central
 cholinergic hypofunction and hence improves memory and cognition. One
 commercially available AChE inhibitor Cognex, which is marketed as a
 treatment for Alzheimer's disease as capsule containing tacrine
 hydrochloride, available from Parke-Davis Division of Warner-Lambert
 Company. Another-commercially available AChE inhibitor is Aricept, which
 is a capsule containing donezepil hydrochloride, available from Eisai.
 Other reported AChE inhibitors include Amirine from Nikken
 Pharmaceuticals, SW-10888 from Sumitomo, MF-217 from Mediolanum
 Pharmaceutici-Angelini, Ro 45-5934, HP-290 from Hoesht-Russel, ENA 713
 from Sandoz, Itameline from Hoesht, Metrifonate from Bayer-Wiles, Tak 177
 from Takeda, CP 118.954 from Pfizer, Galanthamine from Naedheim
 Pharmaceuticals, ONO 1603 from Ono, Zifrosilone from Marion Merrel Dow.
 See, for example those AChE inhibitors set forth in Brufani et al,
 Alzheimer Disease: From Molecular Biology to Therapy, eds. Becker et al.,
 pp. 171-177 (1996); Schmidt et al., Alzheimer Disease: From Molecular
 Biology to Therapy, eds. Becker et al., pp. 217-221 (1996); Vargas et al.,
 Alzheimer Disease: From Molecular Biology to Therapy, eds. Becker et al.,
 pp. 251-255 (1996); Greig et al., Alzheimer Disease: From Molecular
 Biology to Therapy, eds. Becker et al., pp. 231-237 (1996); and Giacobini,
 Alzheimer Disease: From Molecular Biology to Therapy eds. Becker et al.,
 pp. 187-204 (1996). Such AChE inhibitors include eptastigmine, metrifonate
 and phenserine. However, certain AChE inhibitors have limited efficacy,
 are difficult to titrate, can affect liver function, are contraindicated
 in many disease states, and can cause side effects (e.g., hepatotoxicity,
 headache, myalgia, nausea/vomiting, dyspepsia, dizziness, ataxia,
 anorexia, and diarrhea).
 It would be desirable to provide a useful method for the prevention and
 treatment of a condition or disorder by administering to a patient
 susceptible to or suffering from such a condition or disorder a
 therapeutic capable of effecting the ACh level within that patient. It
 would be highly beneficial to provide individuals suffering from certain
 disorders (e.g., CNS diseases) with interruption of the symptoms of those
 disorders by the administration of a pharmaceutical composition containing
 an active ingredient having nicotinic pharmacology and which has a
 beneficial effect (e.g., upon the functioning of the CNS), but which does
 not provide any significant associated side effects. It would be highly
 desirable to provide a pharmaceutical composition incorporating a compound
 which interacts with nicotinic receptors, such as those which have the
 potential to affect the functioning of the CNS, but which compound when
 employed in an amount sufficient to affect the functioning of the CNS,
 does not significantly affect those receptor subtypes which have the
 potential to induce undesirable side effects (e.g., appreciable activity
 at skeletal muscle and ganglia sites).
 SUMMARY OF THE INVENTION
 The present invention relates to a method for the prevention or treatment
 of a variety of conditions or disorders, and particularly those disorders
 characterized by dysfunction of nicotinic cholinergic neurotransmission.
 The present invention also relates to a method for the prevention or
 treatment of disorders, such as central nervous system (CNS) disorders,
 which are characterized by an alteration in normal neurotransmitter
 release. The methods involve administering to a subject an effective
 amount of a pharmaceutical composition of the present invention patients
 suffering from or susceptible to such disorders. Of particular interest is
 a method involving the co-administration of (i) at least one nicotinic
 compound capable of interacting with nicotinic cholinergic receptors
 (e.g., a nicotinic agonist selective for the .alpha.4.beta.2 nicotinic
 acetylcholine receptor (nAChR) subtype and/or a nicotinic agonist
 selective for the .alpha.4.beta.4 nAChR subtype), and (ii) a component
 capable of inhibiting the activity of acetylcholinesterase (i.e., an
 acetylcholinesterase inhibitor). Preferably, the components of an
 effective dose of the pharmaceutical composition of the present invention
 includes a combination of submaximal doses of (i) a compound capable of
 interacting with nicotinic cholinergic receptors (e.g., a nicotinic
 agonist selective for the .alpha.4.beta.2 nicotinic acetylcholine receptor
 (nAChR) subtype and/or a nicotinic agonist selective for the
 .alpha.4.beta.4 nAChR subtype), and (ii) an AChE inhibitor.
 The present invention, in another aspect, relates to a pharmaceutical
 composition comprising an effective amount of a compound of the present
 invention. Such a pharmaceutical composition incorporates a compound that
 has the capability of interacting with relevant nicotinic receptor sites
 (e.g., a nicotinic agonist), and a compound that is an AChE inhibitor.
 Such a pharmaceutical composition hence has the capability of acting as a
 therapeutic agent in the prevention or treatment of a variety of
 conditions and disorders, particularly those disorders characterized by an
 alteration in normal neurotransmitter release.
 The pharmaceutical compositions of the present invention are useful for the
 prevention and treatment of CNS disorders. Each pharmaceutical composition
 provides therapeutic benefit to individuals suffering from certain CNS
 disorders and exhibiting clinical manifestations of such disorders in that
 at least one component of that composition has the potential to (i)
 exhibit nicotinic pharmacology and affect nicotinic receptors sites in the
 CNS (e.g., act as a pharmacological agonist to activate nicotinic
 receptors), and (ii) elicit neurotransmitter secretion, and hence prevent
 and suppress the symptoms associated with those diseases; and at least one
 component of the composition has the potential to inhibit AChE, the enzyme
 that hydrolyzes the endogenous neurotransmitter, acetylcholine. In
 addition, the compounds are expected to have the potential to (i) increase
 the number of nicotinic cholinergic receptors of the brain of the patient,
 (ii) exhibit neuroprotective effects and (iii) not provide appreciable
 adverse side effects associated with the administration of certain levels
 of nicotinic agonists or AChE inhibitors (e.g., increased heart rate,
 changes in blood pressure, hepatotoxicity, headache, myalgia,
 nausea/vomiting, dyspepsia, dizziness, ataxia, anorexia, and diarrhea).
 The pharmaceutical compositions of the present invention are believed to
 be safe and effective with regards to prevention and treatment of CNS
 disorders.
 The foregoing and other aspects of the present invention are explained in
 detail in the detailed description and examples set forth below.
 DETAILED DESCRIPTION OF THE INVENTION
 Compounds capable of interacting with nicotinic cholinergic receptors can
 vary. Such compounds exhibit nicotinic pharmacology. Such compounds are
 selective to nicotinic cholinergic receptors in that such compounds bind
 with high affinity to relevant receptor subtypes (e.g., those compounds
 exhibit binding constants of less than 1,000 nM). See, Cheng t al.,
 Biochem. Pharmacol. 22: 3099 (1973). Preferably, such compounds are
 nicotinic agonists. Nicotinic agonists are ligands that activate receptors
 (i.e., promote opening of ion channels) upon interaction of those ligands
 with the binding sites of those receptors. See, Bencherif et al., JPET
 279: 1413-1421 (1996). Nicotinic agonists useful in carrying out the
 present invention can vary. Such agonists include nicotine and its analogs
 and derivatives. Exemplary nicotinic agonists are set forth in U.S. Pat.
 No. 4,965,074 to Leeson; U.S. Pat. No. 5,242,935 to Lippiello et al.; U.S.
 Pat. Nos. 5,276,043; 5,227,391 to Caldwell et al.; U.S. Pat. No. 5,583,140
 to Bencherif et al.; U.S. Pat. No. 5,516,785 to Zoltewicz et al.; PCT WO
 96/31475 and European Patent Application No. 588,917. Existing nicotinic
 agonists providing cognitive benefit are observed to bind to the
 .alpha..sub.4.beta..sub.2 or .alpha..sub.4.beta..sub.4 nAChR subtypes.
 See, Bencherif et al., CNS Drug Review, 3(4): 325-345 (1998). See, also,
 Wilkie et al., Biochem. Soc. Trans. 21: 429-431 (1993) and Wonnacott et
 al., In: Effects of Nicotine on Biological Systems II: 87-94 (1995).
 Certain nicotinic agonists are those that act a ligands at the
 .alpha.4.beta.2 nAChR subtype. Examples of such compounds include those
 compounds (e.g., heterocyclic ether derivatives) set forth in PCT WO
 94/08992 and those compounds (e.g., isoxazole and isothiazole compounds)
 set forth in PCT WO 92/21339. Especially preferred compounds are aryl
 substituted amines (e.g., metanicotine, and metanicotine analogs and
 derivatives), such as those types of compounds set forth in U.S. Pat. No.
 5,212,188 to Caldwell et al.; U.S. Pat. No. 5,597,919 to Dull et al.; U.S.
 Pat. No. 5,616,716 to Dull et al., U.S. Pat. No. 5,663,356 to Ruecroft et
 al. and U.S. Pat. No. 5,726,316 to Crooks et al.; and U.S. patent
 application Ser. Nos. 09/054,130 and 09/098,285 the disclosures of which
 are incorporated herein by reference in their entirety.
 Certain nicotinic agonists are those that act a ligands at the
 .alpha.4.beta.4 nAChR subtype. Examples of such compounds include those
 compounds (e.g., diazabicyclo[3.3.1]nonane derivatives) set forth in PCT
 WO 96/30372, and those compounds set forth in U.S. Pat. No. 5,242,916 to
 Lippiello et al. Another example of such a compound is Sibia's SIB-1553A.
 See, Lloyd et al., Life Sciences, 62(17-18):1601-1606 (1998).
 Acetylcholinesterase inhibitors useful in carrying out the present
 invention can vary. Representative acetylcholinesterase inhibitors include
 galanthamine and analogs thereof (see, U.S. Pat. No. 4,663,318 to Davis,
 Canadian Patent 2,180,703 and PCT WO 8808708), and those compounds set
 forth in European Patent Application 411,534 and U.S. Pat. No. 5,231,093
 to Flanagan et al., U.S. Pat. No. 5,246,947 to Effland et al. One
 commercially available ACHR inhibitor Cognex, which is marketed as a
 treatment for AD as capsule containing tacrine hydrochloride, available
 from Parke-Davis Division of Warner-Lambert Company. Another commercially
 available AChE inhibitor is Aricept, which is a capsule containing
 donezepil hydrochloride, available from Eisai. Other reported AChE
 inhibitors include Amirine from Nikken Pharmaceuticals, SW-10888 from
 Sumitomo, MF-217 from Mediolanum Pharmaceutici-Angelini, Ro 45-5934,
 HP-290 from Hoesht-Russel, ENA 713 from Sandoz, Itameline from Hoesht,
 Metrifonate from Bayer-Wiles, Tak 177 from Takeda, CP 118.954 from Pfizer,
 Galanthamine from Naedheim Pharmaceuticals, ONO 1603 from Ono, Zifrosilone
 from Marion Merrel Dow. See, for example those AChE inhibitors set forth
 in Brufani et al, Alzheimer Disease: From Molecular Biology to Therapy,
 eds. Becker et al., pp. 171-177 (1996); Schmidt et al., Alzheimer Disease:
 From Molecular Biology to Therapy, eds. Becker et al., pp. 217-221 (1996);
 Vargas et al., Alzheimer Disease: From Molecular Biology to Therapy, eds.
 Becker et al., pp. 251-255 (1996); Greig et al., Alzheimer Disease: From
 Molecular Biology to Therapy, eds. Becker et al., pp. 231-237 (1996); and
 Giacobini, Alzheimer Disease: From Molecular Biology to Therapy eds.
 Becker et al., pp. 187-204 (1996). Such AChE inhibitors include
 eptastigmine, metrifonate and phenserine. Representative AChE inhibitors
 are set forth in U.S. Pat. Nos. 4,914,102; 5,100,901; 5,102,891;
 5,166,181; 5,187,165; 5,288,758; 5,302,593; 5,300,517; 5,338,548;
 5,364,864; 5,389,629; 5,391,553; 5,455,245; 5,574,046; 5,602,176;
 5,622,976; 5,663,448; 5,693,668 and 5,744,476; European Patent Application
 Nos. 268,871; 298,202; 409,676; 477,903 and 703,901; and PCT WO 93/13100;
 93/16690; 96/40682; 97/19059 and 97/38993, the disclosures of which are
 incorporated herein by reference in their entirety.
 The present invention relates to a method for providing prevention of a
 condition or disorder to a subject susceptible to such a condition or
 disorder, and for providing treatment to a subject suffering therefrom.
 For example, the method comprises administering to a patient an amount of
 a pharmaceutical composition effective for providing some degree of
 prevention of the progression of a CNS disorder (i.e., provide protective
 effects), amelioration of the symptoms of a CNS disorder, and amelioration
 of the recurrence of a CNS disorder. The method involves administering an
 effective amount of a pharmaceutical composition.
 Pharmaceutical compositions of the present invention are useful for
 treating those types of conditions and disorders for which other types of
 nicotinic compounds and AChE inhibitors have been proposed as
 therapeutics. See, for example, Williams et al. DN&P 7(4):205-227 (1994),
 Arneric et al., CNS Drug Rev. 1(1):1-26 (1995), Arneric et al., Exp. Opin.
 Invest. Drugs 5(1):79-100 (1996), Bencherifet al., JPET 279:1413 (1996),
 Lippiello et al., JPET 279:1422 (1996), Damaj et al., Neuroscience (1997),
 Holladay et al., J. Med. Chem 40(28): 4169-4194 (1997), Bannon et al.,
 Science 279: 77-80 (1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat.
 No. 5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al.,
 and U.S. Pat. No. 5,604,231 to Smith et al. CNS disorders which can be
 treated in accordance with the present invention include presenile
 dementia (early onset Alzheimer's disease), senile dementia (dementia of
 the Alzheimer's type), Parkinsonism including Parkinson's disease,
 Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention
 deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's
 syndrome.
 The pharmaceutical composition also can include various other components as
 additives or adjuncts. Exemplary pharmaceutically acceptable components or
 adjuncts which are employed in relevant circumstances include
 antioxidants, free radical scavenging agents, peptides, growth factors,
 antibiotics, bacteriostatic agents, immunosuppressives, anticoagulants,
 buffering agents, anti-inflammatory agents, anti-pyretics, time release
 binders, anaesthetics, steroids and corticosteroids. Such components can
 provide additional therapeutic benefit, act to affect the therapeutic
 action of the pharmaceutical composition, or act towards preventing any
 potential side effects which may be posed as a result of administration of
 the pharmaceutical composition. In certain circumstances, the
 pharmaceutical composition of the present invention can be employed as
 part of a formulation with other compounds intended to prevent or treat a
 particular disorder.
 The manner in which the pharmaceutical compositions are administered can
 vary. Components of those compositions can be administered by inhalation
 (e.g., in the form of an aerosol either nasally or using delivery articles
 of the type set forth in U.S. Pat. No. 4,922,901 to Brooks et al.);
 topically (e.g., in lotion form); orally (e.g., in liquid form within a
 solvent such as an aqueous or non-aqueous liquid, or within a solid
 carrier); intravenously (e.g., within a dextrose or saline solution); as
 an infusion or injection (e.g., as a suspension or as an emulsion in a
 pharmaceutically acceptable liquid or mixture of liquids); intrathecally;
 intracerebro ventricularly; or transdermally (e.g., using a transdermal
 patch). Although it is possible to administer the compositions in the form
 of a bulk active chemical, it is preferred to present each composition in
 the form of a formulation for efficient and effective administration.
 Exemplary methods for administering such compositions will be apparent to
 the skilled artisan. For example, the compositions can be administered in
 conjunction with a pharmaceutically acceptable carrier, and as such can be
 administered in the form of a tablet, a hard gelatin capsule or as a time
 release capsule. As another example, the compositions can be delivered
 transdermally using the types of patch technologies available from
 Novartis and Alza Corporation. The administration of the pharmaceutical
 compositions of the present invention can be intermittent, or at a
 gradual, continuous, constant or controlled rate to a warm-blooded animal,
 (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or
 monkey); but advantageously is preferably administered to a human being.
 In addition, the time of day and the number of times per day that the
 pharmaceutical formulation is administered can vary. Administration
 preferably is such that the active ingredients of the pharmaceutical
 formulation interact with receptor sites within the body of the subject
 that affect the functioning of the CNS. More specifically, in treating a
 CNS disorder administration preferably is such so as to optimize the
 effect upon those relevant receptor subtypes which have an effect upon the
 functioning of the CNS, while minimizing the effects upon muscle-type
 receptor subtypes. Other suitable methods for administering the
 compositions of the present invention are described in U.S. Pat. No.
 5,604,231 to Smith et al., the disclosure of which is incorporated herein
 by reference in its entirety.
 The appropriate dose of the pharmaceutical composition is that amount
 effective to prevent occurrence of the symptoms of the disorder or to
 treat some symptoms of the disorder from which the patient suffers. By
 "effective amount", "therapeutic amount" or "effective dose" is meant that
 amount sufficient to elicit the desired pharmacological or therapeutic
 effects, thus resulting in effective prevention or treatment of the
 disorder. The effective dose can vary, depending upon factors such as the
 condition of the patient, the severity of the symptoms of the disorder,
 and the manner in which the pharmaceutical composition is administered.
 The effective dose of the composition can differ from patient to patient
 but in general includes amounts starting where CNS effects or other
 desired therapeutic effects occur, but below that amount where significant
 undesirable side effects are observed. Thus, when treating a CNS disorder,
 an effective amount of composition is an amount sufficient to pass across
 the blood-brain barrier of the subject; and with regards to one of the
 components, to bind to relevant receptor sites in the brain of the subject
 and preferably activate relevant nicotinic receptor subtypes (e.g.,
 provide neurotransmitter secretion, thus resulting in effective prevention
 or treatment of the disorder); and with regards to the components of the
 composition, to affect the level of AChE within the brain of the subject.
 Prevention of the disorder is manifested by delaying the onset of the
 symptoms of the disorder. Treatment of the disorder is manifested by a
 decrease in the symptoms associated with the disorder or an amelioration
 of the recurrence of the symptoms of the disorder.
 The present invention involves administering an effective amount of a
 pharmaceutical composition incorporating (1) an effective amount of any or
 all of the components of that composition, or (ii) a sub-threshold or
 submaximal amount of any or all of the components of that composition. A
 submaximal dose is a dose that is not effective to provide a desired
 therapeutic effect; that is, a dose that is less than an active dose.
 Components are employed at submaximal doses (e.g., typically less than 100
 percent, often less than 75 percent, frequently less than 50 percent, and
 even less than 25 percent, of the active dose of that component). Hence,
 there is provided the potential for minimized side effects associated with
 any of these compounds at efficacious doses when not employed as a
 synergistic mixture. However, the components, when used in combination,
 act between the different pathways to maximize the beneficial effects of
 these compounds on cognitive functions. That is, even though each
 component of the pharmaceutical composition is used in amounts that are
 less than the respective minimal effective doses, the combination of
 components provides a therapeutic effect.
 Typically, the effective dose of the pharmaceutical composition generally
 requires administering the compound that has the capability of interacting
 with relevant nicotinic receptor sites (e.g., the nicotinic agonist) in an
 amount of less than 5 mg/kg of patient weight. Often, such compounds are
 administered in an amount less than about 1 mg/kg of patient weight, more
 often less than about 100 ug/kg of patient weight, and frequently between
 about 1 ug and about 100 ug/kg of patient weight, and preferably between
 about 5 ug and about 50 ug/kg of patient weight. The foregoing effective
 doses typically represent that amount administered as a single dose, or as
 one or more doses administered over a 24 hour period.
 The AChE inhibitors are administered in amounts that are dependent upon the
 particular type of compound employed. See, Physicians' Desk Reference.
 Typically, the effective dose of pharmaceutical composition generally
 requires administering the AChE inhibitor in an amount of less than about
 2 mg/kg of patient weight, when the active ingredient is tacrine
 hydrochloride; while such amount is less than about 150 ug/kg patient
 weight, when the active ingredient is donezepil hydrochloride. For
 example, for tacrine hydrochloride, such amount is less than about 1.5
 mg/kg of patient weight, often less than about 1 mg/kg of patient weight,
 and frequently between about 200 ug and about 800 ug/kg of patient weight,
 and usually between about 300 ug and about 600 ug/kg of patient weight.
 For example, for donezepil hydrochloride, such amount is less than about
 100 ug/kg of patient weight, often less than about 75 ug/kg of patient
 weight, and frequently between about 20 ug and about 70 ug/kg of patient
 weight, and usually between about 30 Mg and about 60 ug/kg of patient
 weight. The foregoing effective doses typically represent that amount
 administered as a single dose, or as one or more doses administered over a
 24 hour period.
 Compositions of the present invention, when employed in effective amounts
 in accordance with the method of the present invention, are effective
 towards providing some degree of prevention of the progression of CNS
 disorders, amelioration of the symptoms of CNS disorders, and amelioration
 to some degree of the recurrence of CNS disorders. However, such effective
 amounts of those compositions preferably are not sufficient to elicit any
 appreciable side effects, as is demonstrated by decreased effects on
 preparations believed to reflect effects on the cardiovascular system, or
 effects to skeletal muscle. As such, administration of compositions of the
 present invention provides a broad therapeutic window in which treatment
 of certain CNS disorders is effectively provided, and side effects are
 avoided. That is, an effective dose of a composition of the present
 invention is sufficient to provide the desired effects upon the CNS, but
 is preferably insufficient to provide undesirable side effects.
 Preferably, effective administration of a composition of the present
 invention resulting in treatment of CNS disorders occurs upon
 administration of less half that amount sufficient to cause any side
 effects to a significant degree.

The following examples are provided to illustrate the present invention,
 and should not be construed as limiting thereof. In these examples, all
 parts and percentages are by weight, unless otherwise noted.
 EXAMPLE 1
 A nicotinic agonist selective to an nAChR subtype is
 (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine
 hemigalactarate, which was prepared in accordance with the following
 techniques:
 (2R)-4-Penten-2-ol
 (2R)-4-Penten-2-ol was prepared in 82.5% yield from (R)-(+)-propylene oxide
 according to procedures set forth in A. Kalivretenos, J. K. Stille, and L.
 S. Hegedus, J. Org. Chem. 56: 2883 (1991).
 (2R)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol
 A mixture of 5-bromo-3-isopropoxypyridine (10.26 g, 47.50 mmol),
 (2R)-4-penten-2-ol (4.91 g, 57.00 mmol), palladium(II) acetate (106 mg,
 0.47 mmol), tri-o-tolylphosphine (578 mg, 1.90 mmol), triethylamine (28.46
 mL, 204.25 mmol), and acetonitrile (30 mL) were heated in a sealed glass
 tube at 140.degree. C. for 14 h. The reaction mixture was cooled to
 ambient temperature, diluted with water, and extracted with chloroform
 (3.times.200 mL). The combined chloroform extracts were dried over sodium
 sulfate, filtered, and concentrated by rotary evaporation to give a
 pale-yellow oil (8.92 g, 85.0%).
 (2R)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol p-Toluenesulfonate
 To a stirred solution of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol
 (8.50 g, 38.46 mmol) in dry pyridine (30 mL) at 0.degree. C. was added
 p-toluenesulfonyl chloride (14.67 g, 76.92 mmol). The reaction mixture was
 stirred for 24 h at ambient temperature. The pyridine was removed by
 rotary evaporation. Toluene (50 mL) was added to the residue and removed
 by rotary evaporation. The crude product was stirred with a saturated
 solution of sodium bicarbonate (100 mL) and extracted with chloroform
 (3.times.100 mL). The combined chloroform extracts were dried over sodium
 sulfate, filtered, and concentrated by rotary evaporation to yield a
 dark-brown, viscous oil (11.75 g, 81.5%).
 (2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine
 A mixture of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol
 ptoluenesulfonate (11.00 g, 29.33 mmol), methylamine (200 mL, 40% solution
 in water), and ethyl alcohol (10 mL) was stirred at ambient temperature
 for 18 h. The resulting solution was extracted with chloroform
 (3.times.100 mL). The combined chloroform extracts were dried over sodium
 sulfate, filtered, and concentrated by rotary evaporation. The crude
 product was purified by column chromatography over aluminum oxide, eluting
 with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined
 and concentrated by rotary evaporation, producing an oil. Further
 purification by vacuum distillation furnished 2.10 g (31.0%) of a
 colorless oil, bp 90-100.degree. C. at 0.5 mm Hg.
 (2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine
 Hemigalactarate
 (2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (2.00 g,
 8.55 mmol) was dissolved in ethyl alcohol (20 mL), assisted by warming to
 70.degree. C. The warm solution was treated with galactaric acid (900 mg,
 4.27 mmol) in one portion, followed by the dropwise addition of water (0.5
 mL). The solution was filtered while hot to remove some insoluble
 material. The filtrate was allowed to cool to ambient temperature. The
 resulting crystals were filtered, washed with anhydrous diethyl ether, and
 dried under vacuum at 40.degree. C. to yield a white, crystalline powder
 (750 mg, 26.0%), mp 140-143.degree. C.
 An AChE inhibitor, tacrine, is commercially available as Cognex. Caplets
 containing 40 mg of active ingredient were used for carrying out the
 present example.
 A step-through passive avoidance paradigm is a test is designed to assess
 the ability of a compound to reverse scopolamine-induced amnesia in rats.
 A positive outcome in this paradigm supports the notion that the tested
 compound has potential cognition enhancing effects, an end-point relevant
 to some CNS disorders. Briefly, a Gemini Avoidance System (San Diego
 Instruments) was used for these experiments. During the period of
 habituation, rats received a subcutaneous injection of saline. On the
 acquisition day, each rat received a subcutaneous injection of 0.5
 .mu.mol/kg scopolamine (or saline in the case of the vehicle control
 group) 30 minutes prior to being placed in the chambers. Five minutes
 following scopolamine injection, (or twenty-five minutes before being
 placed in the chamber), each rat was administered a subcutaneous injection
 with one of four doses of the pharmaceutical composition component
 ingredients. Thirty minutes following the scopolamine or vehicle
 injection, each rat was placed in the brightly illuminated chamber, facing
 away from the sliding door. After ten seconds, the door separating the
 chambers opened allowing access to the dark chamber. The time to enter the
 dark chamber was measured. Immediately upon entering the dark chamber, the
 rat received a mild foot-shock (0.5 mAmp) for 2 second duration.
 Twenty-four hours following training, each rat was placed in the light
 chamber facing away from the sliding door. Thirty seconds later the door
 was opened and the rat was allowed to enter the dark chamber. Upon
 entering the dark chamber the sliding door was closed and the rat was
 removed from the apparatus (no shock was delivered). If the rat did not
 enter the dark chamber within 300 seconds, a ceiling score of 300 seconds
 was recorded for that rat, and the rat was removed from the apparatus and
 returned to its home cage. Following saline sub-cutaneous injection,
 animals were not cognitively impaired and did not enter the avoidance
 chamber. The latency was markedly longer (&gt;70 seconds, on average) than
 those rendered amnesic with scopolamine (latency of less than 10 seconds,
 on average). Following treatment with tacrine at 1.2, 4, and 12
 .mu.mol/kg; the latency was unchanged at 1.2 mmol/kg (not significantly
 different than scopolamine), and was increased to 30 and 25 seconds, at 4
 and 12 .mu.mol/kg, respectively. Following treatment with
 (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine at 0.6, 1
 and 3 .mu.mol/kg, the latency increased to approximately 25, 55 and 20
 seconds, respectively. The co-administered combination of tacrine (1.2
 pmol/kg) and
 (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (0.6
 .mu.mol/kg) resulted in increased latency to 40 seconds, which was greater
 than either component alone. Further, the co-administered combination
 provided increased latency at a submaximal dose of tacrine.
 The foregoing is illustrative of the present invention and is not to be
 construed as limiting thereof. The invention is defined by the following
 claims, with equivalents of the claims to be included therein.