[go: up one dir, main page]

WO2009135091A1 - Utilisation d’asénapine et composés associés pour le traitement de maladies ou de conditions neurales ou non - Google Patents

Utilisation d’asénapine et composés associés pour le traitement de maladies ou de conditions neurales ou non Download PDF

Info

Publication number
WO2009135091A1
WO2009135091A1 PCT/US2009/042451 US2009042451W WO2009135091A1 WO 2009135091 A1 WO2009135091 A1 WO 2009135091A1 US 2009042451 W US2009042451 W US 2009042451W WO 2009135091 A1 WO2009135091 A1 WO 2009135091A1
Authority
WO
WIPO (PCT)
Prior art keywords
disease
neuronal
cell
compound
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2009/042451
Other languages
English (en)
Inventor
David T. Hung
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medivation Technologies LLC
Original Assignee
Medivation Technologies LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medivation Technologies LLC filed Critical Medivation Technologies LLC
Publication of WO2009135091A1 publication Critical patent/WO2009135091A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • Neuronal degeneration Conditions producing neuronal degeneration are frequently accompanied by deterioration of cognitive functions, but may also result in neuronal damage, dysfunction, or complications that can be characterized by neurological, neurodegenerative, physiological, psychological, or behavioral aberrations.
  • Such neuronal degeneration may be caused by central or peripheral nervous system damage or dysfunction resulting from injury, such as edema or other trauma, hypoxia or ischemia caused by stroke, cell death caused by epilepsy, spinal muscle atrophy, changes caused by aging, or complications resulting therefrom.
  • Old age is characterized by a sharp increase in the likelihood of developing one or more pathologies and conditions associated with the aging process that are not life-threatening, but that may nevertheless significantly diminish an individual's quality of life.
  • pathologies and conditions in mammals include, for example, age-associated vision disturbance (cataracts), age-associated hair loss (alopecia), age- associated memory impairment (AAMI), age- associated weight loss due to the death of muscular and fatty cells, cartilage injuries, degenerative conditions of cartilage and osteoarthritis.
  • Impaired cognitive functions and memory loss are also a consequence of natural age-related changes (R. Levy (1994) "Aging-associated cognitive decline," Int'l Psychogeriatr. 6:63-68).
  • Such conditions may also result from various pathologies of the central nervous system, both acute ⁇ e.g., physical and psychic trauma, poisoning, hypoxia, stress, etc.) and chronic (e.g., neurodegenerative diseases, depression, alcoholism, neuroinfection, etc.).
  • acute e.g., physical and psychic trauma, poisoning, hypoxia, stress, etc.
  • chronic e.g., neurodegenerative diseases, depression, alcoholism, neuroinfection, etc.
  • MCI mild cognitive impairment
  • patients with mild cognitive impairment are not cognitively impaired to the same extent as patients suffering from Alzheimer's or other similar dementias.
  • MCI patients have difficulty performing complex daily tasks and learning, in contrast to the cognitive impairment associated with Alzheimer's and other similar dementias, which is characterized by inability to perform cognitive tasks relating to social, everyday, and/or professional functions (desadaptations).
  • the etiology of this illness is unknown and, apparently, is not directly related to neurodegenerative processes in the brain (S.I. Gavrilova, "The concept of mild cognitive decline,” in Alzheimer's Disease and Aging (Mater, III Ros. Konf. Moscow, PuI' s) pp. 9-20).
  • vascular pathologies such as acute insufficiency or disturbance of cerebral circulation, ischemic and hemorrhagic insults, and ischemic or hemorrhagic stroke.
  • Such pathologies often lead to disability and a noticeably increased mortality rate.
  • Such insults may cause injury to and the death of significant areas of the brain, thereby impairing cognitive functions and sometimes producing depression and disorientation in addition to neurological deficit (paresis, paralysis) in patients who have suffered an insult (E.I. Gusev and V.I. Skvortsova, in Cerebral ischemia, Moscow, Meditsina, 2001, p. 238; R.G.
  • Non-neuronal pathologies and conditions sometimes associated with age can also impact an individual's quality of life, such as myocardial infarction or other heart disease, diabetes, anorexia or AIDS-, cancer- or chemotherapy- associated wasting, bacterial infection, viral infection, fractures, burns, lacerations, and other injuries.
  • Neuronal diseases or conditions resulting from pathologies of the nervous system both acute (e.g., spinal cord injury, ischemic or hemorrhagic insult, hypoxia, and the like) and chronic (e.g., MCI, autism, multiple sclerosis, and the like), are frequently difficult to treat effectively, as are many non-neuronal pathologies and conditions.
  • the therapeutic agents can improve the memory, improve the quality of life, reduce impairment of cognitive function, limit the extent of disability, limit the extent of injury, and/or prolong the survival time for patients suffering from any of the above diseases or conditions.
  • Compounds of Formula I, II, or III include:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and m are as defined herein, or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing.
  • the compound of Formula I, II, or III is administered in combination with one or more other agents, e.g., a hydrogenated pyrido[4,3-b]indole such as dimebon.
  • the invention embraces methods, combination therapies, pharmaceutical compositions, and kits for treating, preventing, delaying the onset, and/or the development of a neuronal or non-neuronal indication using Compound 1 :
  • the methods, combination therapies, pharmaceutical compositions, and kits for treating, preventing, delaying the onset, and/or the development of a neuronal or non-neuronal indication exclude schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the methods, combination therapies, pharmaceutical compositions, and kits for treating, preventing, delaying the onset, and/or the development of a neuronal or non-neuronal indication include schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • asenapine refers to Compound 1, having the chemical name trans-5-chloro-2-methyl- 2,3,3a, 12b-tetrahydro-lH-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole.
  • Pharmaceutically acceptable salts of asenapine, such as the maleate salt, are embraced by this invention, as are solvates of the free base or salt.
  • the compound of Formula I, II, or III, pharmaceutically acceptable salt thereof, or solvate of any of the foregoing is administered with one or more other agents, e.g., a hydrogenated pyrido[4,3-b]indole such as dimebon or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing.
  • the present invention provides a method of treating a neuronal or non-neuronal indication in an individual in need thereof by administering to the individual an effective amount of a compound of Formula I, II, or III (such as Compound I) or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of slowing the progression of a neuronal or non-neuronal indication in an individual who has a mutated or abnormal gene associated with a neuronal or non-neuronal indication or who has been diagnosed with such an indication by administering to the individual an effective amount of a compound of Formula I, II, or III (such as Compound I) or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of preventing, slowing, or delaying the onset and/or development of a neuronal or non-neuronal indication in an individual who is at risk of developing such a neuronal or non-neuronal indication by administering to the individual an effective amount of a compound of Formula I, II, or III (such as Compound I) or a pharmaceutically acceptable salt or solvate thereof.
  • the neuronal or non-neuronal indication includes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the neuronal or non-neuronal indication excludes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the methods comprises administering to an individual an effective amount of Compound I and dimebon or a pharmaceutically acceptable salt or solvate of the foregoing.
  • neuronal indications include neurodegenerative diseases and disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury- related mild cognitive impairment (MCI), injury -related mild cognitive impairment (MCI) resulting from battlefield injuries, post-concussion syndrome, post-traumatic stress disorder and adjuvant chemotherapy, traumatic brain injury, (TBI), neuronal death mediated ocular disorder, macular degeneration, age-related macular degeneration
  • Exemplary non-neuronal indications include age-associated hair loss (alopecia), age-associated weight loss, age- associated vision disturbance (cataracts), heart disease, diabetes, anorexia, AIDS- or chemotherapy-associated wasting, vascular injury, intestinal injury, cartilage injury, osteoarthritis, bacterial infection, viral infection, a first-, second-, or third-degree burn, a simple, compound, stress, compression fracture, or a laceration.
  • the present invention provides a method of treating
  • the present invention provides a method of slowing the progression of Alzheimer's disease in an individual who has a mutated or abnormal gene associated with Alzheimer's disease or who has been diagnosed with Alzheimer' s disease by administering to the individual an effective amount of a compound of Formula I, II, or III (such as Compound I) or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of preventing, slowing, or delaying the onset and/or development of Alzheimer's disease in an individual who is at risk of developing Alzheimer' s disease by administering to the individual an effective amount of a compound of Formula I, II, or III (such as Compound I) or a pharmaceutically acceptable salt or solvate thereof.
  • the methods comprise administering to an individual an effective amount of Compound I and dimebon or a pharmaceutically acceptable salt or solvate of the foregoing.
  • the present invention provides a method of treating a neurodegenerative disease or condition in an individual in need thereof by administering to the individual an effective amount of a compound of Formula I, II, or III (such as Compound I) or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of slowing the progression of a neurodegenerative disease or condition in an individual who has a mutated or abnormal gene associated with such a disease or condition or who has been diagnosed with such a disease or condition by administering to the individual an effective amount of a compound of Formula I, II, or III (such as Compound I) or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of preventing, slowing, or delaying the onset and/or development of a neurodegenerative disease or condition in an individual who is at risk of developing such a disease or condition by administering to the individual an effective amount of a compound of Formula I, II, or III (such as Compound I) or a pharmaceutically acceptable salt or solvate thereof.
  • the methods comprise administering to an individual an effective amount of Compound I and dimebon or a pharmaceutically acceptable salt or solvate of the foregoing.
  • a neurodegenerative disease or condition is a disease or condition other than schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • a neurodegenerative disease or condition is Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, or canine cognitive dysfunction syndrome (CCDS).
  • the disease or condition is not Alzheimer's disease. In certain embodiments, the disease or condition is not amyotrophic lateral sclerosis (ALS). In certain embodiments, the disease or condition is neither Alzheimer's disease nor amyotrophic lateral sclerosis (ALS). In certain embodiments, the disease or condition is not Huntington's disease. In certain embodiments, the disease or condition is not Parkinson's disease. In certain embodiments, the disease or condition is not schizophrenia, bipolar disorder or psychosis, such as psychosis associated with any of those diseases or conditions.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing any one or more of schizophrenia, bipolar disorder, schizoaffective disorder or psychosis, such as non- Alzheimer' s disease-associated psychosis.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), or schizophrenia.
  • the individual is a canine who has not been diagnosed with canine cognitive dysfunction syndrome (CCDS).
  • CCDS canine cognitive dysfunction syndrome
  • compositions and methods of stimulating neurite outgrowth and/or enhancing neurogenesis in an individual having a neuronal indication comprising administering an amount of any of: (1) a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt or solvate thereof (2) a combination of (i) a compound of Formula I, II, or III or a pharmaceutically acceptable salt or solvate thereof and (ii) one or more second agents effective to stimulate neurite outgrowth and/or to enhance neurogenesis (e.g., dimebon or a pharmaceutically acceptable salt or solvate thereof).
  • a compound of Formula I, II, or III e.g., asenapine
  • a pharmaceutically acceptable salt or solvate thereof e.g., asenapine
  • one or more second agents effective to stimulate neurite outgrowth and/or to enhance neurogenesis e.g., dimebon or a pharmaceutically acceptable salt or solvate thereof.
  • the therapeutic compound of Formula I, II, or III e.g., asenapine
  • a pharmaceutically acceptable salt or solvate thereof is asenapine.
  • the second agent is a hydrogenated pyrido[4,3-b]indole such as dimebon, or another agent.
  • compositions and methods for treating, preventing, delaying the onset, and/or delaying the development of a neuronal or non-neuronal indication for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial by administering to an individual in need thereof an effective amount of any of: (1) a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt or solvate thereof (2) a combination of (i) a compound of Formula I, II, or III or a pharmaceutically acceptable salt or solvate thereof and (ii) one or more second agents.
  • a compound of Formula I, II, or III e.g., asenapine
  • a pharmaceutically acceptable salt or solvate thereof e.g., asenapine
  • the therapeutic compound of Formula I, II, III e.g., asenapine
  • a pharmaceutically acceptable salt or solvate thereof is asenapine.
  • the second agent is e.g., a hydrogenated pyrido[4,3-b]indole such as dimebon, or another agent.
  • the methods further comprise administration of a growth factor and/or an anti-cell death compound.
  • the methods further comprise administration of a cell.
  • the cell is a multipotential stem cell.
  • the cell is a terminally differentiated cell.
  • the cell is incubated with asenapine.
  • the cell is incubated with a hydrogenated pyrido [4,3-b]indole such as dimebon. In certain aspects, the cell is incubated with asenapine and dimebon.
  • the compound of Formula I, II, or III e.g., asenapine
  • the combination of a compound of Formula I, II, or III e.g., asenapine
  • one or more second agents is administered with a growth factor and an anti-cell death compound.
  • the invention also provides methods of activating a cell, promoting the differentiation of a cell, and/or promoting the proliferation of a cell by incubating the cell with one or more compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salts thereof under conditions sufficient to activate the cell, promote the differentiation of the cell, promote the proliferation of the cell, or any combination of two or more of the foregoing.
  • the methods comprise a second agent.
  • the second agent or pharmaceutically acceptable salt thereof is a hydrogenated pyrido[4,3-b]indole such as dimebon or a pharmaceutically acceptable salt or solvate thereof.
  • the methods comprise a combination of asenapine and dimebon.
  • methods include incubating a cell with Alzheimer's disease with one or more compound of Formula I, II, or III (e.g., asenapine) or pharmaceutically acceptable salts thereof under conditions sufficient to activate the cell, promote the differentiation of the cell, promote the proliferation of the cell, or any combination of two or more of the foregoing.
  • the cell is a neuron.
  • the invention provides a pharmaceutical composition comprising
  • a first therapy that includes a compound of Formula I, II, or III or a pharmaceutically acceptable salt or solvate thereof
  • a second therapy that includes one or more other compounds useful for treating, preventing and/or delaying the onset and/or development of a neuronal or non-neuronal indication, for example a hydrogenated pyrido[4,3-b]indole such as dimebon, and (iii) a pharmaceutically acceptable carrier or excipient.
  • the neuronal or non-neuronal indication includes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the neuronal or non-neuronal indication excludes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the invention also embraces unit dosage forms of a first and a second therapy comprising asenapine and dimebon.
  • the invention includes a kit comprising (a) a first therapy that includes a compound of Formula I, II, or III or a pharmaceutically acceptable salt or solvate thereof and (b) instructions for use in the treatment, prevention, or delaying the onset and/or development of a neuronal or non-neuronal indication.
  • the neuronal or non-neuronal indication includes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the neuronal or non-neuronal indication excludes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • kits of the invention further comprise a second therapy that includes one or more additional compounds useful for treating, slowing the progression, preventing and/or delaying the onset and/or development of a neuronal or non-neuronal indication, for example a hydrogenated pyrido[4,3-b]indole such as dimebon.
  • a second therapy that includes one or more additional compounds useful for treating, slowing the progression, preventing and/or delaying the onset and/or development of a neuronal or non-neuronal indication, for example a hydrogenated pyrido[4,3-b]indole such as dimebon.
  • Figures IA and IB are dose response curves of asenapine for neurite outgrowth in primary rat cortical neurons with a vehicle control and a positive control of brain derived neurotrophic factor (BDNF).
  • BDNF brain derived neurotrophic factor
  • the present invention relates to uses of a compound of Formula I, II, or III (e.g., asenapine), or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) of the foregoing, in treating, preventing, delaying the onset, and/or delaying the development of a number of neuronal and non-neuronal indications.
  • the neuronal or non- neuronal indication includes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the neuronal or non-neuronal indication excludes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the invention embraces a method of administering to an individual in need thereof a pharmaceutical composition comprising a compound of Formula I, II, or III (e.g., asenapine).
  • the invention embraces a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, II, or III (e.g., asenapine) and a second therapy comprising one or more additional compounds.
  • the second therapy is a hydrogenated pyrido [4,3-b]indole such as dimebon or a pharmaceutically acceptable salt thereof.
  • the individual has a disorder for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial for treating, preventing, delaying the onset, and/or delaying the development of the condition.
  • the invention provides a method of treating a condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the invention provides a method of preventing a condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the invention provides a method of delaying the onset of a condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the invention provides a method of delaying the development of a condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • dimebon As described in U.S. Patent Nos. 6,187,785 and 7,071,206, hydrogenated pyrido[4,3-b]indole derivatives, such as dimebon, have NMDA antagonist properties, which make them useful for treating neurodegenerative diseases or conditions. Dimebon has also been reported to be a neuroprotective drug, e.g., a drug that has a beneficial effect on the viability of neurons. For example, more recent trials of dimebon in patients with mild-to-moderate Alzheimer's disease confirm the beneficial effects of dimebon in the treatment of individuals with Alzheimer's disease. Specifically, Alzheimer's patients treated with dimebon have shown improvement (as compared to placebo) in important aspects of cognition over a one-year period.
  • the methods utilizing combination therapy are provided where the first therapeutic agent is asenapine and the second therapeutic agent is dimebon or a pharmaceutically acceptable salt of the foregoing, wherein the method comprises treating a neuronal or non-neuronal indication other than schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the combination therapy comprising asenapine and dimebon results in improved cognition and/or memory as compared to a monotherapy not containing dimebon.
  • a combination therapy comprising asenapine and dimebon or a pharmaceutically acceptable salt thereof is provided for use in treating Alzheimer's disease.
  • Asenapine is under development for the treatment of schizophrenia and bipolar disorder.
  • the human receptor binding affinities and functional characteristics of asenapine have been reported in Shahid, M., et al., "Asenapine: a novel psychopharmacologic agent with a unique human receptor signature," J. Psychopharmacol., February 28, 2008 (electronic publication ahead of print).
  • asenapine As reported by Shahid et al., asenapine, as compared to other antipsychotics, has shown high affinity and a different rank order of binding affinities (pKO for serotonin receptors (5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5 (8.8), 5-HT6 (9.6), and 5-HT7 (9.9)), adrenoceptors (alphal (8.9), alpha2A (8.9), alpha2B (9.5), and alpha2C (8.9)), dopamine receptors (Dl (8.9), D2 (8.9), D3 (9.4), and D4 (9.0)) and histamine receptors (Hl (9.0) and H2 (8.2)).
  • serotonin receptors 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2
  • Asenapine showed much lower affinity (pKj ⁇ 5) for muscarinic receptors and has affinity for H2 receptors. Relative to its D2 receptor affinity, asenapine had a higher affinity for 5-HT2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT6, alpha2B, and D3 receptors, suggesting stronger binding to these targets at therapeutic doses.
  • Asenapine behaves as a potent antagonist (pKB) at 5-HT1A (7.4), 5-HT1B (8.1), 5-HT2A (9.0), 5-HT2B (9.3), 5-HT2C (9.0), 5-HT6 (8.0), 5-HT7 (8.5), D2(9.1), D3 (9.1), alpha2A (7.3), alpha2B (8.3), alpha2C (6.8), and Hl (8.4) receptors.
  • asenapine and other compounds of Formula I, II, or III will behave similarly to dimebon and will therefore be effective in treating, preventing, delaying the onset, and/or delaying the development of neuronal and non-neuronal diseases and conditions.
  • asenapine and other compounds of Formula I, II, or III will be effective in treating neuronal and non-neuronal diseases or conditions for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • use of asenapine in individuals having such diseases or conditions may improve key aspects of cognitive function, including, but not limited to, memory, language, and more complex functions including, but not limited to, awareness of time and place and praxis.
  • agents e.g., a hydrogenated pyrido[4,3-b]indole such as dimebon
  • an individual intends a mammal, including but not limited to human, bovine, primate, equine, canine, feline, porcine, and ovine animals.
  • the invention finds use in both human medicine and in the veterinary context, including use in agricultural animals and domestic pets.
  • the individual may be a human who has been diagnosed with or is suspected of having a disease or condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the indication may be a neuronal disease or condition or a non-neuronal disease or condition.
  • the disease or condition may involve neurodegeneration, or degenerative disorders or trauma relating to non-neuronal diseases or conditions.
  • the individual may be a human who exhibits one or more symptoms associated with a neuronal disease or condition.
  • the individual may be a human who has a mutated or abnormal gene associated with a disease or condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the individual may be a human who is genetically or otherwise predisposed to developing a disease or condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing any one or more of schizophrenia, bipolar disorder, schizoaffective disorder or psychosis, such as non- Alzheimer' s disease-associated psychosis.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing Alzheimer's disease.
  • the individual is a human who has not been diagnosed with Huntington's disease, Parkinson's disease or amyotrophic lateral sclerosis (ALS).
  • the individual is a canine who has not been diagnosed with canine cognitive dysfunction syndrome (CCDS).
  • CCDS canine cognitive dysfunction syndrome
  • beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition.
  • beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • treatment of such a disease or condition with a therapeutic compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof, such as asenapine is accompanied by no or fewer side effects than are associated with currently available therapies and/or improves the quality of life of the individual.
  • beneficial or desired clinical results of treatment or treating Alzheimer's disease include, but are not limited to, one or more of the following: inhibiting or suppressing the formation of amyloid plaques; reducing, removing, or clearing amyloid plaques; improving cognition (e.g., improving any one or more of memory, language, awareness of time and place, and praxis) or reversing cognitive decline; sequestering soluble AB peptide circulating in biological fluids; reducing AB peptide (including soluble and deposited) in a tissue (e.g., the brain); inhibiting and/or reducing accumulation of AB peptide in the brain; inhibiting and/or reducing toxic effects of AB peptide in a tissue (e.g., the brain); decreasing brain atrophy; decreasing one or more symptoms resulting from the disease (e.g., abnormalities of memory, problem solving, language, calculation, visuospatial perception, judgment and/or behavior, inability to care for oneself, etc.); increasing the quality of life; decreasing the dose
  • a method of the invention reduces the severity of one or more symptoms associated with Alzheimer's disease by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving the treatment of the invention.
  • the invention also embraces treating, preventing, delaying the onset, and/or delaying the development of diseases or conditions for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • delay development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition and/or slowing the progression or altering the underlying disease process and/or course once it has developed.
  • This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that "delays" development of a disease or condition is a method that reduces the probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method, including stabilizing one or more symptoms resulting from the disease. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. Development of such diseases or conditions can be detected using standard clinical techniques, such as standard neurological examination, patient interview, neural imaging, detecting alterations of levels of specific proteins in the serum or cerebrospinal fluid, computerized tomography (CT), or magnetic resonance imaging (MRI). Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • an "at risk” individual is an individual who is at risk of developing a disease or condition.
  • An individual “at risk” of developing such a disease or condition may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein.
  • At risk denotes that an individual has one or more so- called risk factors, which are measurable parameters that correlate with development of diseases or conditions for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • An individual having one or more of those risk factors has a higher probability of developing such a disease or condition than an individual without those risk factor(s).
  • Risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (i.e., hereditary) considerations, and environmental exposure.
  • Individuals at risk for diseases or conditions include, e.g., those having relatives who have experienced the disease or condition, those whose risk is determined by analysis of genetic or biochemical markers, those with positive results in a blood test for any proteins present in blood plasma and/or cerebrospinal fluid (CSF) known to predict clinical disease, and the like.
  • CSF cerebrospinal fluid
  • individuals who are at risk of developing Alzheimer's disease include, e.g., those having relatives who have experienced the disease, those whose risk is determined by analysis of genetic or biochemical markers, those with positive results in a blood test for any signaling proteins present in blood plasma and/or cerebrospinal fluid ("CSF") known to predict clinical Alzheimer's diagnosis (see, e.g., S. Ray et al., "Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins," Nature Medicine, published online October 14, 2007), and individuals experiencing a loss of sense of smell.
  • CSF cerebrospinal fluid
  • Genetic markers of risk for Alzheimer's disease include mutations in the APP gene, particularly mutations at position 717 and positions 670 and 671, which are referred to as the Hardy and Swedish mutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997).
  • Other markers of risk are mutations in the presenilin genes (e.g., PSl or PS2), ApoE4 alleles, family history of Alzheimer's disease, hypercholesterolemia, and/or atherosclerosis.
  • non-neuronal indications or “non-neuronal disease or condition” refers to and intends diseases or conditions that are believed to involve, or be associated with, or do involve or are associated with non-neuronal cell death and/or impaired non-neuronal function or decreased non-neuronal function or a disease or condition involving degenerative disorders or trauma relating to non-neuronal cells.
  • non-neuronal cells include, but are not limited to, a skin cell, a hematopoietic cell, a smooth muscle cell, a cardiac cell, a cardiac muscle cell, a skeletal muscle cell, a bone cell, a cartilage cell, a pancreatic cell or an adipocyte.
  • Non-neuronal pathologies and conditions can also impact an individual's quality of life.
  • Exemplary non-neuronal indications include age- associated hair loss (alopecia), age-associated weight loss, age-associated vision disturbance (cataracts), heart disease, diabetes, anorexia, AIDS- or chemotherapy- associated wasting, vascular injury, intestinal injury, cartilage injury, osteoarthritis, bacterial infection, viral infection, a first-, second-, or third-degree burn, a simple, compound, stress, or compression fracture, or a laceration.
  • Treating non-neuronal diseases or conditions with the methods disclosed herein refers to treating certain aspects of such diseases that would benefit from activated, proliferated, or differentiated cells.
  • the methods, kits, and compositions disclosed herein would be used to induce multipotential stem cells to differentiate into cardiac myocytes, and the resulting cells could be used to repair damage to the heart muscle resulting from an MI by autologous transplantation.
  • the methods kits and compositions disclosed herein would be used to induce multipotential stem cells to differentiate into skin cells, and the resulting cells could be used to repair severe burns by skin grafts.
  • the compositions, methods, and kits described herein can be used to treat non-neuronal diseases or conditions producing degeneration or dysfunction of non-neuronal cell types.
  • compositions, methods and kits of the invention thus have a "cell protective effect" such that they reduce, eliminate, or prevent cell damage, including non-neuronal cell damage or degeneration.
  • non-neuronal cell degeneration may be caused by cell damage or dysfunction resulting from injury, including various types of trauma, changes caused by aging, or complications resulting therefrom.
  • neuronal indications or “neuronal disease or condition” refers to and intends diseases or conditions that are believed to involve, or be associated with, or do involve or are associated with neuronal cell death and/or impaired neuronal function or decreased neuronal function.
  • the compositions, methods, and kits described herein can be used to treat neuronal diseases or conditions producing neuronal degeneration, and frequently accompanied by deterioration of cognitive functions as well as neuronal damage, dysfunction, or complications characterized by neurological, neurodegenerative, physiological, psychological, or behavioral aberrations.
  • neuronal indications include neurodegenerative diseases, conditions, and disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI), injury -related mild cognitive impairment (MCI) resulting from battlefield injuries, post-concussion syndrome, posttraumatic stress disorder and adjuvant chemotherapy, traumatic brain injury, (TBI), neuronal death mediated ocular disorder, macular degeneration, age-related macular degeneration, autism, including autism spectrum disorder, Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cord injury, myasthenia gravis, Guillain
  • compositions, methods and kits of the invention thus have a "cell protective effect" such that they reduce, eliminate, or prevent cell damage, including neuronal cell damage or degeneration.
  • neuronal degeneration may be caused by central or peripheral nervous system damage or dysfunction resulting from injury, such as edema or other trauma, hypoxia or ischemia caused by stroke, cell death caused by epilepsy, spinal muscle atrophy, changes caused by aging, or complications resulting therefrom.
  • neuron represents a cell of ectodermal embryonic origin derived from any part of the nervous system of an animal.
  • Neurons express well-characterized neuron- specific markers, including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2, and class III tubulin. Included as neurons are, for example, hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory, sympathetic, septal cholinergic, and cerebellar neurons.
  • neurogenesis refers to the generation of new nerve cells from undifferentiated neuronal progenitor cells, also known as multipotential neuronal stem cells.
  • Neurogenesis actively produces new neurons, astrocytes, glia, Schwann cells, oligodendrocytes and other neural lineages. Much neurogenesis occurs early in human development, though it continues later in life, particularly in certain localized regions of the adult brain.
  • Multipotential neuronal stem cells the self-renewing, multipotent cells that generate the main phenotypes of the nervous system, have been isolated from various areas of the adult brain, including the hippocampus, the dentate gyrus, and the subventricular zone, and have also been isolated from areas not normally associated with neurogenesis, such as the spinal cord.
  • neural connectivity refers to the number, type, and quality of connections (“synapses”) between neurons in an organism. Synapses form between neurons, between neurons and muscles (a "neuromuscular junction"), and between neurons and other biological structures, including internal organs, endocrine glands, and the like. Synapses are specialized structures by which neurons transmit chemical or electrical signals to each other and to non-neuronal cells, muscles, tissues, and organs. Compounds that affect neural connectivity may do so by establishing new synapses (e.g., by neurite outgrowth or neurite activation) or by altering or remodeling existing synapses. Synaptic remodeling refers to changes in the quality, intensity or type of signal transmitted at particular synapses.
  • the term "purified cell” means a cell that has been separated from one or more components that are present when the cell is produced. In some embodiments, the cell is at least about 60%, by weight, free from other components that are present when the cell is produced. In various embodiments, the cell is at least about 75%, 90%, or 99%, by weight, pure.
  • a purified cell can be obtained, for example, by purification (e.g., extraction) from a natural source, fluorescence-activated cell-sorting, or other techniques known to the skilled artisan. Purity can be assayed by any appropriate method, such as fluorescence- activated cell- sorting. In some embodiments, the purified cell is incorporated into a pharmaceutical composition of the invention or used in a method of the invention. The pharmaceutical composition of the invention may have additives, carriers, or other components in addition to the purified cell.
  • multipotential stem cell refers to a cell that (i) has the potential of differentiating into at least two cell types and (ii) exhibits self-renewal, meaning that at a cell division, at least one of the two daughter cells will also be a stem cell.
  • the non-stem cell progeny of a single MSC are capable of differentiating into multiple cell types.
  • non-stem cell progeny of neuronal stem cells are capable of differentiating into neurons, astrocytes, Schwann cells, and oligodendrocytes.
  • non-stem cell progeny of non-neuronal stem cells have the potential to differentiate into other cell types, including non- neuronal cell types (e.g., a skin cell, a hematopoietic cell, a smooth muscle cell, a cardiac muscle cell, a skeletal muscle cell, a bone cell, a cartilage cell, a pancreatic cell or an adipocyte).
  • non- neuronal cell types e.g., a skin cell, a hematopoietic cell, a smooth muscle cell, a cardiac muscle cell, a skeletal muscle cell, a bone cell, a cartilage cell, a pancreatic cell or an adipocyte.
  • the stem cell is "multipotent" because its progeny have multiple differentiative pathways.
  • neuropathy refers to a disorder characterized by altered function and structure of motor, sensory, and autonomic neurons of the nervous system, initiated or caused by a primary lesion or other dysfunction of the nervous system.
  • the four cardinal patterns of peripheral neuropathy are polyneuropathy, mononeuropathy, mononeuritis multiplex and autonomic neuropathy.
  • the most common form is (symmetrical) peripheral polyneuropathy, which mainly affects the feet and legs.
  • a radiculopathy involves spinal nerve roots, but if peripheral nerves are also involved the term radiculoneuropathy is used.
  • the form of neuropathy may be further broken down by cause, or the size of predominant fiber involvement, i.e. large fiber or small fiber peripheral neuropathy.
  • Neuropathy may be associated with varying combinations of weakness, autonomic changes and sensory changes. Loss of muscle bulk or fasciculations, a particular fine twitching of muscle may be seen. Sensory symptoms encompass loss of sensation and "positive" phenomena including pain. Neuropathies are associated with a variety of disorders, including diabetes (i.e., diabetic neuropathy), fibromyalgia, multiple sclerosis, and herpes zoster infection, as well as with spinal cord injury and other types of nerve damage.
  • diabetes i.e., diabetic neuropathy
  • fibromyalgia fibromyalgia
  • multiple sclerosis sclerosis
  • herpes zoster infection as well as with spinal cord injury and other types of nerve damage.
  • geroprotective activity means a biological activity that slows down ageing and/or prolongs life and/or increases or improves the quality of life via a decrease in the amount and/or the level of intensity of pathologies or conditions that are not life-threatening but are associated with the aging process and which are typical for elderly people.
  • Pathologies or conditions that are not life-threatening but are associated with the aging process include such pathologies or conditions as loss of sight (cataract), deterioration of the dermatohairy integument (alopecia), and an age-associated decrease in weight due to the death of muscular and/or fatty cells.
  • neurodegenerative disease or condition As used herein, the term "neurodegenerative disease or condition" or
  • neurodegenerative indication includes diseases in which neuronal cells degenerate to bring about a deterioration of cognitive functions or result in damage, dysfunction, or complications that may be characterized by neurological, neurodegenerative, physiological, psychological, or behavioral aberrations.
  • diseases include Huntington's disease and related polyglutamine expansion diseases, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Down's syndrome, frontal lobe dementia (Pick's Disease), progressive supranuclear palsy (PSP), HIV-associated dementia, Le wy body disease, Menkes disease, Wilson disease, Creutzfeldt- Jakob disease, Fahr disease, canine cognitive dysfunction syndrome (CCDS).
  • the term "neurodegenerative disease or condition” excludes schizophrenia, bipolar disorder or psychosis, such as psychosis associated with any of those diseases or conditions.
  • Alzheimer's disease refers to a degenerative brain disorder characterized clinically by progressive memory deficits, confusion, behavioral problems, inability to care for oneself, gradual physical deterioration and, ultimately, death. Approximately 15 million people worldwide are affected by Alzheimer's disease, and the number is expected to increase dramatically as lifespans increase. Histologically, the disease is characterized by neuritic plaques, found primarily in the association cortex, limbic system and basal ganglia. The major constituent of these plaques is amyloid beta peptide (AB), which is the cleavage product of beta amyloid precursor protein (BAPP or APP).
  • AB amyloid beta peptide
  • APP is a type I transmembrane glycoprotein that contains a large ectopic N-terminal domain, a transmembrane domain and a small cytoplasmic C-terminal tail.
  • Alternative splicing of the transcript of the single APP gene on chromosome 21 results in several isoforms that differ in the number of amino acids.
  • AB appears to have a central role in the neuropathology of Alzheimer's disease. Familial forms of the disease have been linked to mutations in APP and the presenilin genes (Tanzi et al, 1996, Neurobiol. Dis., 3:159-168; Hardy, 1996, Ann. Med., 28:255-258).
  • Mitochondrial dysfunction has also been reported to be an important component of Alzheimer's disease (Bubber et al, Mitochondrial abnormalities in Alzheimer brain: Mechanistic Implications, Ann Neurol, 2005, 57(5), 695-703; Wang et al,. Insights into amyloid- ⁇ -induced mitochondrial dysfunction in Alzheimer disease, Free Radical Biology & Medicine, 2007, 43, 1569-1573; Swerdlow et al., Mitochondria in Alzheimer's disease, Int. Rev.
  • Huntington's disease refers to a fatal neurological disorder characterized clinically by symptoms such as involuntary movements, cognition impairment or loss of cognitive function and a wide spectrum of behavioral disorders. Common motor symptoms associated with Huntington's disease include chorea (involuntary writhing and spasming), clumsiness, and progressive loss of the abilities to walk, speak (e.g., exhibiting slurred speech) and swallow. Other symptoms of Huntington's disease can include cognitive symptoms such as loss of intellectual speed, attention and short-term memory and/or behavioral symptoms that can span the range of changes in personality, depression, irritability, emotional outbursts and apathy. Clinical symptoms typically appear in the fourth or fifth decade of life.
  • Huntington's disease is a devastating and often protracted illness, with death usually occurring approximately 10-20 years after the onset of symptoms.
  • Huntington's disease is inherited through a mutated or abnormal gene encoding an abnormal protein called the mutant huntingtin protein; the mutated huntingtin protein produces neuronal degeneration in many different regions of the brain.
  • the degeneration focuses on neurons located in the basal ganglia, structures deep within the brain that control many important functions including coordinating movement, and on neurons on the outer surface of the brain or cortex, which controls thought, perception and memory.
  • ALS myotrophic lateral sclerosis
  • ALS includes all of the classifications of ALS known in the art, including, but not limited to classical ALS (typically affecting both lower and upper motor neurons), Primary Lateral Sclerosis (PLS, typically affecting only the upper motor neurons), Progressive Bulbar Palsy (PBP or Bulbar Onset, a version of ALS that typically begins with difficulties swallowing, chewing and speaking), Progressive Muscular Atrophy (PMA, typically affecting only the lower motor neurons) and familial ALS (a genetic version of ALS).
  • classical ALS typically affecting both lower and upper motor neurons
  • PPS Primary Lateral Sclerosis
  • PBP or Bulbar Onset Progressive Bulbar Palsy
  • PMA Progressive Muscular Atrophy
  • familial ALS a genetic version of ALS
  • CCDS cancer cognitive dysfunction syndrome
  • canines such as dogs
  • Diagnosis of CCDS in canines, such as dogs is generally a diagnosis of exclusion, based on thorough behavior and medical histories and the presence of clinical symptoms of CCDS that are unrelated to other disease processes. Owner observation of age-related changes in behavior is a practical means used to detect the possible onset of CCDS in aging domestic dogs.
  • CCDS cardiovascular disease senor
  • Symptoms of CCDS include memory loss, which in domestic dogs may be manifested by disorientation and/or confusion, decreased or altered interaction with family members and/or greeting behavior, changes in sleep-wake cycle, decreased activity level, and loss of house training or frequent, inappropriate elimination.
  • a canine suffering from CCDS may exhibit one or more of the following clinical or behavioral symptoms: decreased appetite, decreased awareness of surroundings, decreased ability to recognize familiar places, people or other animals, decreased hearing, decreased ability to climb up and down stairs, decreased tolerance to being alone, development of compulsive behavior or repetitive behaviors or habits, circling, tremors or shaking, disorientation, decreased activity level, abnormal sleep wake cycles, loss of house training, decreased or altered responsiveness to family members, and decreased or altered greeting behavior.
  • CCDS can dramatically affect the health and well-being of an afflicted canine.
  • the companionship offered by a pet with CCDS can become less rewarding as the severity of the disease increases and its symptoms become more severe.
  • Parkinson's disease refers to any medical condition wherein an individual experiences one or more symptoms associated with Parkinson's disease, such as without limitation one or more of the following symptoms: rest tremor, cogwheel rigidity, bradykinesia, postural reflex impairment, good response to L-dopa treatment, the absence of prominent oculomotor palsy, cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia.
  • the present invention is utilized for the treatment of a dopaminergic dysfunction-related disorder.
  • the individual with Parkinson's disease has a mutation or polymorphism in a synuclein, parkin or NURRl nucleic acid that is associated with Parkinson's disease.
  • the individual with Parkinson's disease has defective or decreased expression of a nucleic acid or a mutation in a nucleic acid that regulates the development and/or survival of dopaminergic neurons.
  • neuroneuronal death-mediated ocular disease refers to an ocular disease in which death of the neuron is implicated in whole or in part.
  • the disease may involve death of photoreceptors.
  • the disease may involve retinal cell death.
  • the disease may involve ocular nerve death by apoptosis.
  • Particular neuronal death-mediated ocular diseases include but are not limited to macular degeneration, glaucoma, retinitis pigmentosa, congenital stationary night blindness (Oguchi disease), childhood onset severe retinal dystrophy, Leber congenital amaurosis, Bardet-Biedle syndrome, Usher syndrome, blindness from an optic neuropathy, Leber's hereditary optic neuropathy, color blindness and Hansen-Larson-Berg syndrome.
  • macular degeneration or "age-related macular degeneration” includes all forms and classifications of macular degeneration known in the art, including, but not limited to diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium.
  • the term thus encompasses disorders such as age-related macular degeneration (ARMD) as well as rarer, earlier-onset dystrophies that in some cases can be detected in the first decade of life.
  • AMD age-related macular degeneration
  • Other maculopathies include North Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt's disease, pattern dystrophy, Best disease, and Malattia Leventinese.
  • MCI cognitive impairment
  • a cognitive disorder characterized by a more pronounced deterioration in cognitive functions than is typical for normal age-related decline.
  • MCI is characterized by subtle, clinically manifest deficits in cognition, memory, and functioning, amongst other impairments, which are not of sufficient magnitude to fulfill criteria for diagnosis of Alzheimer's disease or other dementia.
  • MCI also encompasses injury-related MCI, defined herein as cognitive impairment resulting from certain types of injury, such as nerve injury (i.e., battlefield injuries, including post-concussion syndrome, post-traumatic stress disorder, and the like), neurotoxic treatment (i.e., adjuvant chemotherapy resulting in "chemo brain” and the like), and tissue damage resulting from physical injury, which is separate and distinct from mild cognitive impairment resulting from ischemic or hemorrhagic stroke, ischemia, hemorrhagic insult, blunt force trauma, and the like.
  • nerve injury i.e., battlefield injuries, including post-concussion syndrome, post-traumatic stress disorder, and the like
  • neurotoxic treatment i.e., adjuvant chemotherapy resulting in "chemo brain” and the like
  • tissue damage resulting from physical injury which is separate and distinct from mild cognitive impairment resulting from ischemic or hemorrhagic stroke, ischemia, hemorrhagic insult, blunt force trauma, and the like.
  • TBI traumatic brain injury
  • Symptoms of TBI can range from mild, moderate to severe and can significantly affect many cognitive (deficits of language and communication, information processing, memory, and perceptual skills), physical (ambulation, balance, coordination, fine motor skills, strength, and endurance), and psychological skills.
  • AAMI age-associated memory impairment
  • GDS stage 2 on the global deterioration scale (GDS) (Reisberg, et al. (1982) Am. J. Psychiatry 139: 1136-1139) which differentiates the aging process and progressive degenerative dementia in seven major stages.
  • the first stage of the GDS is one in which individuals at any age have neither subjective complaints of cognitive impairment nor objective evidence of impairment. These GDS stage 1 individuals are considered normal.
  • AAMI refers to persons in GDS stage 2, who may differ neurophysiologically from elderly persons who are normal and free of subjective complaints, i.e., GDS stage 1.
  • GDS stage 1 For example, AAMI subjects have been found to have more electrophysiologic slowing on a computer analyzed EEG than GDS stage 1 elderly persons (Prichep, John, Ferris, Reisberg, et al. (1994) Neurobiol. Aging 15: 85-90).
  • autism refers to a brain development disorder that impairs social interaction and communication and causes restricted and repetitive behavior, typically appearing during infancy or early childhood. The cognitive and behavioral defects are thought to result in part from altered neural connectivity. Autism encompasses related disorders sometimes referred to as “autism spectrum disorder,” as well as Asperger syndrome and Rett syndrome.
  • nerve injury refers to physical damage to nerves, such as avulsion injury (i.e., where a nerve or nerves have been torn or ripped) or spinal cord injury (i.e., damage to white matter or myelinated fiber tracts that carry sensation and motor signals to and from the brain).
  • Spinal cord injury can occur from many causes, including physical trauma (i.e., car accidents, sports injuries, and the like), tumors impinging on the spinal column, developmental disorders, such as spina bifida, and the like.
  • myasthenia gravis refers to a non-cognitive neuromuscular disorder caused by immune-mediated loss of acetylcholine receptors at neuromuscular junctions of skeletal muscle.
  • MG typically appears first as occasional muscle weakness in approximately two-thirds of patients, most commonly in the extraocular muscles. These initial symptoms eventually worsen, producing drooping eyelids (ptosis) and/or double vision (diplopia), often causing the patient to seek medical attention.
  • ptosis drooping eyelids
  • diplopia double vision
  • Generalized MG often affects muscles that control facial expression, chewing, talking, swallowing, and breathing; before recent advances in treatment, respiratory failure was the most common cause of death.
  • the term "Guillain-Barre syndrome” refers to a non-cognitive disorder in which the body's immune system attacks part of the peripheral nervous system.
  • the first symptoms of this disorder include varying degrees of weakness or tingling sensations in the legs.
  • the weakness and abnormal sensations spread to the arms and upper body. These symptoms can increase in intensity until certain muscles cannot be used at all and, when severe, the patient is almost totally paralyzed.
  • the disorder is life threatening - potentially interfering with breathing and, at times, with blood pressure or heart rate - and is considered a medical emergency.
  • MS multiple sclerosis
  • CNS central nervous system
  • MS central nervous system
  • It may cause numerous symptoms, many of which are non-cognitive, and often progresses to physical disability.
  • MS affects the areas of the brain and spinal cord known as the white matter.
  • White matter cells carry signals between the grey matter areas, where the processing is done, and the rest of the body. More specifically, MS destroys oligodendrocytes which are the cells responsible for creating and maintaining a fatty layer, known as the myelin sheath, which helps the neurons carry electrical signals.
  • MS results in a thinning or complete loss of myelin and, less frequently, the cutting (transection) of the neuron's extensions or axons.
  • myelin is lost, the neurons can no longer effectively conduct their electrical signals.
  • Almost any neurological symptom can accompany the disease.
  • MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms).
  • SPMS secondary-progressive MS
  • combination therapy is meant a first therapy that includes a compound of Formula I, II, or III (e.g., asenapine), or a pharmaceutically acceptable salt or solvate of the foregoing, in conjunction with a second therapy that includes one or more other compounds or pharmaceutically acceptable salts thereof (e.g., a hydrogenated pyrido [4,3- b]indole such as dimebon) or therapies (e.g., surgical procedures) useful for treating, preventing, delaying the onset, and/or delaying the development of indications that implicate cell death and/or decreased cell function.
  • the indications would benefit from the activation, differentiation, and/or proliferation of one or more cell types.
  • vascular endothelial cell growth factor refers to a VEGF protein or fragment thereof, such as any protein that results from alternate splicing of mRNA from a single, 8 exon, VEGF gene or homolog thereof.
  • the different VEGF splice variants are referred to by the number of amino acids they contain.
  • the isoforms are VEGF121, VEGF145, VEGF165, VEGF189 and VEGF206; the rodent orthologs of these proteins contain one less amino acid.
  • VEGF vascular endothelial growth factor receptors 6a, 6b and 7 of the VEGF gene. These domains have important functional consequences for the VEGF splice variants as they mediate interactions with heparan sulfate proteoglycans and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate the VEGF signaling receptors. VEGF exerts neuroprotective effects via its cell surface receptor FIk-I.
  • the amino acid sequence of the VEGF protein or protein fragment is at least or about 50%, 60%, 70%, 80%, 90%, 95% or 100% identical to that of the corresponding region of a human VEGF protein.
  • the VEGF fragment contains at least 25, 50, 75, 100, 150 or 200 contiguous amino acids from a full-length VEGF protein and has at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of an activity of a corresponding full-length VEGF protein.
  • trophic growth factor refers to a growth factor that inhibits or prevents cell death, promotes cell survival, and/or enhances cell function (e.g., neurite outgrowth or neurogenesis).
  • trophic growth factors include IGF-I, fibroblast growth factor (FGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), granulocyte colony stimulating factor (G-CSF), granulocyte-macrocyte colony stimulating factor (GM-CSF), neurotrophin-3, glial derived neurotrophic factor (GDNF), epidermal growth factor (EGF) or TGFa and mimics and fragments thereof.
  • the amino acid sequence of a trophic growth factor or fragment thereof is at least 50%, 60%, 70%, 80%, 90%, 95% or 100% identical to that of the corresponding region of a human growth factor.
  • the growth factor fragment contains at least 25, 50, 75, 100, 150 or 200 contiguous amino acids from a full-length growth factor and has at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of an activity of a corresponding full-length growth factor. Examples of other trophic growth factors are described herein, including IGF-I, FGF, NGF, BDNF, GCS-F, GMCS-F, mimics and fragments thereof.
  • the growth factor fragment contains at least 25, 50, 75, 100, 150 or 200 contiguous amino acids from a full-length growth factor and has at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of an activity of a corresponding full-length growth factor.
  • hypooxia inducible factor (HIF) activator refers to a compound that increases an activity of a HIF.
  • HIFs are transcription factors that respond to changes in available oxygen in the cellular environment, such as decreases in oxygen or hypoxia.
  • the activator increases an activity of a HIF by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or more as compared to the corresponding activity in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the combination therapy.
  • HIF prolyl 4-hydroxylase inhibitor is meant a compound that reduces or eliminates an activity of a HIF prolyl 4-hydroxylase.
  • the alpha subunit of HIF-I is a target for prolyl hydroxylation by HIF prolyl-hydroxylase, which makes HIF-I alpha a target for degradation by the E3 ubiquitin ligase complex.
  • the inhibitor reduces an activity of a HIF prolyl 4-hydroxylase by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the combination therapy.
  • anti-apoptotic compound or "anti-cell death compound” refers to a compound that reduces or eliminates cell death or programmed cell death.
  • the compound reduces cell death or programmed cell death (e.g., neuronal cell death in the brain or a region of the brain) by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding cell death or programmed cell death in the same subject prior to treatment or compared to the corresponding cell death in other subjects not receiving the combination therapy.
  • anti-apoptotic or anti-cell death compounds include IAP proteins, Bcl-2 proteins, Bcl-X L , Trk receptors, Akt, PI3 kinase, Gab, Mek, E1B55K, Raf, Ras, PKC, PLC, FRS2, rAPs/SH2B, Np73, fragments thereof, and mimics thereof.
  • an effective amount refers to an amount of a compound (e.g., asenapine), which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist, should be effective in a given therapeutic form.
  • an effective amount may be in one or more doses because a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • an effective dosage may be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, e.g., a hydrogenated pyrido[4,3-b]indole such as dimebon, a desirable or beneficial result may be or is achieved.
  • a combination therapy of the invention may involve administration of compounds sequentially, simultaneously, or continuously using the same or different routes of administration for each compound.
  • an effective amount of a combination therapy includes an amount of the first therapy and an amount of the second therapy that when administered sequentially, simultaneously, or continuously produces a desired outcome. Suitable doses of any of the coadministered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • treatment with the combination of the first and second therapies may result in an additive or even synergistic (e.g., greater than additive) result compared to administration of either therapy alone.
  • a smaller amount of each pharmaceutically active compound is used as part of a combination therapy compared to the amount generally used for individual therapy.
  • the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual therapies alone.
  • the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of a pharmaceutically active compound in a combination therapy than the amount generally used for individual therapy.
  • the use of a small amount of pharmaceutically active compound results in a reduction in the number, severity, frequency, or duration of one or more side-effects associated with the compound.
  • unit dosage form refers to a pharmaceutical formulation that contains a predetermined dose of a compound of Formula I, II, or III (e.g., asenapine) in an amount sufficient to treat, prevent, delay the onset, and/or delay the development of an indication that implicates cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types.
  • a unit dosage form may also contain a predetermined dose of any combination therapy as described herein, such as a predetermined dose of a compound of Formula I, II, or III, or pharmaceutically acceptable salt thereof, and a predetermined dose of a hydrogenated pyrido [4,3 -b] indole such as dimebon.
  • a “therapeutically effective amount” refers to an amount of a compound sufficient to produce a desired therapeutic outcome (e.g., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of a neurodegenerative disease or condition).
  • beneficial or desired results include, but are not limited to, for example, clinical results such as improving cognition or reversing cognitive decline; decreasing one or more symptoms resulting from the disease (biochemical, histologic and/or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disease; increasing the quality of life of those suffering from the disease; decreasing the dose of other medications required to treat the disease; enhancing effect of another medication; delaying the progression of the disease and/or prolonging survival of patients; and other results noted herein.
  • desired therapeutic outcomes include inhibiting or suppressing the formation of amyloid plaques; reducing, removing, or clearing amyloid plaques; and/or sequestering soluble AB peptide circulating in biological fluids.
  • a “prophylactically effective amount” refers to an amount of a compound sufficient to prevent or reduce the severity of one or more future symptoms of an indication that implicates cell death and/or decreased cell function and/or conditions that would benefit from the activation, differentiation, and/or proliferation of one or more cell types when administered to an individual who is susceptible and/or who may develop such an indication.
  • beneficial or desired results include, but are not limited to, for example, results such as eliminating or reducing the risk of the disease and lessening the severity or delaying the onset of the disease, including biochemical, histologic, and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease.
  • spontaneous administration means that a first therapy and a second or subsequent therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes.
  • the first and second therapies may be contained in the same composition (e.g., a composition comprising both a compound of Formula I, II, or III and a growth factor and/or an anti-cell death compound, or a composition comprising both asenapine and dimebon) or in separate compositions (e.g., a compound of Formula I, II, or III is contained in one composition and a growth factor and/or an anti-cell death compound is contained in another composition, or asenapine is contained in one composition and dimebon is contained in another composition).
  • a composition comprising both a compound of Formula I, II, or III and a growth factor and/or an anti-cell death compound, or a composition comprising both asenapine and dimebon
  • a compound of Formula I, II, or III is contained in one composition and a growth factor and/or an anti-cell death compound is contained in another composition
  • asenapine is contained in one composition and dimebon is contained in another composition
  • the term "sequential administration" means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, or 60 minutes, or more than about any of 1 hour to about 24 hours, about 1 hour to about 48 hours, about 1 day to about 7 days, about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 month to about 3 months, or about 1 month to about 6 months.
  • Either the first therapy or the second therapy may be administered first.
  • the first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.
  • the invention embraces the sequential administration of all combinations described herein, such as those described in the preceding paragraph.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable.
  • the pharmaceutically acceptable material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • alkyl refers to and includes saturated hydrocarbon substituents that are either unbranched or branched. Alkyl groups may have 1 to 6 carbon atoms (“C 1 -C 6 alkyl”), or 1 to 4 carbon atoms (“Ci-C 4 alkyl”). When an alkyl group is indicated, all isomers having that number of carbon atoms are intended; thus, for example, “butyl” includes re- butyl, sec-butyl, isobutyl, and tert-butyl, and "propyl” includes re-propyl and isopropyl.
  • alkyl is further exemplified by groups such as methyl, ethyl, neopentyl, tert-pentyl, n- heptyl, octyl, and the like.
  • aralkyl refers to a substituent in which an aryl (e.g., phenyl, naphthalenyl, azulenyl, etc.) moiety is attached to an alkyl moiety. In most cases, an aralkyl group is attached to a parent structure via the alkyl moiety.
  • Aralkyl groups may have 7 to 10 carbon atoms ("C 7 -C 1 O aralkyl").
  • Aralkyl groups, particularly C7-C10 aralkyl groups include benzyl, phenylethyl, phenylpropyl, and 1-methylphenylethyl.
  • alkoxy refers to and includes the group -O-alkyl. Alkoxy groups may have 1 to 6 carbon atoms ("C 1 -C 6 alkoxy”), or 1 to 4 carbon atoms ("Ci-C 4 alkoxy"). As with an alkyl group, when an alkoxy group is indicated, all isomers having that number of carbon atoms are intended. Alkoxy includes, by way of example, methoxy, ethoxy, w-propoxy, isopropoxy, w-butoxy, tert-butoxy, sec-butoxy, w-pentoxy, w-hexoxy, 1 ,2- dimethylbutoxy, and the like.
  • alkylthio refers to and includes the group -S-alkyl. Alkylthio groups may have 1 to 6 carbon atoms ("C 1 -C 6 alkylthio"), or 1 to 4 carbon atoms ("C 1 - C 4 alkylthio "). As with an alkyl group, when an alkylthio group is indicated, all isomers having that number of carbon atoms are intended.
  • Alkylthio includes, by way of example, methylthio, ethylthio, w-propylthio, isopropylthio, w-butylthio, tert-butylthio, sec-butylthio, w-pentylthio, n- hexylthio, 3-methylpentan-2-ylthio, and the like.
  • halo refers to and includes substituents from Group 17 of the Periodic Table of Elements.
  • halo groups include, for example, fluoro, chloro, bromo, and iodo.
  • salt or “pharmaceutically acceptable salt” refer to an acid addition salt, a base addition salt, or a quaternary ammonium salt of a compound of the invention.
  • the invention embraces uses of a compound of Formula I, II, or III (e.g., asenapine) in the methods, combination therapies, formulations, kits and other inventions disclosed herein.
  • a compound of Formula I, II, or III e.g., asenapine
  • Compounds for use in the methods, combination therapies, formulations and kits and other inventions described herein include a compound of Formula I, II, or III (e.g., asenapine), or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) of the foregoing.
  • a compound of Formula I, II, or III e.g., asenapine
  • a pharmaceutically acceptable salt thereof e.g., asenapine
  • a solvate e.g., hydrate
  • the invention employs a compound of Formula I:
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, and trifluoromethyl;
  • R5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C7-C10 ar alkyl; m is 1 or 2;
  • X is selected from the group consisting of -O-, -S-, -N(R 6 )-, and -CH 2 -;
  • Re is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or an N-oxide, a pharmaceutically acceptable salt of the foregoing, or a solvate of any of the proceeding. Accordingly, the invention embraces uses of a compound of Formula I, wherein in one variation, the compound is the N-oxide variant shown as Formula Ia:
  • the invention embraces uses of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing, wherein the compound is not the N- oxide variant.
  • the invention thus embraces methods of treating neuronal and non-neuronal indications in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the invention employs a compound of Formula II,
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, and trifluoromethyl;
  • R5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C7-C10 ar alkyl; or an N-oxide, a pharmaceutically acceptable salt of the foregoing, or a solvate of any of the proceeding. Accordingly, the invention embraces uses of a compound of Formula II, wherein in one variation, the compound is the N-oxide variant of Formula Ha:
  • the invention embraces uses of a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing, wherein the compound is not the N- oxide variant.
  • the invention thus embraces methods of treating neuronal and non-neuronal indications in a subject in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the invention employs a compound of
  • the invention employs the compound asenapine or a pharmaceutically acceptable salt thereof, such as the maleate salt.
  • Pharmaceutically acceptable acid addition salts according to the invention are contemplated and may be prepared by reacting a pharmaceutically acceptable acid with a free base compound of Formulas I- III (e.g., asenapine). Different ratios of the pharmaceutically acceptable acid may be used with the free base compound of Formulas I-III (e.g., asenapine) depending upon the desired salt.
  • a sulfate or bisulfate compound of Formulas I-III e.g., asenapine
  • Some pharmaceutically acceptable acids suitable for use in preparing salts of compounds of Formulas I-III include, but are not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, or benzoic acid.
  • salts of compounds of Formulas I-III formed using the foregoing pharmaceutically acceptable acids include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, methanesulfonate ("mesylate”), ethane sulfonate (“esylate”), p-toluenesulfonate (“tosylate”), acetate, propionate, glycolate, maleate, malonate, succinate, tartrate, citrate, ascorbate, salicylate, or benzoate salts.
  • Pharmaceutically acceptable base addition salts are contemplated and may be prepared by reacting a pharmaceutically acceptable base with a compound of Formula I, II, or III, wherein the compound of Formula I, or II has an acidic functional group (e.g., when one or more of R 1 , R 2 , R 3 , and R 4 are hydroxy).
  • acid addition salts different ratios of the pharmaceutically acceptable base may be used with the compound of Formula I, II, or III depending upon the desired salt of Formula I, II, or III.
  • salts such alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, and ammonium salts may be formed from compounds of Formula I, II, or III.
  • Organic amines such as benzathine (N 5 N'- dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-l,3-propa-nediol), and procaine may also be used in certain embodiments.
  • benzathine N 5 N'- dibenzylethylenediamine
  • choline diethanolamine
  • ethylenediamine meglumine (N- methylglucamine)
  • benethamine N-benzylphenethylamine
  • Quaternary ammonium salts are also embraced by the invention and may be obtained by reacting a compound of Formulas I-III (e.g., asenapine) with an alkyl halide (e.g., methyl iodide, methyl bromide, methyl chloride) or alkyl pseudohalide (e.g., methyl tosylate, methyl mesylate, methyl triflate).
  • a compound of Formulas I-III e.g., asenapine
  • an alkyl halide e.g., methyl iodide, methyl bromide, methyl chloride
  • alkyl pseudohalide e.g., methyl tosylate, methyl mesylate, methyl triflate
  • N-oxides of compounds of Formula I-III may be obtained by oxidation of a free base compound of Formulas I-III (e.g., asenapine) with an inorganic oxidant (e.g., hydrogen peroxide, Oxone®) or an organic peroxide (e.g., m-chloroperoxybenzoic acid, mono magnesium perphthalate).
  • an inorganic oxidant e.g., hydrogen peroxide, Oxone®
  • an organic peroxide e.g., m-chloroperoxybenzoic acid, mono magnesium perphthalate
  • compositions of compounds of Formulas I-III may be employed.
  • the invention may employ a solvate of a compound of the invention or a pharmaceutically acceptable salt thereof, such as a solvate of the compound asenapine.
  • the invention may employ a hydrate of a pharmaceutically acceptable salt of any of Formulas I-III (e.g., asenapine). Suitable solvates are known in the art and include but are not limited to hydrates.
  • a compound of Formulas any of I-III (e.g., asenapine) has at least two stereogenic centers.
  • a compound of any of Formulas I-III may exist in as many as four stereoisomeric forms (e.g., enantiomers, diastereomers, meso compounds, etc.); however, it is understood by a person having ordinary skill in the art that, depending on substitution, particularly if a substituent has a stereogenic center, a compound of Formula I, II, or III may exist in more than four stereoisomeric forms.
  • Compounds of Formulas I-III are trans when the compounds have an S, S or R,R configuration (in accordance with Cahn-Ingold-Prelog priority rules).
  • Compounds of Formulas I-III are cis when the compounds have an S,R or R,S configuration.
  • the invention embraces use of compounds of the formulae detailed herein in substantially pure stereochemical forms or as mixtures of stereochemical forms.
  • a composition of the invention may comprise a compound of Formulas I-III (e.g., asenapine) in substantially pure form, such as a composition of substantially pure enantiomer, diastereomer, or meso compound.
  • a composition of substantially pure compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% impurities comprising the compound in a different stereoisomeric form.
  • a composition of substantially pure enantiomer means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the other enantiomer or another diastereomer or another compound.
  • a composition of the invention may comprise a mixture of stereoisomeric forms, wherein the mixture may comprise enantiomers, diastereomers, meso compounds, or the like, in equal or unequal amounts.
  • a composition may comprise a mixture of 2, 3, or 4 such stereoisomers in any ratio. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted.
  • the compounds of Formulas I-III may be prepared by any of the methods known in the art. Exemplary preparations of the compounds of Formulas I-III are described in US 4145434, US 2005/0209250, and US 2006/0084692, which are incorporated herein by reference in their entireties and specifically with respect to methods of making compounds of Formula I-III, including but not limited to asenapine. [0095] For instance, compounds of Formulas I-III may be readily prepared by reduction of compounds of Formula IV:
  • amide functionality of compounds of Formula IV may be reduced in accordance with any method known to a person having ordinary skill in the art.
  • Diisobutylaluminum hydride, lithium borohydride, sodium trimethoxyborohydride, and lithium aluminum hydride are suitable examples of metal hydrides that may be used to reduce the amide functionality of compounds of Formula IV.
  • a double-bond, if present in a compound of Formula IV, may be reduced prior to reducing the amide functionality. This may be preferable as metal hydride reduction of an a, ⁇ - unsaturated amide of Formula IV may yield partially reduced products; that is, the product compound of Formulas I-III may be contaminated with an analogous compound having an 3a, 12b double -bond.
  • Suitable methods for reducing a double-bond of an a, ⁇ -unsaturated amide prior to reducing the amide functionality include catalytic hydrogenation (e.g., PtO 2 ZH 2 ), treatment with magnesium in alcohol (e.g., methanol), and Birch reduction (e.g., Na(s) in NH 3 (I)).
  • a double-bond, if present in a compound of Formula IV, may be conveniently reduced together with the amide functionality.
  • diborane alkali metals such as sodium (e.g., sodium in alcohol), or lithium aluminum hydride together with and aluminum halide (e., AlCl 3 ) may be used.
  • the enamine functionality of compounds of Formula V may be reduced in accordance with any method known to a person having ordinary skill in the art.
  • Sodium borohydride, lithium borohydride, formic acid, catalytic hydrogenation (e.g., PtO 2 ZH 2 ), and Birch reduction are some suitable examples of reagents and methods that may be used to reduce the enamine functionality of compounds of Formula V.
  • X, R 1 , R 2 , R 3 , R 4 , and R 5 are as previously described and B " represents an anion such as a halide, tosylate, sulphate, phosphate, acetate, propionate, etc.
  • An alkali metal ⁇ e.g., Na(s)
  • a suitable solvent e.g., an alcohol such as methanol, ethanol, or isopropanol
  • an alcohol such as methanol, ethanol, or isopropanol
  • Table 1 lists compounds that may be prepared in accordance with the methodology described above and used in the methods of treating, preventing, and/or delaying the onset or development of neuronal and non-neuronal indications for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial as described herein.
  • Listing of compounds in more than one stereochemical form separated by "and/or” indicates that such compounds may be used as a mixture of stereochemical forms in any ratio (e.g., 50:50) or as substantially pure compounds.
  • stereochemical form e.g., 2,3,3a,12b-tetrahydro-lH-dibenz[2,3;6,7]oxepino[4,5-c]pyrrole
  • a mixture of stereochemical forms e.g., a racemic mixture, or a mixture of diastereomers in any ratio
  • a substantially pure stereoisomeric form e.g., a single diasteriomer or a single enantiomer. described herein.
  • any of the methods described herein may employ (i) a compound of Formula I, II, or III and/or a cell and (ii) one or more second or additional/subsequent therapies, including a hydrogenated pyrido[4,3-b]indole such as dimebon (2,8-dimethyl-5-[2-(6- methylpyridin-3-yl)ethyl]-3,4-dihydro-lH-pyrido[4,3-b]indole), or a pharmaceutically acceptable salt thereof or solvate of the foregoing and/or one or more growth factors, anti-cell death compounds, and/or any other compounds for use in a second or additional therapy as disclosed in WO2008/051599 which is incorporated herein by reference.
  • a hydrogenated pyrido[4,3-b]indole such as dimebon (2,8-dimethyl-5-[2-(6- methylpyridin-3-yl)ethyl]-3,4-d
  • dimebon dihydrochloride dimebon -2HCL
  • Methods of making dimebon are known.
  • Dimebon may also be made by methods detailed in PCT Application No. PCT/US2009/035992, which is incorporated herein by reference in its entirety and specifically with respect to methods of making dimebon.
  • Compounds for use in the methods, compositions, and kits described herein may include growth factors (e.g., vascular endothelial cell growth factors and/or trophic growth factors), fragments thereof, and compounds that mimic their effect.
  • growth factors include NT-3, NT-4/5, HGF, CNTF, TGF-alpha, TGF-beta family members, neurotrophin-3, PDGF, GDNF (glial-derived neurotrophic factor), EGF family members, IGF, insulin, BMPs, Wnts, hedgehogs, heregulins, fragments thereof, and mimics thereof.
  • Compounds for use in the methods, compositions, and kits described herein may include vascular endothelial cell growth factors (VEGF), fragments thereof, and/or compound that mimic their effect.
  • VEGF molecules include VEGF 121, VEGF 145, VEGF 165, VEGF189, VEGF206, other gene isoforms and fragments thereof (Sun F.Y., Guo X., "Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor," J. Neurosci. Res., 2005, 79(1-2): 180-4).
  • the VEGF fragment contains at least 25, 50, 75, 100, 150 or 200 contiguous amino acids from a full-length VEGF protein and has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of an activity of a corresponding full-length VEGF protein.
  • Compounds for use in the methods, compositions, and kits described herein may include trophic growth factors ⁇ e.g., IGF-I, FGF (acidic and basic), NGF, BDNF, GCS-F and/or GMCS-F), fragments thereof, and compounds that mimic their effect.
  • trophic growth factors e.g., IGF-I, FGF (acidic and basic), NGF, BDNF, GCS-F and/or GMCS-F
  • GCS-F and GMCS-F stimulate new neuron growth. Because trophic growth factors may stimulate cell growth, they are expected to improve, stabilize, eliminate, delay, or prevent a disease or condition or which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the combination of hydrogenated pyrido[4,3-b]indole such as dimebon and a trophic growth factor may reduce the apoptosis rate that is seen with new cell growth stimulation.
  • An exemplary compound that mimics the effects of nerve growth factor is Xaliproden (Sanofi-Aventis) [SR 57746A, xaliprodene; Xaprila].
  • anti-cell death compounds e.g., anti-apoptotic compounds
  • anti-cell death compounds include anti-apoptotic compounds, such as IAP proteins, Bcl-2 proteins, BCI-X L , Trk receptors, Akt, PB kinase, Gab, Mek, E1B55K, Raf, Ras, PKC, PLC, FRS2, rAPs/SH2B, Np73, fragments thereof, and mimics thereof.
  • the second therapy of a combination therapy is any one or more of the following: an agent (e.g., a compound) that increases the amount or activity of acetylcholine (e.g., an acetylcholinesterase inhibitor, a butyrylcholinesterase inhibitor or an acetylcholine receptor agonist), a NMDA receptor antagonist, an inhibitor of amyloid AB peptide or amyloid plaque, a phosphodiesterase 5 (PDE5) inhibitor, a phosphodiesterase 4 (PDE4) inhibitor, a monoamine oxidase inhibitor, a VEGF protein, a trophic growth factor, a HIF activator, a HIF prolyl 4-hydroxylase inhibitor, an anti-apoptotic compound or anti-cell death compound, an ADNP agonist or analog, an ADNF agonist or analog, an activator of an AMPA-type glutamate receptor, a serotonin 5-HT1A receptor agonist, a serotonin
  • an agent e.
  • the second therapy may be an acetylcholinesterase inhibitor such as (a) donepezil (2-[(l-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-l-one) or a pharmaceutically acceptable salt thereof, such as donepezil hydrochloride marketed under the name Aricept ® ; (b) rivastigmine or a pharmaceutically acceptable salt thereof, such as rivastigmine tartrate marketed under the name Exelon ® , or (c) galantamine or a pharmaceutically acceptable salt thereof, such as galantamine hydrobromide marketed under the name Razadyne ® .
  • donepezil (2-[(l-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-l-one
  • a pharmaceutically acceptable salt thereof such as donepezil hydrochloride marketed under the name Aricept ®
  • the second therapy may be an NMDA receptor antagonist such as memantine or a pharmaceutically acceptable salt thereof, such as memantine hydrochloride marketed under the name Namenda ® .
  • the second therapy comprises the compound risperidone. It is recognized that the compounds Aricept ® , Exelan ® , Razadyne ® and Namenda ® as used herein may be the same as or bioequivalent to the compounds marketed under the names Aricept ® , Exelan ® , Razadyne ® and Namenda ® and which received U.S. FDA market approval.
  • Exemplary AChE inhibitors include Aricept ® (donepezil), Exelon ® (rivastigmine tartrate), Razadyne ® (Reminyl, galantamine), ladostigil and Tacrine ® (Cognex, 9- amino-l,2,3,4-tetrahydroacridine hydrochloride).
  • Exemplary BChE inhibitors include Exelon ® (rivastigmine tartrate) and cymserine analogs, such as (-)-N 1 -phenethylnorcymserine (PEC) and O- ⁇ -bisnorcymserine (BNC).
  • An exemplary acetylcholine receptor agonist is TC- 1734 (Targacept), which is an orally active neuronal nicotinic acetylcholine receptor agonist with antidepressant, neuroprotective and long-lasting cognitive effects.
  • NMDA receptor antagonists include Memantine (Namenda ® sold by Forest, Axura ® sold by Merz, Akatinol ® sold by Merz, Ebixa ® sold by Lundbeck), Neramexane (Forest Labs), Amantadine, AP5 (2-amino-5- phosphonopentanoate, APV), Dextrorphan, Ketamine, MK-801 (dizocilpine), Phencyclidine, Riluzole and 7-chlorokynurenate.
  • Exemplary inhibitor of amyloid AB peptide or amyloid plaque include 3-amino-l-propanesulfonic acid (Tramiprosate, AlzhemedTM) by Neurochem (Gervais et al., "Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis," Neurobiol Aging, May 1, 2006), PosiphenTM (Axonyx), Flurizan (Myriad), Kiacta or Fibrillex (NC-503, Eprodisate disodium, sodiuml,3-propanedisulfonate, 1,3-propanedisulphonic acid, 1,3-PDS), PBT-2 (Prana), Memryte (leuprolide) (Voyager), AN- 1792 (Elan/Wyeth), AAB-OOl (Elan/Wyeth), and ACC-001 (Elan/Wyeth).
  • Exemplary PDE5 inhibitors are l-[[3-(6,7-dihydro- l-methyl-7-oxo-3-propyl-lHpyrazolo[4,3- ⁇ i]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4- methylpiperazine citrate (sildenafil, Viagra ® , sold by Pfizer), (6R-trans)-6-(l,3-benzodioxol-5- yl)- 2,3,6,7, 12, 12a-hexahydro-2-methyl-pyrazino [I 1 , 2':1,6] pyrido [3, 4-b] indole- 1,4-dione (tadalafil, Cialis ® , sold by LillylCOS), Levitra ® (vardenafil, sold by Bayer Pharmaceutical and Glaxo-Smith-Kline-Beecham/Schering Plough) and zaprinast (Nakamizo
  • An exemplary monoamine oxidase inhibitor is 5- (N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline (also referred to as M30), isocarboxazid (Marplan), moclobemide (Aurorix, Manerix, Moclodura ® ), phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Selegiline, Eldepryl), emsam, nialamide, iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida), iproclozide, ladostigil and toloxatone.
  • An exemplary ADNP analog is AL- 108 (Allon), which is an intranasally formulated eight amino acid neuroprotective peptide analog of ADNP.
  • An exemplary ADNF peptide agonist is AL-208 (Allon), which is a nine amino acid peptide, Ser-Ala-Leu-Leu-Arg- Ser-Ile-Pro-Ala (SALLRSIPA), with neuroprotective activity.
  • CX717 (Cortex) and CX516 (Cortex) are exemplary positive modulators of the AMPA-type glutamate receptor.
  • Xaliproden (Sanofi-Aventis) [SR 57746A, xaliprodene; Xaprila] is an exemplary serotonin 5-HT1A receptor agonist that also mimics the effects of nerve growth factor.
  • Lecozotan (SRA-333, Wyeth) is an exemplary selective serotonin IA receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.
  • An exemplary nicotinic alpha-7 receptor agonist includes MEM 3454 (Memory Pharma), which is a partial agonist of the nicotinic alpha-7 receptor.
  • An exemplary neuronal L-type calcium channel modulator includes MEM 1003 (Memory Pharma).
  • An exemplary 5-HT4 receptor agonist includes PRX-03140 (Predix), which is a highly selective, small-molecule agonist.
  • An exemplary anti-inflammatory agent includes VP-025 (Vasogen), which is a bilayered phospholipid microparticle that interacts with macrophages and other cells of the immune system, eliciting an anti-inflammatory response.
  • the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of neuronal and non-neuronal indications in mammals, such as humans.
  • the compounds described herein may also be used to treat, prevent, delay the onset and/or delay the development of neuronal and non-neuronal indications for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial in mammals, such as humans.
  • the present invention provides a variety of methods, such as those described in the "Brief Summary of the Invention" and elsewhere in this disclosure.
  • the methods of the invention can employ any of the compounds described herein (e.g., any of the compounds of Formula I, II, or III, including but not limited to the compounds listed in Table 1).
  • the invention provides methods for treating, preventing, delaying the onset, and/or delaying the development of neuronal and non-neuronal indications.
  • the neuronal and non-neuronal indications are those for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • Exemplary diseases and conditions include diseases and conditions that are believed to involve or be associated with, or involve or are associated with, one or more of the following: cell death, cell injury, cell loss, impaired or decreased cell function, impaired or decreased cell proliferation, or impaired or decreased cell differentiation, where the cell may be any cell type, including the specific cell types described herein.
  • the disease or condition may be one in which the activation, differentiation, and/or proliferation of cells such as neuronal stem cells or neurons or non-neuronal cells is expected to be or is beneficial.
  • Some exemplary cell types include any stem cell (such as any self-renewing, multipotential cell).
  • Other exemplary cell types including but not limited to those described below under the heading "Exemplary Cells and Methods" may be modulated using the therapies and methods of the invention.
  • the invention embraces treating, preventing, delaying the onset, and/or delaying the development of a neuronal or non-neuronal indication that is believed to or does involve cell death, cell injury, cell loss, impaired or decreased cell function, impaired or decreased cell proliferation, or impaired or decreased cell differentiation, where the cell may be any specific cell type described herein.
  • the invention also provides methods of stimulating neurite outgrowth and/or enhancing neurogenesis in an individual comprising treating the individual with an amount of a therapeutic compound of Formulas I- III or a pharmaceutically acceptable salt thereof effective to stimulate neurite outgrowth and/or to enhance neurogenesis.
  • a therapeutic compound of Formulas I- III or pharmaceutically acceptable salt thereof is asenapine.
  • the invention also provides methods of activating a cell, promoting the differentiation of a cell, and/or promoting the proliferation of a cell by incubating the cell with one or more compounds of Formula I, II, or III, or pharmaceutically acceptable salts thereof.
  • the cell is also incubated with one or more growth factors and/or anti-cell death compounds.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the neuronal or non-neuronal indication includes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis. In another variation, the neuronal or non-neuronal indication excludes schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • the invention also provides methods for treating, preventing, delaying the onset, and/or delaying the development of Alzheimer's disease.
  • activation, differentiation, and/or proliferation of one or more cell types is beneficial for treating, preventing, delaying the onset, and/or delaying the development of Alzheimer' s disease.
  • Neuronal indications include diseases or conditions that are believed to involve, or be associated with, or do involve or are associated with neuronal cell death and/or impaired neuronal function or decreased neuronal function. Such diseases or conditions frequently produce neuronal degeneration accompanied by deterioration of cognitive functions as well as neuronal damage, dysfunction, or complications characterized by neurological, neurodegenerative, physiological, psychological, or behavioral aberrations.
  • Non- neuronal indications include diseases or conditions that are believed to involve, or be associated with, or do involve or are associated with non-neuronal cell death and/or impaired non-neuronal function or decreased non-neuronal function or a disease or condition involving degenerative disorders or trauma relating to non-neuronal cells.
  • non-neuronal cells include, but are not limited to, a skin cell, a hematopoietic cell, a smooth muscle cell, a cardiac cell, a cardiac muscle cell, a skeletal muscle cell, a bone cell, a cartilage cell, a pancreatic cell or an adipocyte.
  • Non-neuronal pathologies and conditions, including those sometimes associated with age, can severely impact an individual's quality of life.
  • neuronal indications include, but are not limited to, neurodegenerative diseases and disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI) resulting from battlefield injuries, post-concussion syndrome, posttraumatic stress disorder and adjuvant chemotherapy, traumatic brain injury, (TBI), neuronal death mediated ocular disorder, macular degeneration, age-related macular degeneration, autism, including autism spectrum disorder, Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cord injury, myasthenia
  • Exemplary non- neuronal indications include age-associated hair loss (alopecia), age-associated weight loss, age- associated vision disturbance (cataracts), heart disease, diabetes, anorexia, AIDS- or chemotherapy-associated wasting, vascular injury, intestinal injury, cartilage injury, osteoarthritis, bacterial infection, viral infection, a first-, second-, or third-degree burn, a simple, compound, stress, or compression fracture, or a laceration.
  • the methods of the invention are used to treat, prevent, delay the onset, and/or delay the development of neuronal indications.
  • compositions that inhibit neuronal death, maintain neuronal phenotype, repair neuronal damage, promote the proliferation of neurons, promote the differentiation of neurons, promote the activation of neurons (such as neurite outgrowth) or any combination of two or more of the foregoing are desirable.
  • Injury-induced expression of neurotrophic factors and corresponding receptors may play an important role in the ability of nerve regeneration. Neurotrophins like GDNF (Hiwasa et al. , Neurosci. Letts. 238:115-118, 1997; Nakajima et al, Brain Res.
  • Neurite outgrowth is a process by which neurons achieve connectivity and is stimulated by neuronal growth factors, neurotransmitters, and electrical activity.
  • G-protein coupled receptors such as D2 dopamine and cortical neurons, serotonin- IB receptors and thalamic neurons, CBl cannabinoid receptor in Neuro2A cells, cilliary neurotrophic factor (CNTF), neurotrophin-3, and FGF (acidic/basic) in a variety of neurons.
  • G-protein coupled receptors such as D2 dopamine and cortical neurons, serotonin- IB receptors and thalamic neurons, CBl cannabinoid receptor in Neuro2A cells, cilliary neurotrophic factor (CNTF), neurotrophin-3, and FGF (acidic/basic) in a variety of neurons.
  • Various methods are disclosed herein, such as methods of extending neuronal survival and/or enhancing neuronal function and/or inhibiting cell death, which may include decreasing the amount of and/or extent of neuronal death or delaying the onset of neuronal death.
  • the methods described may also be used in a method of treating, preventing, delaying the onset, and/or delaying the development of an indication that is associated with neuronal cell death, including but not limited to the indications and conditions described in more detail herein.
  • the method comprises administering to an individual an effective amount of any of the following: (1) a therapeutic compound of Formula I, II or III or a pharmaceutically acceptable salt thereof, (2) a combination of (i) a therapeutic compound of Formula I, II or III or a pharmaceutically acceptable salt thereof and (ii) one or more second agents.
  • the one or more second agents is a hydrogenated pyrido[4,3-b]indole, e.g., dimebon or another agent.
  • the methods further comprise administration of a growth factor and/or an anti-cell death compound.
  • the methods further comprise administration of therapeutic compounds of Formula I, II, or III or pharmaceutically acceptable salts thereof, or combinations thereof further comprising a cell.
  • the cell is a multipotential stem cell.
  • the cell is a terminally differentiated cell.
  • the cell is incubated with asenapine.
  • the cell is incubated with dimebon.
  • the cell is incubated with asenapine and dimebon.
  • the therapeutic compound of Formula I, II or III or the combination of a therapeutic compound of Formula I, II or III and one or more second agents is administered with a growth factor and an anti-cell death compound.
  • the invention provides methods of treating, preventing, delaying the onset, and/or delaying the development of a neuronal indication, the method comprising administering to an individual in need thereof an effective amount of a first therapy comprising a therapeutic compound of Formulas I- III or a pharmaceutically acceptable salt thereof.
  • the invention provides methods of treating, preventing, delaying the onset, and/or delaying the development of a neuronal indication, the method comprising administering to an individual in need thereof an effective amount of a combination of (i) a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof, and (ii) one or more second agents, e.g., a hydrogenated pyrido[4,3-b]indole such as dimebon.
  • the therapeutic compound of Formulas I-III or pharmaceutically acceptable salt thereof is asenapine.
  • the one or more second agents is a hydrogenated pyrido[4,3-b]indole such as dimebon or another agent.
  • the methods further comprise administration of a growth factor and/or an anti-cell death compound.
  • the methods further comprise administration of therapeutic compounds of Formulas I, II, or III or pharmaceutically acceptable salts thereof or combinations thereof further comprising a cell.
  • the cell is a multipotential stem cell.
  • the cell is a terminally differentiated cell.
  • the cell is incubated with asenapine.
  • the cell is incubated with dimebon.
  • the cell is incubated with asenapine and dimebon.
  • the therapeutic compound of Formula I, II or III is administered with a growth factor and an anti-cell death compound.
  • the invention provides methods of treating, preventing, delaying the onset, and/or delaying the development of a non-neuronal indication, the method comprising administering to an individual in need thereof an effective amount of a first therapy comprising a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof.
  • the invention provides methods of treating, preventing, delaying the onset, and/or delaying the development of a non-neuronal indication, the method comprising administering to an individual in need thereof an effective amount of a combination of (i) a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof, and (ii) one or more second agents.
  • the therapeutic compound of Formulas I-III or pharmaceutically acceptable salt thereof is asenapine.
  • the one or more second agents is a hydrogenated pyrido[4,3-b]indole such as dimebon or another agent.
  • the methods further comprise administration of a growth factor and/or an anti-cell death compound.
  • the methods further comprise administration of therapeutic compounds of Formulas I-III or pharmaceutically acceptable salts thereof or combinations thereof further comprising a cell.
  • the cell is a multipotential stem cell.
  • the cell is a terminally differentiated cell.
  • the cell is incubated with asenapine.
  • the cell is incubated with dimebon.
  • the cell is incubated with asenapine and dimebon.
  • the therapeutic compound of Formula I, II or III is administered with a growth factor and an anti-cell death compound.
  • the neuronal indication is a neurodegenerative disease and disorder such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI), injury -related mild cognitive impairment (MCI) resulting from battlefield injuries, post-concussion syndrome, posttraumatic stress disorder and adjuvant chemotherapy, traumatic brain injury, (TBI), neuronal death mediated o
  • AAMI age-associated memory impairment
  • MCI mild
  • the non-neuronal indication is age-associated hair loss (alopecia), age- associated weight loss, age-associated vision disturbance (cataracts), heart disease, diabetes, anorexia, AIDS- or chemotherapy-associated wasting, vascular injury, intestinal injury, cartilage injury, osteoarthritis, bacterial infection, viral infection, a first-, second-, or third-degree burn, a simple, compound, stress, or compression fracture, or a laceration.
  • the disease or condition is not Alzheimer's disease. In certain embodiments, the disease or condition is not amyotrophic lateral sclerosis (ALS). In certain embodiments, the disease or condition is neither Alzheimer's disease nor amyotrophic lateral sclerosis (ALS). In certain embodiments, the disease or condition is not Huntington's disease. In certain embodiments, the disease or condition is not Parkinson's disease. In certain embodiments, the disease or condition is not schizophrenia, bipolar disorder or psychosis, such as psychosis associated with any of those diseases or conditions.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing any one or more of schizophrenia, bipolar disorder, schizoaffective disorder or psychosis, such as non- Alzheimer' s disease-associated psychosis.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), or schizophrenia.
  • the individual is a canine who has not been diagnosed with canine cognitive dysfunction syndrome (CCDS).
  • CCDS canine cognitive dysfunction syndrome
  • the invention provides methods of treating, preventing, delaying the onset, and/or delaying the development of Alzheimer' s disease, the method comprising administering to an individual in need thereof an effective amount of a first therapy comprising a therapeutic compound of Formulas I- III or a pharmaceutically acceptable salt thereof.
  • the invention provides methods of treating, preventing, delaying the onset, and/or delaying the development of Alzheimer' s disease, the method comprising administering to an individual in need thereof an effective amount of a combination of (i) a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof, and (ii) one or more second agents.
  • the therapeutic compound of Formulas I-III or pharmaceutically acceptable salt thereof is asenapine.
  • the one or more second agents is a hydrogenated pyrido[4,3-b]indole such as dimebon or another agent.
  • the methods further comprise administration of a growth factor and/or an anti-cell death compound.
  • the methods further comprise administration of therapeutic compounds of Formulas I-III or pharmaceutically acceptable salts thereof or combinations thereof further comprising a cell.
  • the cell is a multipotential stem cell.
  • the cell is a terminally differentiated cell.
  • the cell is incubated with asenapine.
  • the cell is incubated with dimebon.
  • the cell is incubated with asenapine and dimebon.
  • the therapeutic compound of Formula I, II or III is administered with a growth factor and an anti-cell death compound.
  • the invention provides methods of treating, preventing, delaying the onset, and/or delaying the development of a neurodegenerative disease or condition (e.g., Huntington's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease), the method comprising administering to an individual in need thereof an effective amount of a first therapy comprising a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof.
  • a neurodegenerative disease or condition e.g., Huntington's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease
  • the invention provides methods of treating, preventing, delaying the onset, and/or delaying the development of (e.g., Huntington's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease), the method comprising administering to an individual in need thereof an effective amount of a combination of (i) a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof, and (ii) one or more second agents.
  • the therapeutic compound of Formulas I-III or pharmaceutically acceptable salt thereof is asenapine.
  • the one or more second agents is a hydrogenated pyrido[4,3-b]indole such as dimebon or another agent.
  • the methods further comprise administration of a growth factor and/or an anti-cell death compound.
  • the methods further comprise administration of therapeutic compounds of Formulas I-III or pharmaceutically acceptable salts thereof or combinations thereof further comprising a cell.
  • the cell is a multipotential stem cell.
  • the cell is a terminally differentiated cell.
  • the cell is incubated with asenapine.
  • the cell is incubated with dimebon.
  • the cell is incubated with asenapine and dimebon.
  • the therapeutic compound of Formula I, II or III is administered with a growth factor and an anti-cell death compound.
  • the invention also provides a method of treating Alzheimer's disease in a patient in need thereof comprising administering to the individual an effective amount of a compound of Formulas I-III ⁇ e.g., asenapine), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of decreasing the intensity or severity of the symptoms of Alzheimer's disease in an individual who is diagnosed with Alzheimer's disease comprising administering to the individual an effective amount of a compound of Formulas I-III (e.g., asenapine), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of increasing the survival time of an individual diagnosed with Alzheimer's disease comprising administering to the individual an effective amount of a compound of Formulas I-III ⁇ e.g., asenapine), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of enhancing the quality of life of an individual diagnosed with Alzheimer's disease comprising administering to the individual an effective amount of a compound of Formulas I-III (e.g., asenapine), or a pharmaceutically acceptable salt thereof. Methods of enhancing cognition are included in this invention.
  • the present invention provides a method of delaying the onset and/or development of Alzheimer's disease in an individual who is considered at risk for developing Alzheimer's disease (e.g., an individual whose one or more family members have had Alzheimer's disease or an individual who has been diagnosed as having a genetic mutation associated with Alzheimer's disease) comprising administering to the individual an effective amount of a compound of Formulas I-III (e.g., asenapine), or pharmaceutically acceptable salt thereof.
  • a compound of Formulas I-III e.g., asenapine
  • the present invention provides a method of delaying the onset and/or development of Alzheimer's disease in an individual who is genetically predisposed to developing Alzheimer's disease comprising administering to the individual an effective amount of a compound of Formulas I-III (e.g., asenapine), or a pharmaceutically acceptable salt thereof.
  • a compound of Formulas I-III e.g., asenapine
  • the present invention provides a method of delaying the onset and/or development of Alzheimer's disease in an individual having a mutated or abnormal gene associated with Alzheimer's disease (e.g., an APP mutation, a presenilin mutation and/or an ApoE4 allele), but who has not been diagnosed with Alzheimer's disease comprising administering to the individual an effective amount of a compound of Formulas I-III (e.g., asenapine), or a pharmaceutically acceptable salt thereof.
  • a compound of Formulas I-III e.g., asenapine
  • the method delays or prevents one or more biochemical, histologic and/or behavioral symptoms of the disease, one or more complications of the disease, and/or one or more intermediate pathological phenotypes presenting during development of the disease.
  • the present invention provides a method of preventing
  • Alzheimer's disease in an individual who is genetically predisposed to developing Alzheimer's disease or who has a mutated or abnormal gene associated with Alzheimer's disease but who has not been diagnosed with Alzheimer's disease comprising administering to the individual an effective amount of a compound of Formulas I-III (e.g., asenapine), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of preventing the onset and/or development of Alzheimer's disease in an individual who is not identified as genetically predisposed to developing Alzheimer's disease comprising administering to the individual an effective amount of a compound of Formulas I-III (e.g., asenapine), or a pharmaceutically acceptable salt thereof.
  • the method comprises use of a compound of Formula I or Formula II (e.g., asenapine), or a pharmaceutically acceptable salt thereof in any of the above methods, e.g., treating and/or preventing and/or delaying the onset or development of Alzheimer's disease in a human.
  • a compound of Formula I or Formula II e.g., asenapine
  • a pharmaceutically acceptable salt thereof e.g., treating and/or preventing and/or delaying the onset or development of Alzheimer's disease in a human.
  • the method of the invention employs administering a combination therapy comprising asenapine and dimebon.
  • the individual has a neuronal or non-neuronal indication for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial for treating, preventing, delaying the onset, and/or delaying the development of the condition.
  • the invention provides a method of treating a neuronal or non-neuronal indication for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the invention provides a method of preventing a neuronal or non-neuronal indication for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the invention provides a method of delaying the onset of a neuronal or non-neuronal indication for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial. In one embodiment, the invention provides a method of delaying the development of a neuronal or non-neuronal indication for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • the invention provides a method of treating, preventing, delaying the onset, and/or delaying the development of a neuronal or non-neuronal indication for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial, the method comprising administering to an individual in need thereof an effective amount of a therapeutic compound of Formula I- III or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating, preventing, delaying the onset, and/or delaying the development of a neuronal or non-neuronal indication for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial, the method comprising administering to an individual in need thereof an effective amount of a combination of (i) a therapeutic compound of Formula I, II or III or a pharmaceutically acceptable salt thereof and (ii) one or more second agents.
  • the therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof is asenapine.
  • the one or more second agents is a hydrogenated pyrido[4,3-b]indole such as dimebon or another agent.
  • the cell type is selected from the group consisting of multipotential stem cells, neuronal stem cells, non-neuronal cell and neurons.
  • the cell type is a neuron, and the method increases the length of one or more axons of the neuron.
  • the cell type is a neuronal stem cell, and the method promotes the differentiation of the neuronal stem cell into a neuron.
  • the neuronal stem cell differentiates into a hippocampal neuron, a cortical neuron, or a spinal motor neuron.
  • the multipotential stem cell is a non-neuronal stem cell and the method promotes the differentiation of the non-neuronal stem cell.
  • the non-neuronal stem cell differentiates into a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • the first and second therapies are administered sequentially. In one embodiment, the first and second therapies are administered simultaneously. In one embodiment, the first and second therapies are contained in the same pharmaceutical composition. In one embodiment, the first and second therapies are contained in separate pharmaceutical compositions. In one embodiment, the first and second therapies have at least an additive effect. In one embodiment, the first and second therapies have a synergistic effect.
  • the present invention provides a method of treating, preventing, delaying the onset, and/or delaying the development of neuronal and non-neuronal indications that implicate cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in an individual in need thereof comprising administering to the individual an effective amount of a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, II, or III e.g., asenapine
  • the present invention provides a method of decreasing the intensity or severity of the symptoms of neuronal and non-neuronal indications that implicate cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in an individual diagnosed with such an indication comprising administering to the individual an effective amount of a compound of Formula I, II or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, II or III e.g., asenapine
  • the present invention provides a method of increasing the survival time of an individual diagnosed with a neuronal or non-neuronal indication that implicates cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types comprising administering to the individual an effective amount of a compound of Formula I, II or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of enhancing the quality of life of an individual diagnosed with such an indication comprising administering to the individual an effective amount of a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of delaying the onset and/or development of neuronal or non-neuronal indications that implicate cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in an individual who is considered at risk for developing such an indication (e.g., an individual whose one or more family members have had such an indication, or an individual who has been diagnosed as having a genetic mutation associated with such an indication), the method comprising administering to the individual an effective amount of a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, II, or III e.g., asenapine
  • the present invention provides a method of delaying the onset and/or development of neuronal and non-neuronal indications that implicate cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in an individual who is genetically predisposed to developing such an indication comprising administering to the individual an effective amount of a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, II, or III e.g., asenapine
  • the present invention provides a method of delaying the onset and/or delaying the development of neuronal and non-neuronal indications that implicate cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in an individual having a mutated or abnormal gene associated with such an indication (e.g., an APP mutation, a presenilin mutation and/or an ApoE4 allele in Alzheimer's disease), but who has not been diagnosed, the method comprising administering to the individual an effective amount of a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, II, or III e.g., asenapine
  • the methods of delaying the onset of such indications delay or prevent one or more biochemical, histologic and/or behavioral symptoms of the indication, one or more complications of the indication, and/or one or more intermediate pathological phenotypes presenting during development of the indication.
  • the present invention provides a method of preventing neuronal or non-neuronal indications that implicate cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in an individual who is genetically predisposed to developing such an indication.
  • the present invention provides a method of preventing such indications in an individual who has a mutated or abnormal gene associated with such an indication, but who has not been diagnosed, the method comprising administering to the individual an effective amount of a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of preventing the onset and/or development of a neuronal or non-neuronal indication that implicates cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in an individual who is not identified as genetically predisposed to developing such an indication, the method comprising administering to the individual an effective amount of a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, II, or III e.g., asenapine
  • the method comprises use of a compound of Formula I, II, or III (e.g., asenapine) or a pharmaceutically acceptable salt thereof in any of the above methods, e.g., treating and/or preventing and/or delaying the onset or delaying the development of an indication that implicates cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in a human.
  • a compound of Formula I, II, or III e.g., asenapine
  • a pharmaceutically acceptable salt thereof e.g., treating and/or preventing and/or delaying the onset or delaying the development of an indication that implicates cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types in a human.
  • the method of the invention employs administering a combination therapy comprising asenapine and a hydrogenated pyrido[4,3-b]indole such as dimebon.
  • the invention also embraces combination therapy using any one or more of the exemplary compounds listed, exemplified, or defined herein.
  • the combination therapy comprises asenapine, dimebon and an additional second therapy, which may be any of the second therapies detailed herein.
  • the amount of the first therapy e.g., asenapine
  • the second therapy or the combined therapy is administered in an amount sufficient to increase the amount or activity of acetylcholine, reduce an activity of an acetylcholinesterase or a butyrylcholinesterase, increase an activity of an acetylcholine receptor, reduce an activity of an NMDA receptor, reduce an activity of an amyloid AB peptide, reduce the amount of amyloid plaque, reduce an activity of a PDE5 or PDE4, reduce an activity of a monoamine oxidase, increase an activity or amount of a VEGF protein, increase an activity or amount of a trophic growth factor, increase an activity of a HIF, reduce an activity of a HIF prolyl 4-hydroxylases, increase an activity or amount of an ADNP, increase an activity or amount of an ADNF, increase an activity of AMPA-type glutamate receptor, increase an activity of a serotonin 5-HT1A receptor, reduce an activity of
  • one or more of these activities changes by at least or about
  • the amount of the first therapy, the second therapy or the combined therapy is an amount sufficient to produce a desired therapeutic outcome (e.g., reducing the severity and/or duration of, stabilizing the severity of, or eliminating one or more symptoms of the indication being treated, prevented, or delayed).
  • the methods of the invention involve administering a combination therapy comprising asenapine and dimebon.
  • the invention provides methods of stimulating neurite outgrowth in an individual comprising treating the individual with an amount of a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof effective to stimulate neurite outgrowth.
  • the invention provides methods of enhancing neurogenesis in an individual comprising treating the individual with an amount of a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof effective to enhance neurogenesis.
  • the invention provides methods of stimulating neurite outgrowth and enhancing neurogenesis in an individual comprising treating the individual with an amount of a therapeutic compound of Formulas I-III or a pharmaceutically acceptable salt thereof effective to stimulate neurite outgrowth and to enhance neurogenesis.
  • the therapeutic compound of Formulas I-III or pharmaceutically acceptable salt thereof is asenapine.
  • the method further comprises administration of a growth factor and/or an anti- cell death compound and/or one or more second agent, such as a hydrogenated pyrido[4,3- b]indole (e.g., dimebon)), acetylcholinesterase inhibitor, butyrylcholinesterase inhibitor, acetylcholine receptor agonist, an inhibitor of amyloid AB peptide or amyloid plaque, or any other compounds for use in a second or additional therapy as described herein.
  • the indication has a neuronal or non-neuronal indication other than schizophrenia, bipolar disorder, schizoaffective disorder, or psychosis.
  • an individual has or is suspected of having Alzheimer's disease.
  • the individual has a neuronal indication such as
  • Alzheimer's disease Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury- related mild cognitive impairment (MCI), injury -related mild cognitive impairment (MCI) resulting from battlefield injuries, post-concussion syndrome, post-traumatic stress disorder and adjuvant chemotherapy, traumatic brain injury, (TBI), neuronal death mediated ocular disorder, macular degeneration, age-related macular degeneration, autism, including autism spectrum disorder, Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cord injury, myasthenia gravis, Guillain-Barre syndrome, multiple sclerosis, diabetic neuropathy, fibromy
  • the individual has a non-neuronal indication such as heart disease, diabetes, anorexia, AIDS-, cancer- or chemotherapy-associated wasting, vascular injury, intestinal injury, cartilage injury, osteoarthritis, bacterial infection, viral infection, a first-, second-, or third- degree burn, a simple, compound, stress, or compression fracture of a bone, or a laceration.
  • a non-neuronal indication such as heart disease, diabetes, anorexia, AIDS-, cancer- or chemotherapy-associated wasting, vascular injury, intestinal injury, cartilage injury, osteoarthritis, bacterial infection, viral infection, a first-, second-, or third- degree burn, a simple, compound, stress, or compression fracture of a bone, or a laceration.
  • a combination of Formula I, II, or III and a second agent is administered orally, intravenously, intraperitoneally, subcutaneously, intrathecally, intramuscularly, intraocularly, transdermally, or topically (i.e., as eye drops or ear drops).
  • first and the second agents may be administered by the same or different routes and may be administered simultaneously or sequentially.
  • a dose of a therapeutic compound of Formula I, II, or III is administered once daily, twice daily, three times daily, or at higher frequencies.
  • a dose of a therapeutic composition of Formula I, II, or III is administered once a week, twice a week, three times a week, four times a week, or at higher frequencies.
  • a dose of a therapeutic compound of Formula I, II, or III is administered as a controlled release formulation every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, or at even longer intervals.
  • a dose (e.g., a dose for oral administration) of about 1 ng/day, 10 ng/day, 100 ng/day, 250 ng/day, 500 ng/day, 1 ⁇ g/day, 5 ⁇ g/day, 10 ⁇ g/day, 20 ⁇ g/day, 25 ⁇ g/day, 40 ⁇ g/day, 80 ⁇ g/day, 125 ⁇ g/day, 160 ⁇ g/day, 320 ⁇ g/day, or 120 mg/day of a therapeutic compound of Formulas I-III or pharmaceutically acceptable salt thereof is administered.
  • the therapeutic compound of Formulas I-III or pharmaceutically acceptable salt thereof is administered directly by infusion to the brain (e.g., intrathecal or intraventricular administration) at a dose of about 1 ng/day, 10 ng/day, 100 ng/day, 250 ng/day, 500 ng/day, 1 ⁇ g/day, 5 ⁇ g/day, 10 ⁇ g/day, 20 ⁇ g/day, 25 ⁇ g/day, 40 ⁇ g/day, 80 ⁇ g/day, 125 ⁇ g/day, 160 ⁇ g/day, 320 ⁇ g/day, or 120 mg/day.
  • a slow release pump or other device in the brain issued to administer any of the doses described herein.
  • the invention provides methods of activating a cell by incubating the cell with one or more therapeutic compounds of Formula I, II, or III or pharmaceutically acceptable salts thereof under conditions sufficient to activate the cell.
  • a therapeutic compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof can be used to activate neurons by stimulating neurite outgrowth and/or neurogenesis.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof can be used to activate other cell types as well, including any of the cell types described herein, including non-neuronal cells.
  • Some exemplary cell types include any stem cell (such as any self-renewing, multipotential cell).
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • a therapeutic compound such as asenapine in saline is added to cells at a concentration ranging from about 1 pM to about 5 mM, from about 10 pM to about 500 ⁇ M, from about 50 pM to about 100 ⁇ M, from about 0.25 nM to about 20 ⁇ M, from about 1 nM to about 5 ⁇ M, from about 6 nM to about 800 nM, from about 30 nM to about 160 nM.
  • the cell is also incubated with a growth factor (e.g., a VEGF protein or a trophic growth factor) and/or an anti-cell death compound.
  • a growth factor e.g., a VEGF protein or a trophic growth factor
  • the cell can be incubated with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof before, during, or after it is incubated with a growth factor and/or an anti-cell death compound.
  • incubation with a growth factor and/or an anti-cell death compound produces an additive or synergistic effect compared to incubation with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof alone.
  • the cell is incubated with both a growth factor and an anti-cell death compound.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the cell is incubated with dimebon and optionally with asenapine.
  • the incubation occurs ex vivo or in vivo.
  • a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered to an individual (i.e., an individual in need of one or more cell types) to activate a cell (e.g., a neuronal stem cell or a neuronal cell or a non-neuronal cell) in vivo.
  • a growth factor and/or an anti-cell death compound is administered to the individual to enhance the activation of a cell (e.g., a neuronal stem cell or a neuronal cell or non- neuronal cell) in vivo.
  • a dose of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered orally, intravenously, intraperitoneally, subcutaneously, intrathecally, intramuscularly, intraocularly, transdermally, or topically (i.e., as eye drops or ear drops).
  • a dose of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered once daily, twice daily, three times daily, or at higher frequencies.
  • a dose of a therapeutic composition is administered once a week, twice a week, three times a week, four times a week, or at higher frequencies.
  • a dose of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered as a controlled release formulation every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, or at even longer intervals.
  • a dose (e.g., a dose for oral administration) of about 1 ng/day, 10 ng/day, 100 ng/day, 250 ng/day, 500 ng/day, 1 ⁇ g/day, 5 ⁇ g/day, 10 ⁇ g/day, 20 ⁇ g/day, 40 ⁇ g/day, 80 ⁇ g/day, 160 ⁇ g/day, 320 ⁇ g/day, or 120 mg/day of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered directly by infusion to the brain (e.g., intrathecal or intraventricular administration) at a dose of about 1 ng/day, 10 ng/day, 100 ng/day, 250 ng/day, 500 ng/day, 1 ⁇ g/day, 5 ⁇ g/day, 10 ⁇ g/day, 20 ⁇ g/day, 25 ⁇ g/day, 40 ⁇ g/day, 80 ⁇ g/day, 125 ⁇ g/day, 160 ⁇ g/day, 320 ⁇ g/day, or 120 mg/day.
  • a slow release pump or other device in the brain is used to administer any of the doses described herein.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the cell is a neuron with axons that are at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% longer (i) than the axons prior to incubation of the cell or (ii) than the axons of the corresponding control cell that was incubated under the same conditions without a therapeutic compound of Formula I, II, or III, growth factor, or anti-cell death compound.
  • the invention also features methods of promoting the differentiation and/or proliferation of a cell by incubating a cell with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof under conditions sufficient to promoting the differentiation and/or proliferation of the cell.
  • Some exemplary cell types include any multipotential stem cell (such as any self -renewing, multipotential cell).
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • a therapeutic compound such as asenapine in saline is added to cells at a concentration ranging from about 1 pM to about 5 mM, from about 10 pM to about 500 ⁇ M, from about 50 pM to about 100 ⁇ M, from about 0.25 nM to about 20 ⁇ M, from about 1 nM to about 5 ⁇ M, from about 6 nM to about 800 nM, from about 30 nM to about 160 nM.
  • the cell is also incubated with a growth factor (e.g., a VEGF protein or a trophic growth factor) and/or an anti-cell death compound.
  • a growth factor e.g., a VEGF protein or a trophic growth factor
  • the cell can be incubated with a therapeutic compound of Formula I, II, or III before, during, or after it is incubated with a growth factor and/or an anti-cell death compound.
  • incubation with a growth factor and/or an anti-cell death compound produces an additive or synergistic effect compared to incubation with a therapeutic compound of Formula I, II, or III alone.
  • the incubation occurs ex vivo or in vivo.
  • a therapeutic compound of Formula I, II, or III is administered to an individual (i.e., an individual in need of one or more cell types) to promote the differentiation and/or proliferation of a cell (e.g., a neuronal stem cell or a neuronal cell or a non-neuronal cell) in vivo.
  • a growth factor and/or an anti-cell death compound is administered to the individual to enhance the differentiation and/or proliferation of a cell (e.g., a neuronal stem cell or a neuronal cell or non-neuronal cell) in vivo.
  • a dose of a therapeutic compound of Formula I, II, or III is administered orally, intravenously, intraperitoneally, subcutaneously, intrathecally, intramuscularly, intraocularly, transdermally, or topically (i.e., as eye drops or ear drops).
  • a dose of a therapeutic compound of Formula I, II, or III is administered once daily, twice daily, three times daily, or at higher frequencies.
  • a dose of a therapeutic composition is administered once a week, twice a week, three times a week, four times a week, or at higher frequencies.
  • a dose of a therapeutic compound of Formula I, II, or III is administered as a controlled release formulation every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, or at even longer intervals.
  • a dose e.g., a dose for oral administration
  • a dose for oral administration of about 1 ng/day, 10 ng/day, 100 ng/day, 250 ng/day, 500 ng/day, 1 ⁇ g/day, 5 ⁇ g/day, 10 ⁇ g/day, 20 ⁇ g/day, 25 ⁇ g/day, 40 ⁇ g/day, 80 ⁇ g/day, 125 ⁇ g/day, 160 ⁇ g/day, 320 ⁇ g/day, or 120 mg/day of a therapeutic compound of Formula I, II, or III is administered.
  • the therapeutic compound of Formula I, II, or III is administered directly by infusion to the brain (e.g., intrathecal or intraventricular administration) at a dose of about 1 ng/day, 10 ng/day, 100 ng/day, 250 ng/day, 500 ng/day, 1 ⁇ g/day, 5 ⁇ g/day, 10 ⁇ g/day, 20 ⁇ g/day, 25 ⁇ g/day, 40 ⁇ g/day, 80 ⁇ g/day, 125 ⁇ g/day, 160 ⁇ g/day, 320 ⁇ g/day, or 120 mg/day.
  • a slow release pump or other device in the brain issued to administer any of the doses described herein.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the invention provides a method of promoting the differentiation and/or proliferation of a cell comprising incubating a cell with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof under conditions sufficient to promote the differentiation and/or proliferation of the cell.
  • the differentiation and/or proliferation comprises neurite outgrowth and/or neurogenesis of the cell.
  • the differentiation and/or proliferation comprises neurite outgrowth.
  • the differentiation and/or proliferation comprises neurogenesis.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the method further comprises incubating the cell with a growth factor and/or an anti-cell death compound.
  • the cell type is selected from the group consisting of multipotential stem cells, neuronal stem cells, non- neuronal cell and neurons.
  • the cell type is a neuron, and the method increases the length of one or more axons of the neuron.
  • the cell type is a neuronal stem cell, and the method promotes the differentiation of the neuronal stem cell into a neuron.
  • the neuronal stem cell differentiates into a hippocampal neuron, a cortical neuron, or a spinal motor neuron.
  • the non-neuronal stem cell differentiates into a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • the incubation occurs ex vivo. In one embodiment, the incubation occurs in vivo.
  • the invention provides a method of stimulating neurite outgrowth and/or enhancing neurogenesis of a cell comprising incubating a cell with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof under conditions sufficient to stimulate neurite outgrowth and/or to enhance neurogenesis of the cell.
  • the therapeutic compound of Formula I, II, or III is asenapine.
  • the method further comprises incubating the cell with a growth factor and/or an anti-cell death compound.
  • the cell type is selected from the group consisting of multipotential stem cells, neuronal stem cells, non-neuronal cells and neurons.
  • the cell type is a neuron, and the method increases the length of one or more axons of the neuron.
  • the cell type is a neuronal stem cell, and the method promotes the differentiation of the neuronal stem cell into a neuron.
  • the neuronal stem cell differentiates into a hippocampal neuron, cortical neuron, or spinal motor neuron.
  • the non-neuronal stem cell differentiates into a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • the incubation occurs ex vivo. In one embodiment, the incubation occurs in vivo.
  • the number of cells increase by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, compared to (i) the number of cell(s) prior to incubation or (ii) the number of cells generated from the same number of starting control cell(s) that were incubated under the same conditions without a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof, growth factor, or anti-cell death compound.
  • the invention features methods for differentiating multipotential stem cells (MSCs) by isolating MSCs from an individual, culturing the isolated MSCs in vitro, incubating the cultured MSCs with an amount of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof effective to induce the multipotential stem cells to differentiate, and selecting the desired differentiated cell type from culture.
  • the method comprises incubating a multipotential stem cell isolated from an individual with an amount of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof effective to induce the multipotential stem cells to differentiate.
  • the MSCs differentiate into cortical neurons, hippocampal neurons, or spinal motor neurons.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • MSCs are cells that have the potential to differentiate into at least two different cell types and divide asymmetrically, meaning that at each cell division, at least one of the two progeny cells produced will also be a multipotential stem cell.
  • MSCs are isolated from adult human or fetal tissues, including the umbilical cord. MSCs can be isolated from various regions of the brain, including the hippocampus, the dentate gyrus, and the subventricular region. MSCs can also be isolated from deep layers of the skin, bone marrow or plasma. Where MSCs are isolated as part of a complex biological mixture, such as bone marrow, plasma, or other tissue samples, additional purification steps may be required. MSCs may be separated from differentiated cells and other biological materials by any standard method known to one of ordinary skill in the art, such as flow cytometry, density gradient centrifugation, and the like.
  • MSCs are washed and triturated if necessary, then suspended in appropriate culture medium (i.e., Neurobasal medium (GIBCO)) to the desired concentration and placed in an appropriate culture vessel containing the suitable culture medium.
  • appropriate culture medium i.e., Neurobasal medium (GIBCO)
  • the culture medium can be supplemented with factors that promote cell growth as desired, including, for example, serum-free culture supplements such as B27 (GIBCO), L-glutamine (GIBCO), growth factors and the like.
  • the MSCs can be cultured in supplemented or unsupplemented medium in the absence of other cell types.
  • the MSCs can be co-cultured with differentiated cell types from the same or a different developmental context.
  • neuronal MSCs obtained from the hippocampus can be cultured with differentiated neurons, oligodendrocytes, glial cells, or Schwann cells.
  • Cells can be grown in a variety of culture vessels depending on the desired quantity and application, including flasks or wells on poly-L-lysine-coated plates, under standard conditions, such as 37 0 C in 5% CO 2 -95% air atmosphere.
  • a therapeutic compound of Formula I, II, or III, or pharmaceutically acceptable salt thereof, such as asenapine in saline at a concentration sufficient to induce differentiation.
  • the cells may also be treated with a growth factor and/or an anti-cell death compound.
  • the MSCs are induced to differentiate into specific cell types, such as neurons, astrocytes, Schwann cells, or oligodendrocytes, by treatment with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof at a concentration ranging from about 1 pM to about 5 mM, from about 10 pM to about 500 ⁇ M, from about 50 pM to about 100 ⁇ M, from about 0.25 nM to about 20 ⁇ M, from about 1 nM to about 5 ⁇ M, from about 6 nM to about 800 nM, from about 30 nM to about 160 nM.
  • a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof at a concentration ranging from about 1 pM to about 5 mM, from about 10 pM to about 500 ⁇ M, from about 50 pM to about 100 ⁇ M, from about 0.25 nM to about 20 ⁇ M, from about 1 nM to about 5 ⁇ M, from about 6 n
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine in saline.
  • the MSCs differentiate into cortical neurons, hippocampal neurons, or spinal motor neurons.
  • the MSCs are treated with a therapeutic compound of Formula I, II, or III such as asenapine and one or more other compounds, such as a growth factor, or an anti-cell death compound, or another second agent, such as a hydrogenated pyrido[4,3-b]indole such as dimebon. If the MSCs are treated with such a combination of compounds, the compounds may be administered simultaneously or sequentially in any order.
  • the MSCs are neuronal-lineage- specific stem cells (i.e., neuronal stem cells) that have the potential to differentiate into at least two cell types selected from a neuron, an astrocyte, a Schwann cell, and an oligodendrocyte, and exhibit self -renewal.
  • the MSCs are multipotential stem cells from other lineages.
  • the neuronal stem cells differentiate into hippocampal neurons, cortical neurons, or spinal motor neurons.
  • the non-neuronal stem cell differentiates into a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • cells of the desired type are then selected and purified from culture.
  • Differentiated cells of the desired cell type can be purified from in vitro cell cultures, for example, by identifying cells positive for particular cell-type-specific surface markers (i.e., the neuron- specific marker NeuN and the like), and sorting cells positive or negative for the desired markers from a mixed population of cultured cells. Such sorting may be performed, for example, by flow cytometry or other established methods known to one of ordinary skill in the art.
  • the invention provides a method of differentiating multipotential stem cells comprising incubating cultured multipotential stem cells isolated from an individual with an amount of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof effective to induce the multipotential stem cells to differentiate.
  • the therapeutic compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof is asenapine.
  • the multipotential stem cell is a neuronal stem cell or a non-neuronal stem cell.
  • the neuronal stem cell differentiates into a hippocampal neuron, a cortical neuron, or a spinal motor neuron.
  • the non- neuronal stem cell differentiates into a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • the method further comprises the step of incubating the multipotential stem cells with a growth factor and/or an anti-cell death compound.
  • the method further comprises the step of selecting a differentiated cell type from culture.
  • the selected differentiated cell type is a hippocampal neuron, a cortical neuron, or a spinal motor neuron.
  • the selected differentiated cell type is a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • Differentiated cells i.e., neurons or non-neuronal cells
  • the invention features methods of improving the treatment of an individual suffering from any one of a variety of neuronal or non- neuronal indications by administering an effective amount of differentiated cells (i.e., neurons) produced by the methods of the invention.
  • the effective amount of differentiated cells can be administered to an individual by any conventional method of administration known to one of ordinary skill in the art, including perfusion, injection, and surgical implantation.
  • Administration can be systemic, for example, by intravenous administration, or local, for example by direct injection or surgical implantation at a particular site.
  • sites of administration include, for example, the site of an avulsion or spinal cord injury, in a particular region of the brain having lesions or other neuronal defects, or in a muscle group associated with symptoms of a neuronal indication, such as the facial muscles of an individual having myasthenia gravis.
  • the differentiated cells are from the same species as the individual being treated. In some embodiments, the differentiated cells are from the individual being treated or a relative of the individual being treated.
  • treatment of non-neuronal indications includes, but is not limited to, treatment of degenerative disorders or trauma, and the treatment includes administration of non-neuronal cells, such as cardiac cells for the treatment of heart disease, pancreatic islet cells for the treatment of diabetes, adipocytes for the treatment of anorexia or wasting associated with many diseases including AIDS, cancer, and cancer treatments, smooth muscle cells to be used in vascular grafts and intestinal grafts, cartilage to be used to treat cartilage injuries and degenerative conditions of cartilage and osteoarthritis, and replace cells damaged or lost to bacterial or viral infection, or those lost to traumatic injuries such as burns, fractures, and lacerations.
  • non-neuronal cells such as cardiac cells for the treatment of heart disease, pancreatic islet cells for the treatment of diabetes, adipocytes for the treatment of anorexia or wasting associated with many diseases including AIDS, cancer, and cancer treatments, smooth muscle cells to be used in vascular grafts and intestinal grafts, cartilage to be used to
  • Cells that have been incubated with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof are useful to treat, prevent, delay the onset, and/or delay the development of a condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial in an individual, such as a human.
  • one or more cells e.g., neuronal stem cells or non-neuronal stem cells and/or neuronal cells or non-neuronal cells
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the cell(s) are also incubated with a growth factor (e.g., a VEGF protein or a trophic growth factor) and/or an anti-cell death compound.
  • the cells(s) are incubated with a therapeutic compound of Formula I, II, or III before, during, or after they are incubated with a growth factor and/or an anti-cell death compound. An effective amount of the incubated cell(s) is administered to the individual.
  • a therapeutic compound of Formula I, II, or III, a growth factor, an anti-cell death compound, or any combination of two or more of the foregoing are also administered to the individual.
  • the therapeutic compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof, growth factor, and/or anti-cell death compound may be administered sequentially or simultaneously with the administration of the cell(s).
  • the invention provides a method of treating, preventing, delaying the onset, and/or delaying the development of a condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial, the method comprising administering to an individual in need thereof an effective amount of a first therapy comprising a cell that has been incubated with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof under conditions sufficient to activate the cell, promote the differentiation of the cell, promote the proliferation of the cell, or any combination of two or more of the foregoing.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the method further comprises administering a second therapy comprising a growth factor and/or anti-cell death compound to the individual.
  • the cell type is selected from the group consisting of multipotential stem cells, neuronal stem cells, non-neuronal cell and neurons.
  • the multipotential stem cell is a non-neuronal stem cell.
  • the cell type is a neuron, and the method increases the length of one or more axons of the neuron.
  • the cell type is a neuronal stem cell, and the method promotes the differentiation of the neuronal stem cell into a neuron.
  • the neuronal stem cell differentiates into a hippocampal neuron, cortical neuron, or spinal motor neuron.
  • the cell type is a non-neuronal stem cell
  • the method promotes the differentiation of the non-neuronal stem cell into a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • cells that have not been previously incubated with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof can be administered to an individual (e.g., a human) to treat, prevent, delay the onset and/or delay the development of a condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial.
  • a cell is administered in combination with one or more therapeutic compounds of Formula I, II, or III to the individual.
  • a growth factor and/or an anti-cell death compound is also administered to the individual.
  • both a growth factor and an anti-cell death compound are administered to the individual.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof, growth factor, and/or anti-cell death compound promotes the activation, differentiation, and/or proliferation of the administered cells in vivo. In some embodiments, the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof, growth factor, and/or anti-cell death compound promotes the activation, differentiation, and/or proliferation of endogenous cells that were not transplanted into the individual. In some embodiments, the transplanted cell is from the same species as the individual being treated. In some embodiments, the transplanted cell is from the individual being treated or a relative of the individual being treated.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof, growth factor, and/or anti-cell death compound may be administered sequentially or simultaneously with the administration of the cell(s).
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the invention provides a method of treating, preventing, delaying the onset, and/or delaying the development of a condition for which the activation, differentiation, and/or proliferation of one or more cell types is beneficial, the method comprising administering to an individual in need thereof an effective amount of a combination of (i) a first therapy comprising a cell and (ii) a second therapy comprising a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the method further comprises administering a second therapy comprising a growth factor and/or anti-cell death compound to the individual.
  • the cell type is selected from the group consisting of multipotential stem cells, neuronal stem cells, non-neuronal cell and neurons.
  • the cell type is a neuron, and the method increases the length of one or more axons of the neuron.
  • the cell type is a neuronal stem cell, and the method promotes the differentiation of the neuronal stem cell into a neuron.
  • the neuronal stem cell differentiates into a hippocampal neuron, cortical neuron, or spinal motor neuron.
  • the multipotential stem cells are non-neuronal stem cells.
  • the non-neuronal stem cell differentiates into a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • the first and second therapies are administered sequentially. In one embodiment, the first and second therapies are administered simultaneously. In one embodiment, the first and second therapies are contained in the same pharmaceutical composition. In one embodiment, the first and second therapies are contained in separate pharmaceutical compositions. In one embodiment, the first and second therapies have at least an additive effect. In one embodiment, the first and second therapies have a synergistic effect.
  • the invention provides a method of aiding in the treatment of an individual, comprising administering to the individual a first therapy comprising a multipotential stem cell and a second therapy comprising an amount of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof effective to induce the multipotential stem cell to differentiate.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is asenapine.
  • the method further comprises administering a second therapy comprising a growth factor and/or anti-cell death compound to the individual.
  • the multipotential stem cell is a neuronal stem cell or a non-neuronal stem cell.
  • the neuronal stem cell differentiates into a hippocampal neuron, a cortical neuron, or a spinal neuron.
  • the non- neuronal stem cell differentiates into a skin cell, a cardiac muscle cell, a skeletal muscle cell, a liver cell, a kidney cell, or a cartilage cell.
  • the first and second therapies are administered sequentially. In one embodiment, the first and second therapies are administered simultaneously. In one embodiment, the first and second therapies are contained in the same pharmaceutical composition. In one embodiment, the first and second therapies are contained in separate pharmaceutical compositions. In one embodiment, the first and second therapies have at least an additive effect. In one embodiment, the first and second therapies have a synergistic effect.
  • the invention provides a method of aiding in the treatment of an individual having a neuronal indication or a non-neuronal indication comprising administering to the individual differentiated cells produced by any of the methods described herein.
  • the differentiated cells are hippocampal neurons, cortical neurons, or spinal motor neurons.
  • the differentiated cells are non-neuronal cells.
  • the differentiated cells are skin cells, cardiac muscle cells, skeletal muscle cells, liver cells, or kidney cells.
  • the non-neuronal cells are skin cells.
  • the differentiated cells are administered systemically by intravenous injection.
  • the differentiated cells are administered locally by direct injection or surgical implantation.
  • a dose of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered orally, intravenously, intraperitoneally, subcutaneously, intrathecally, intramuscularly, intraocularly, transdermally, or topically (i.e., as eye drops or ear drops).
  • a dose of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered once daily, twice daily, three times daily, or at higher frequencies.
  • a dose of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered once a week, twice a week, three times a week, four times a week, or at higher frequencies.
  • a dose of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered as a controlled release formulation every week, two weeks, every three weeks, every four weeks, every five weeks, every six weeks, or at even longer intervals.
  • a dose (e.g., a dose for oral administration) of about 1 ng/day, 10 ng/day, 100 ng/day, 250 ng/day, 500 ng/day, 1 ⁇ g/day, 5 ⁇ g/day, 10 ⁇ g/day, 20 ⁇ g/day, 25 ⁇ g/day, 40 ⁇ g/day, 80 ⁇ g/day, 120 ⁇ g/day, 160 ⁇ g/day, 320 ⁇ g/day, or 120 mg/day of a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered.
  • the therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered directly by infusion to the brain (e.g., intrathecal or intraventricular administration) at a dose of about 1 ng/day, 10 ng/day, 100 ng/day, 250 ng/day, 500 ng/day, 1 ⁇ g/day, 5 ⁇ g/day, 10 ⁇ g/day, 20 ⁇ g/day, 25 ⁇ g/day, 40 ⁇ g/day, 80 ⁇ g/day, 120 ⁇ g/day, 160 ⁇ g/day, 320 ⁇ g/day, or 120 mg/day.
  • a slow release pump or other device in the brain issued to administer any of the doses described herein.
  • the therapeutic compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof is asenapine.
  • the method involves administration of a therapy that contains a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof, such as asenapine, and a cell, where the cell is an exemplary cell type as described in U.S. Publication No. 2007/0110730, which is hereby incorporated by reference in its entirety.
  • the method involves incubating a cell with a therapeutic compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof wherein the cell is an exemplary cell type as described in U.S. Publication No. 2007/0110730.
  • the cell that has been incubated with a therapeutic compound of Formula I, II, or III or pharmaceutically acceptable salt thereof is administered to an individual in need thereof, such as an individual who has or is suspected of having a neuronal or non-neuronal indication. Any of the methods described herein can be used generate new cells to treat an injury or disease.
  • the cells are from tissues that have a high turnover rate or that are more likely to be subject to injury or disease, such as the epithelium or blood cells.
  • the stem cells are multipotential cells that are capable of long-term self-renewal over the lifetime of a mammal.
  • stem cells may themselves be transplanted or, alternatively, they may be induced to produce differentiated cells (e.g., neurons, oligodendrocytes, Schwann cells, or astrocytes) for transplantation.
  • Transplanted stem cells may also be used to express therapeutic molecules, such as growth factors, cytokines, anti-apoptotic proteins, and the like.
  • stem cells are a potential source of cells for alternative treatments of diseases involvin 1 gO loss of cells or tissues.
  • the cells are capable of differentiating as dopaminergic neurons.
  • Other exemplary cells can differentiate as numerous mesodermal derivatives including smooth muscle cells, adipocytes, cartilage, bone, skeletal muscle, and cardiac muscle, and are expected to be capable of producing other mesodermal derivatives including kidney and hematopoietic cells.
  • the cells express markers of endodermal differentiation, and are expected to differentiate to cell types including pancreatic islet cells (e.g., a (alpha), ⁇ (beta), ⁇ (phi), d (delta) cells), hepatocytes, and the like.
  • the cells are capable of differentiating into cells derived from all three germ layers.
  • the cells are used for autologous or heterologous transplants to treat, for example, other neurodegenerative diseases, disorders, or abnormal physical states.
  • the cell(s) is the progeny of a multipotent stem cell purified from a peripheral tissue of a postnatal mammal.
  • the cell(s) is a mitotic cell or a differentiated cell (e.g., a neuron, an astrocyte, an oligodendrocyte, a Schwann cell, or a non-neural cell).
  • exemplary neurons include neurons expressing one or more of the following neurotransmitters: dopamine, GABA, glycine, acetylcholine, glutamate, and serotonin.
  • non-neural cells include cardiac muscle cells, pancreatic cells (e.g., islet cells (a (alpha), ⁇ (beta), ⁇ (phi), and d (delta) cells), exocrine cells, endocrine cells, chondrocytes, osteocytes, skeletal muscle cells, smooth muscle cells, hepatocytes, hematopoietic cells, and adipocytes.
  • pancreatic cells e.g., islet cells (a (alpha), ⁇ (beta), ⁇ (phi), and d (delta) cells
  • exocrine cells e.g., endocrine cells, chondrocytes, osteocytes, skeletal muscle cells, smooth muscle cells, hepatocytes, hematopoietic cells, and adipocytes.
  • These non-neural cell types include both mesodermal and endodermal derivatives.
  • the differentiated cells are purified.
  • the invention features a method of treating an individual having a disease associated with cell loss.
  • the method includes the step of transplanting cells such as multipotent stem cells into the region of the individual in which there is cell loss.
  • the method prior to the transplanting step, includes the steps of providing a culture of peripheral tissue and isolating a cell such as a multipotent stem cell from the peripheral tissue.
  • the tissue may be derived from the same patient (autologous) or from either a genetically related or unrelated individual.
  • the method may further include the step of differentiating (or allowing the differentiation of) the cell into a desired cell type to replace the cells that were lost.
  • the region is a region of the CNS or PNS, but can also be cardiac tissue, pancreatic tissue, or any other tissue in which cell transplantation therapy is possible.
  • the method includes the step of delivering the cells to the site of cell damage via the bloodstream, wherein the cells home to the site of cell damage.
  • the method for treating an individual includes the transplantation of the differentiated cells which are the progeny of stem cells.
  • Multipotent stem cells have tremendous capacity to differentiate into a range of neural and non-neural cell types.
  • the non-neural cell types include both mesodermal and endodermal derivatives.
  • the cells are capable of differentiating to derivatives of all three germ layers. This capacity can be further influenced by modulating the culture conditions to influence the proliferation, differentiation, and survival of the cells.
  • modulating the culture conditions includes increasing or decreasing the serum concentration.
  • modulating the culture conditions includes increasing or decreasing the plating density.
  • modulating the culture conditions includes the addition of one or more pharmacological agents to the culture medium.
  • modulating the culture conditions includes the addition of one or more therapeutic proteins (e.g., growth factors or anti-apoptotic proteins) to the culture medium.
  • therapeutic proteins e.g., growth factors or anti-apoptotic proteins
  • pharmacological agents, therapeutic proteins, and small molecules can be administered individually or in any combination, and combinations of any of the pharmaceutical agents, therapeutic proteins, and small molecules can be co-administered or administered at different times.
  • the cell is a purified multipotent stem cell from peripheral tissues of mammals, including skin, olfactory epithelium, and tongue. These cells proliferate in culture, so that large numbers of stem cells can be generated. These cells can be induced to differentiate, for example, into neurons, astrocytes, and/or oligodendrocytes by altering the culture conditions. They can also be induced to differentiate into non-neural cells such as smooth muscle cells, cartilage, bone, skeletal muscle, cardiac muscle, and adipocytes. The substantially purified neural stem cells are thus useful for generating cells for use, for example, in autologous transplants for the treatment of degenerative disorders or trauma (e.g., spinal cord injury).
  • degenerative disorders or trauma e.g., spinal cord injury
  • multipotent stem cells may be differentiated into dopaminergic neurons and implanted in the substantia nigra or striatum of a Parkinson's disease patient.
  • the cells may be used to generate oligodendrocytes for use in autologous transplants for the treatment of multiple sclerosis.
  • the multipotent stem cells may be used to generate Schwann cells for treatment of spinal cord injury, cardiac cells for the treatment of heart disease, or pancreatic islet cells for the treatment of diabetes.
  • the multipotent stem cells are used to generate adipocytes for the treatment of anorexia or wasting associated with many diseases including AIDS, cancer, and cancer treatments.
  • multipotent stem cells may be used to generate smooth muscle cells to be used in vascular grafts.
  • multipotent stem cells may be used to generate cartilage to be used to treat cartilage injuries and degenerative conditions of cartilage.
  • multipotent stem cells may be used to replace cells damaged or lost to bacterial or viral infection, or those lost to traumatic injuries such as burns, fractures, and lacerations.
  • the cells may be genetically modified to express, for example, a growth factor or an anti-apoptotic protein.
  • the proliferation, differentiation, or survival of the cells can be influenced by modulating the cell culture conditions including increasing or decreasing the concentration of serum in the culture medium and increasing or decreasing the plating density.
  • the cells are presorted prior to plating and differentiation such that only a sub-population of the cells are subjected to the differentiation conditions. Presorting of the cells can be done based on expression (or lack of expression) of a gene or protein, or based on differential cellular properties including adhesion and morphology.
  • the invention also features the use of the cells of this invention to introduce therapeutic compounds of Formula I, II, or III or pharmaceutically acceptable salt thereof into the diseased, damaged, or physically abnormal CNS, PNS, or other tissue. Accordingly, the invention embraces a method of administering to an individual a therapy that contains a therapeutic compound of Formulas I- III or pharmaceutically acceptable salt thereof, such as asenapine, and a cell, such as a cell associated with the central nervous system (CNS), peripheral nervous system (PNS) or other tissue.
  • a therapy that contains a therapeutic compound of Formulas I- III or pharmaceutically acceptable salt thereof, such as asenapine
  • a cell such as a cell associated with the central nervous system (CNS), peripheral nervous system (PNS) or other tissue.
  • the invention also embraces a method of administering to an individual a cell, such as a cell associated with the CNS, PNS or other tissue that has been incubated with a therapeutic compound of Formulas I- III or pharmaceutically acceptable salt thereof, such as asenapine.
  • a cell such as a cell associated with the CNS, PNS or other tissue that has been incubated with a therapeutic compound of Formulas I- III or pharmaceutically acceptable salt thereof, such as asenapine.
  • suitable regulatory elements may be derived from a variety of sources, and may be readily selected by one with ordinary skill in the art. Examples of regulatory elements include a transcriptional promoter and enhancer or RNA polymerase binding sequence, and a ribosomal binding sequence, including a translation initiation signal.
  • the recombinant molecule may be introduced into the stem cells or the cells differentiated from the stem cells using in vitro delivery vehicles such as retroviral vectors, adenoviral vectors, DNA virus vectors, and liposomes. They may also be introduced into such cells in vivo using physical techniques such as microinjection and electroporation or chemical methods such as incorporation of DNA into liposomes. Such standard methods can be used to either transiently or stably introduce heterologous recombinant molecules into the cells.
  • the genetically altered cells may be encapsulated in microspheres and implanted into or in proximity to the diseased or damaged tissue.
  • the cells are used for the treatment of a neurological indication.
  • the cells such as multipotent stem cells are used as a source of non-neural cells, for example adipocytes, bone, cartilage, and smooth muscle cells.
  • non-neural cells for example adipocytes, bone, cartilage, and smooth muscle cells.
  • PCT publication WO99/16863 describes the differentiation of forebrain multipotent stem cells into cells of the hematopoietic cell lineage in vivo.
  • the invention features methods of treating an individual having any disease or disorder characterized by cell loss by administering multipotent stem cells or cells derived from these cells to that patient and allowing the cells to differentiate to replace the cells lost in the disease or disorder.
  • transplantation of multipotent stem cells and their progeny provide an alternative to bone marrow and hematopoietic stem cell transplantation to treat blood-related disorders.
  • Multipotent stem cells provide, for example, cultures of adipocytes and smooth muscle cells for study in vitro and for transplantation.
  • Adipocytes secrete a variety of growth factors that may be desirable in treating cachexia, muscle wasting, and eating disorders.
  • Smooth muscle cells may be, for example, incorporated into vascular grafts, intestinal grafts, etc.
  • Cartilage cells have numerous orthopedic applications to treat cartilage injuries ⁇ e.g., sports injuries), as well as degenerative diseases and osteoarthritis.
  • the cartilage cells can be used alone, or in combination with matrices well known in the art. Such matrices are used to mold the cartilage cells into requisite shapes. Exemplary Indications
  • the diseases or condition is a neuronal indication or a neurodegenerative disease and disorder such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI) resulting from battlefield injuries, post-concussion syndrome, posttraumatic stress disorder and adjuvant chemotherapy, traumatic brain injury, (TBI), neuronal death mediated ocular disorder, macular
  • AAMI age-associated memory impairment
  • MCI mild cognitive impairment
  • MCI injury-related mild cognitive impairment
  • MCI injury-related mild cognitive impairment
  • MCI injury-related mild cognitive impairment
  • MCI
  • the disease or condition is a non-neuronal indication, such as age- associated hair loss (alopecia), age- associated weight loss, age-associated vision disturbance (cataracts), heart disease, diabetes, anorexia, AIDS- or chemotherapy-associated wasting, vascular injury, intestinal injury, cartilage injury, osteoarthritis, bacterial infection, viral infection, a first-, second-, or third-degree burn, a simple, compound, stress, or compression fracture, or a laceration.
  • alopecia age- associated hair loss
  • weight loss age-associated weight loss
  • cataracts age-associated vision disturbance
  • heart disease diabetes
  • anorexia AIDS- or chemotherapy-associated wasting
  • vascular injury intestinal injury
  • cartilage injury cartilage injury
  • osteoarthritis bacterial infection
  • viral infection a first-, second-, or third-degree burn
  • simple, compound, stress, or compression fracture or a laceration.
  • the disease or condition is not Alzheimer's disease. In certain embodiments, the disease or condition is not amyotrophic lateral sclerosis (ALS). In certain embodiments, the disease or condition is neither Alzheimer's disease nor amyotrophic lateral sclerosis (ALS). In certain embodiments, the disease or condition is not Huntington's disease. In certain embodiments, the disease or condition is not Parkinson's disease. In certain embodiments, the disease or condition is not schizophrenia, bipolar disorder or psychosis, such as psychosis associated with any of those diseases or conditions.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing any one or more of schizophrenia, bipolar disorder, schizoaffective disorder or psychosis, such as non- Alzheimer' s disease-associated psychosis.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), or schizophrenia.
  • the individual is a canine who has not been diagnosed with canine cognitive dysfunction syndrome (CCDS).
  • CCDS canine cognitive dysfunction syndrome
  • the invention embraces methods for the simultaneous or sequential administration of a combination of (i) a compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof and (ii) one or more second agents, e.g., a hydrogenated pyrido[4,3-b]indole such as dimebon. Also embraced are methods further comprising administration of a growth factor and/or an anti-cell death compound, or administration of compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof or combinations thereof further comprising a cell. Also embraced are methods further comprising administering multipotential stem cells or terminally differentiated cells.
  • compounds of Formula I, II or III may be administered to the individual in any available dosage form.
  • compounds of Formula I, II, or III e.g., asenapine
  • compounds of Formula I, II, or III are administered to the individual as a conventional immediate release dosage form.
  • compounds of Formula I, II, or III are administered to the individual as a sustained release form or part of a sustained release system, such as a system capable of sustaining the rate of delivery of one or more compounds to an individual for a desired duration, which may be an extended duration such as a duration that is longer than the time required for a corresponding immediate-release dosage form to release the same amount (e.g., by weight or by moles) of compound(s), and can be hours or days.
  • a desired duration may be any of, for example, at least about 6 hours or at least about 12 hours or at least about 24 hours or at least about 30 hours or at least about 48 hours or at least about 72 hours or at least about 96 hours or at least about 120 hours or at least about 144 or more hours, and can be at least about one week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 8 weeks, or at least about 16 weeks or more.
  • Compounds of Formula I, II, or III may be formulated for any available delivery route, whether immediate or sustained release, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, intraperitoneal, subcutaneous, or intravenous), intrathecal, intraocular, topical or transdermal delivery form for delivery by the corresponding route.
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, intraperitoneal, subcutaneous, or intravenous
  • intrathecal intraocular, topical or transdermal delivery form for delivery by the corresponding route.
  • a compound may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules and soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules and soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultice
  • a combination of (i) a compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof and (ii) one or more second agents, e.g., a hydrogenated pyrido[4,3- b]indole such as dimebon may be formulated for the same or different delivery route.
  • each pharmaceutically active compound of Formula I, II, or III e.g., asenapine
  • a compound of the invention is administered in a dosage of any one of 1 mg or 5 mg or 10 mg or 20 mg given one or twice or thrice daily.
  • exemplary dosages for the compounds of Formula I, II, or III (e.g., asenapine), or pharmaceutically acceptable salts thereof include but are not limited to 5 mg or 10 mg twice daily.
  • the compound, such as asenapine is administered as a sublingual formulation.
  • the daily dose (or other dosage frequency) of a compound of Formula I, II, or III may involve administering the compound to the individual in a dose of between about 0.1 and about 10 mg/kg of body weight, at least once a day and during the period of time required to achieve the therapeutic effect.
  • the daily dose (or other dosage frequency) of a compound of Formula I, II, or III is between about 0.1 and about 8 mg/kg; or between about 0.1 to about 6 mg/kg; or between about 0.1 and about 4 mg/kg; or between about 0.1 and about 2 mg/kg; or between about 0.1 and about 1 mg/kg; or between about 0.5 and about 10 mg/kg; or between about 1 and about 10 mg/kg; or between about 2 and about 10 mg/kg; or between about 4 to about 10 mg/kg; or between about 6 to about 10 mg/kg; or between about 8 to about 10 mg/kg; or between about 0.1 and about 5 mg/kg; or between about 0.1 and about 4 mg/kg; or between about 0.5 and about
  • a daily dosage of a compound of Formula I, Formula II or Formula III is less than about 0.1 mg/kg, which may include but is not limited to, a daily dosage of about 0.05 mg/kg.
  • Dimebon may also be administered in any of the doses, formulations, or routes of administration described herein for compounds of Formula I, II, or III (e.g., asenapine).
  • Compounds of Formula I, II, or III, such as asenapine may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual's life.
  • the dosing frequency can be about a once weekly dosing.
  • the dosing frequency can be about a once daily dosing.
  • the dosing frequency can be more than about once weekly dosing.
  • the dosing frequency can be less than three times a day dosing.
  • the dosing frequency can be two times a day dosing.
  • the dosing frequency can be about three times a week dosing.
  • the dosing frequency can be about a four times a week dosing.
  • the dosing frequency can be about a two times a week dosing.
  • the dosing frequency can be more than about once weekly dosing but less than about daily dosing.
  • the dosing frequency can be about a once monthly dosing.
  • the dosing frequency can be about a twice weekly dosing.
  • the dosing frequency can be more than about once monthly dosing but less than about once weekly dosing.
  • the dosing frequency can be intermittent (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more).
  • the dosing frequency can be continuous (e.g., once weekly dosing for continuous weeks).
  • any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein, for example, the dosing frequency can be a once daily dosage of less than 0.1 mg/kg or less than about 0.05 mg/kg of a compound of Formula I, II, or III (e.g., asenapine).
  • the dosage or dosing frequency of a compound of Formula I, II, or III may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the dosage or dosing frequency of a combination of (i) a compound of Formula I, II, or III or a pharmaceutically acceptable salt thereof and (ii) one or more second agents, e.g., a hydrogenated pyrido[4,3-b]indole such as dimebon may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • One or more compounds (e.g., asenapine or asenapine and dimebon) described herein may be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
  • a pharmacologically acceptable carrier which are known in the art.
  • the carrier may be in various forms.
  • pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents, or antioxidants.
  • Therapeutic forms may be represented by a usual standard dose and may be prepared by a known pharmaceutical method. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 th ed. (2000), which is incorporated herein by reference.
  • the pharmaceutical composition comprises a compound of Formula I, II, or III (e.g., asenapine) in an amount sufficient to produce a desired therapeutic outcome (e.g., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of the indication to be treated.
  • the pharmaceutical composition comprises a compound of Formula I, II, or III (e.g., asenapine) in an amount sufficient to prevent or reduce the severity of one or more future symptoms of the indication to be treated when administered to an individual who is susceptible and/or who may develop such a disease or condition.
  • the compound of the invention is formulated for sublingual administration.
  • One or more compounds e.g., asenapine or asenapine and dimebon
  • compounds e.g., asenapine or asenapine and dimebon
  • kits comprising one or more compounds as described herein.
  • the kits may employ any of the compounds disclosed herein and instructions for use.
  • the kit includes one or more compounds of Formula I, II, or III (e.g., asenapine) or pharmaceutically acceptable salts thereof useful for treating, preventing, delaying the onset, and/or delaying the development of a neuronal or non-neuronal indication.
  • the kit includes one or more compounds of Formula I, II, or III (e.g., asenapine) or pharmaceutically acceptable salts thereof useful for treating, preventing, delaying the onset, and/or delaying the development of an indication that implicates cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types.
  • the kit employs asenapine.
  • the compound may be formulated in any acceptable form.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for any one or more of the stated uses (e.g., treating and/or preventing and/or delaying the onset and/or the development of any indication disclosed herein.
  • the amount of pharmaceutical formulation comprising a compound of Formula I, II, or III (e.g., asenapine) in a kit is an amount sufficient to produce a desired therapeutic outcome (e.g., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of an indication to be treated).
  • the amount of pharmaceutical formulation comprising a compound of Formula I, II, or III or pharmaceutically acceptable salt thereof (e.g., asenapine) in a kit is an amount sufficient to prevent or reduce the severity of one or more future symptoms of the desired indication when administered to an individual who is susceptible to and/or who may develop such an indication.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound(s) described herein.
  • Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., plastic bags), and the like.
  • Each component if there is more than one component can be packaged in separate containers or some components can be combined in one container where cross -reactivity and shelf life permit.
  • Kits may optionally provide additional components such as buffers.
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention (e.g., treating, preventing, delaying the onset, and/or delaying the development of an indication implicating cell death and/or decreased cell function and that would benefit from the activation, differentiation, and/or proliferation of one or more cell types).
  • the instructions included with the kit generally include information as to the components and their administration to an individual, such as information regarding dosage, dosing schedule, and route of administration.
  • kits may be provided that contain sufficient dosages of a compound of Formula I, II, or III (e.g., asenapine) as disclosed herein to provide effective treatment of an individual having an indication to be treated for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • Example 1 Increase in neurite outgrowth of cortical neurons cultured with asenapine
  • Asenapine was tested to determine its ability to stimulate neurite outgrowth of cortical neurons in vitro.
  • Mixed cortical cultures were prepared from El 8 Wistar rat embryos (National Animal Center, Kuopio, Finland). The cortices were dissected out and the tissue was cut to small pieces. The cells were separated by 15-min incubation with DNase and papain. The cells were collected by centrifugation (1500 rpm, 5 minutes).
  • the tissue was triturated and the cells were plated on poly-L-lysine-coated 48-well plates in minimal essential medium supplemented with 2 g/L glucose, 2 mM glutamine, 10 ⁇ g/mL gentamicin, 10 % HS-HI, and 10% heat-inactivated fetal bovine serum (FBS-HI), and maintained at +37 0 C, 5% CO 2 /95% air.
  • minimal essential medium supplemented with 2 g/L glucose, 2 mM glutamine, 10 ⁇ g/mL gentamicin, 10 % HS-HI, and 10% heat-inactivated fetal bovine serum (FBS-HI)
  • test compound (10, 100 and 1000 nM) and positive controls (BDNF from Peprotech at 50, 100 and 150 ng/mL) were pipetted on wells in minimal essential medium + supplements + 5 % HS-HI. Cells were incubated 48 h at +37 0 C, 5% COi/95% air. Control wells received no treatment.
  • PBS Buffered Saline
  • Figures IA and IB are asenapine dose response curves for neurite outgrowth of primary rat cortical neurons.
  • Low concentrations (i.e., 10-1000 nanomolar (nM)) of asenapine stimulate neurite outgrowth of primary rat cortical neurons.
  • Asenapine is also tested to determine its ability to stimulate neurite outgrowth of hippocampal neurons and spinal motor neurons in vitro. Similar methods are used to test the ability of asenapine to stimulate neurite outgrowth in other types of neurons.
  • Standard methods are used to isolate spinal motor neurons.
  • hippocampal neurons a female rat of 19 days gestation is killed by cervical dislocation, and the fetuses are removed from the uterus. Their brains are removed and placed in ice-cold medium of Leibovitz (L15, Gibco, Invitrogen). Meninges are carefully removed, and the hippocampus dissected out.
  • the hippocampal neurons are dissociated by trypsinization for 30 minutes at 37 0 C (Trypsin- EDTA; Gibco) in the presence of DNAse I (Roche; Meylan). The reaction is stopped by the addition of DMEM (Gibco) cell culture medium with 10% of FBS (Gibco).
  • the suspension is triturated with a 10-mL pipette using a needle syringe 21G and centrifuged at 350 x g for 10 minutes at room temperature.
  • the resulting pellet is resuspended in culture medium containing Neurobasal medium (Gibco) supplemented with 2% B27 supplement (Gibco) and 2 mM of glutamine (Gibco).
  • Viable cells are counted in a Neubauer cytometer using the trypan blue exclusion test (Sigma) and seeded on the basis of 30,000 cells per Petri dish (Nunc) precoated with poly-L-lysine.
  • the length measurements are made by analysis of the pictures using software from Image-Pro Plus (France). The results are expressed as mean (s.e.m.). Statistical analysis of the data is performed using one way analysis of variance (ANOVA). Where applicable, Fisher's PLSD test is used for multiple pairwise comparison. The level of significance is set at p ⁇ 0.05.
  • the effect of asenapine on neurite outgrowth using primary hippocampal neurons is evaluated by measuring neurite length (expressed % of control) and number of neurites per neuron.
  • the effects of vehicle, asenapine and BDNF (50 ng/mL) are determined after incubations of 24 hours, 48 hours and 72 hours.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vitro model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vitro model system.
  • Asenapine is tested to determine its ability to increase neurogenesis in vivo. In particular, the ability of asenapine to promote neurogenesis in the brain (such as hippocampal neurogenesis) of healthy rats is determined.
  • Wistar rats are obtained from Charles River or Harlan Winkelmann (Germany).
  • mice Male rats are approximately 3 months old upon arrival at the animal colony. Animals are kept in an animal facility under standardized conditions and according to the appropriate institutional animal care and welfare guidelines. A record of bodyweights is maintained. The animals are allowed to acclimatize for at least one week prior to any experimental manipulations. Twelve rats per group are maintained on a 12 hour light/dark cycle. Three backup animals are maintained in order to compensate for animal loss. All rats are housed in groups of four per cage and have ad libitum access to food and water.
  • Rats are randomly allocated to four different treatment groups receiving intraperitoneal (i.p.) 5-bromo-2-deoxyuridine (BrdU, Sigma #B9285, 50 mg/kg body weight (b.w.)) and either (i) asenapine at 10 mg/kg b.w./twice a day; (ii) asenapine at 30 mg/kg b.w./twice a day; (iii) asenapine at 60 mg/kg b.w./twice a day; or (iv) 0.2 mL vehicle (saline) twice a day.
  • PrdU 5-bromo-2-deoxyuridine
  • BrdU a synthetic nucleoside analog of thymidine
  • Asenapine and vehicle are administered orally twice a day in a volume of 0.2 mL. BrdU is administered every other day.
  • the daily asenapine or vehicle treatment is performed several minutes before BrdU treatment.
  • animals are sacrificed approximately four hours after the last asenapine treatment and one day after the last BrdU treatment. Diluted asenapine is prepared fresh daily. [0213] At sacrifice, the rats are sedated using standard anesthesia.
  • the brains are cut sagittally using a cryotome and stored at -2O 0 C until staining.
  • the secondary antibodies are a Cy-3-conjugated pure affine goat anti-mouse IgG (H+L) 1:200 (Jackson ImmunoResearch, Cambridgeshire, UK) and a Cy 2-conjugated pure affine F(ab') 2 fragment of donkey anti-sheep IgG (H+L) 1:100 (Jackson ImmunoResearch, Cambridgeshire, UK). Briefly, the anti-NeuN antibody is incubated overnight at 4°C, the Cy3 antibody is incubated the next day for one hour at room temperature, followed by the anti-BrdU antibody overnight at 4 C C and the Cy2 antibody for one hour at room temperature.
  • Tiled images of the sagittal slice including the cortex and the hippocampus are recorded at 200-fold magnification.
  • Each single image used a PCO PixelFly camera mounted on a NikonE800 microscope equipped with a software controlled (StagePro) automatic table. Both fluorescent colors, red for NeuN and green for BrdU, are recorded separately. For quantification, the images are merged.
  • the evaluated variables include the region area, the absolute number of BrdU positive cells, the number of BrdU positive neurons, and the latter two values relative to the measured region area. Evaluations are concentrated on the whole hippocampus, especially the dentate gyrus and the subventricular zone.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 4 Use of an in vivo model to assay the ability of compounds of the invention to treat, prevent and/or delay the onset and/or the development of a neuronal death-mediated ocular disease.
  • In vivo models of ocular diseases can be used to assay the ability of any of the therapies described herein to treat and/or prevent and/or delay the onset and/or the development of a neuronal death-mediated ocular disease.
  • a neuronal death-mediated ocular disease such as macular degeneration, including the dry form of macular degeneration and/or Stargardt macular degeneration (STGD)
  • STGD Stargardt macular degeneration
  • ELOVL4 mutant mouse model as described by G. Karan et al. (Proc. Natl. Acad. ScL USA, 2005, 102(11):4164-4169).
  • This model involves transgenic mice expressing a mutant form of ELO VL4, which causes the mice to develop significant lipofuscin accumulation by the retinal pigment epithelium (RPE) followed by RPE death and photoreceptor degeneration.
  • RPE retinal pigment epithelium
  • mice While mice apparently do not have maculas (the area within the central retina most directly involved with visual acuity), this model does cause degeneration and death of retinal cells in the center of the retina, similar to age-related macular degeneration (ARMD), and also causes retinal deposits that are very similar to drusen, the deposits often associated with ARMD.
  • ARMD age-related macular degeneration
  • This model is believed to closely resemble human dry form macular degeneration and STGD.
  • a high dose of compounds of Formula I-III is a therapy containing 36 ⁇ g/g of body weight per day, or 720 ⁇ g/mouse per day of a therapeutic compound of Formula I, II, or III (e.g., asenapine).
  • a low dose of a therapy is a therapy containing 12 ⁇ g/g of body weight per day, or 240 ⁇ g/mouse per day of a therapeutic compound of Formula I, II, or III (e.g., asenapine).
  • Drinking water therefore contains 240 ⁇ g/mL (high dose) and 80 ⁇ g/mL (low dose) of a therapy.
  • the exact amount of therapy consumed by each animal may be determined retrospectively.
  • neuroprotective effects of compounds of Formula I, Formula II or Formula III may also be tested in this protocol at lower doses, including 0.01 mg/kg, 0.05 mg/kg, 0.10 mg/kg, 1 mg/kg, and 5 mg/kg, or using other models of a neuronal death-mediated ocular disease.
  • Histological sectioning and quantification may be by the methods described by G. Karan et al. (Proc. Natl. Acad. ScL USA, 2005, 102(11):4164-4169), such as those involving microscopy.
  • endpoints may be considered, such as: (1) body weights taken once weekly;
  • mice cageside clinical observations of the mice, such as once/daily to twice/weekly with observations recorded in a lab notebook; (3) collection and analysis of terminal plasma sample for each mouse, with samples kept in EDTA for pharmacokinetic or other analysis; (3) collection and analysis of water bottle samples taken from time to time to document that the therapy is stable during the period in which it is available to the mouse in the water (e.g., save a 0.5 to 1 mL sample, freeze at -80 0 C).
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 5 Anti-ischemic action of asenapine monotherapy or combination therapy in a rat brain model of ischemia produced by irreversible occlusion of the carotid arteries.
  • Rat brain ischemia produced by irreversible occlusion of the carotid arteries, is performed in accordance with "Methodological instructions for the experimental study of preparations for the treatment of cerebral circulation and migraine,” in “Handbook on the experimental (preclinical) study of new pharmacological substances,” Meditsina, Moscow, 2005, pp. 332-338.
  • the animals are divided randomly into groups: group one rats are given asenapine intraperitoneally at 0.1 mg/kg administered 30 minutes after the ligature is tied, then daily for 14 days after operation; group two rats are given nimodipine intraperitoneally at 0.1 mg/kg administered 30 minutes after the ligature is tied, then daily for 14 days after operation. Group one and group two animals are experiencing an acute cerebral circulation disturbance at the time of drug administration. Control group and sham-operated animals are given equivalent volumes of physiological saline (0.9% sodium chloride) at the same times.
  • the data is processed statistically with the aid of the Biostat program, using parametric and nonparametric methods.
  • the number of deaths are recorded in control and experimental groups following surgery, and throughout treatment.
  • Asenapine is expected to reduce the number of rats which died as a result of the ischemia.
  • Nimodipine is expected to have a lesser ability to reduce death of the animals.
  • Rats in the group of animals with ischemic insult are expected to exhibit neurological deviations, characterized by sluggish, weak and slow movements, hemiptosis and ptosis. Those manifestations are expected to decrease over time following the insult.
  • Asenapine administered intraperitoneally at a dose of 0.1 mg/kg is expected to prevent the development of neurological deficit in rats with ischemia, reliably reducing the number of animals with slowness of movements and bilateral hemiptosis in the first week after insult.
  • Nimodipine administered intraperitoneally at a dose of 0.1 mg/kg is expected to have a less significant effect on the induced neurological deficits.
  • Pathological signs that are evaluated included: (1) sluggish, slow or weak movements; (2) limb weakness; (3) unilateral hemiptosis; (4) bilateral hemiptosis; and (5) unilateral ptosis.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 6 Anti-insult action of asenapine monotherapy or combination therapy in an intracerebral post-traumatic hematoma (hemorrhagic insult) model.
  • the animals are divided into 4 groups: sham-operated, a group of animals with hemorrhagic insult, animals with hemorrhagic insult which received asenapine intraperitoneally at a dose of 0.1 mg/kg, and animals with hemorrhagic insult which received nimodipine intraperitoneally at a dose of 0.1 mg/kg.
  • the effects of the substances are recorded 24 hours, and 3, 7 and 14 days after operation.
  • Dimebon and nimodipine are administered intraperitoneally to animals suffering hemorrhagic insult in an identical dose of 0.1 mg/kg 3-3.5 hours after operation, and then daily for 14 days after operation.
  • An equal volume of physiological saline is administered intraperitoneally to the control groups of animals at identical intervals. Each group consists of 9- 18 animals at the start of the experiment.
  • the neurological deficit in the animals is determined using the McGraw Stroke index as modified by LV. Gannushkina (Functional angioarchitectonics of the brain (1977) (Moscow, Meditsina) p. 224). The severity of the condition is determined from the sum of the corresponding scores. The number of rats with mild symptoms up to 2.5 points on the Stroke- index scale (sluggish movements, limb weakness, unilateral hemiptosis, tremor, circular movements) and with severe manifestations of neurological impairment (from 3 to 10 points) - limb paresis, paralysis of lower limbs, lateral position, is noted.
  • Rat deaths are recorded over a 14 day period of observation, and are compared between the experimental and control groups.
  • the data is processed statistically with the aid of the Biostat program, using parametric and nonparametric methods.
  • Nimodipine in a dose of 0.1 mg/kg is employed as the standard, using the scheme described above. Asenapine is expected to reduce the number of animals dying during the period of observation.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 7 Assaying the effect of asenapine monotherapy or combination therapy on cognitive function and memory in mice. [0238] Method. The action of substances on the memory of animals in which there had been no prior destruction of neurons, is studied using the test of recognition of the new location of a known object ("Object location memory test", B. KoIb, K. Buhrmann, R. McDonald and R. Sutherland, Cereb. Cortex, 6 (1994), pp 664-680; D. Gaffan, Eur. J. NeuroscL, 4 (1992), pp. 381-388; T. Steckler, W.H.I.M. Drinkenburgh, A. Sahgal and J.P. Aggleton, Prog. NeurobioL, 54 (1998), pp. 289-311).
  • Object location memory test B. KoIb, K. Buhrmann, R. McDonald and R. Sutherland, Cereb. Cortex, 6 (1994), pp 664-680
  • D. Gaffan Eur. J. NeuroscL
  • This Object Recognition Test is used to study memory. It provides a reliable, easy-to-use assessment tool for analyzing the effects of test compounds on memory in animals. The test can be applied to normal healthy animals (controls), as well as to animals that are models of various neurode "g&e"-nerative diseases.
  • mice are used to exclude any possible negative effects resulting from hormonal changes associated with menstruation in female mice.
  • the animals are kept in a vivarium with 5 to a cage in 12/12 hours light regime with light from 08.00 to 20.00 and free access to water and food.
  • the observation chamber is made from white opaque organic glass and measured 48x38x30 cm. Brown glass vials with a diameter of 2.7 cm and a height of 5.5 cm are used as the test objects. 2-3 minutes before introducing an animal, the chamber and test objects were rubbed with 85% alcohol. The animals are always placed in the centre of the chamber.
  • Asenapine is dissolved in distilled water and administered intragastrically 1 hour before training in a volume of 0.05 mL per 10 g of animal weight. A corresponding volume of solvent is administered to control animals.
  • mice are brought into the test room and acclimatized for 20-30 minutes. After this, each animal is placed for 10 minutes in an empty behavior chamber, which had been pretreated with alcohol, for familiarization. The animal is then replaced in the cage and taken to the vivarium.
  • mice are brought into the test room, acclimatized for 20-30 minutes and then given asenapine solution intragastrically.
  • the compound Memantine ® which at the present time is widely used in clinical practice to treat disorders of mnestic and cognitive functions of varying origin, is used as a control.
  • One hour after administration of the substance an animal is placed in the behavior chamber, on the bottom of which two identical objects for recognition (glass vials) are placed on a diagonal at a distance of 14.5 cm from the corners.
  • the training time for each animal is 20 minutes After 20 minutes, it is replaced in the cage and returned to the vivarium.
  • Testing is performed 48 hours after training. For this purpose, after acclimatization an animal is placed for 1 minute in the chamber for refamiliarization. After a minute it is removed and one object is placed on the bottom of the chamber in a location known to the animal, and the other in a new location. The time spent investigating each object separately over a period of 10 minutes is recorded with an accuracy of 0.1 second using two electronic stopwatches. The behavior of the animals is observed through a mirror. Purposeful approach of an animal's nose towards an object at a distance of 2 cm or direct touching of an object with the nose is regarded as a positive investigative reaction.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 8 Use of an in vitro model to determine the ability of asenapine to treat, prevent and/or delay the onset and/or the development of MCI.
  • In vivo models of MCI can also be used to determine the ability of any of the therapies described herein to treat, prevent and/or delay the onset and/or the development of MCI in mammals, such as humans.
  • Several animal models of MCI have been developed by others.
  • cognition and neuropathology in the aged-canine (dog) has been used by others as a model for MCI and AAMI (Cotman et al, Neurobiol. Aging., 2002, 23(5):809- 18).
  • ischemia reperfusion injury models of brain hypoperfusion can be used.
  • the two-vessel carotid artery occlusion rat model such as the 2- VO system, results in chronic brain hypoperfusion and mimics MCI and vascular changes in AD pathology (Obrenovich et al, Neurotox Res., 10(l):43-56, 2006).
  • De Ia Torre et al. J. Cereb. Blood Flow Metab., 2005, 25(6):663-7 have reported an aging rat model of chronic brain hypoperfusion (CBH) that mimics MCI.
  • CBH chronic brain hypoperfusion
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vitro model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vitro model system.
  • Example 9 Use of an in vitro model to determine the ability of asenapine to treat, prevent and/or delay the onset and/or the development of AAMI.
  • In vivo models of AAMI can also be used to determine the ability of any of the therapies described herein to treat, prevent and/or delay the onset and/or the development of AAMI in mammals, such as humans.
  • Several animal models of AAMI have been developed by others. For example, as noted in the previous example, the canine represent a higher animal model to study the earliest declines in the cognitive continuum that includes AAMI and MCI observed in human aging (Cotman et al., Neurobiol Aging., 2002, 23(5):809-18).
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vitro model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vitro model system.
  • Example 10 Use of an in vivo model to determine the ability of methods of the invention to treat spinal cord injury.
  • Asenapine is diluted to the appropriate concentration in sterile saline solution.
  • Animals in group 1 are given asenapine at 10 mg/kg twice daily for eight weeks.
  • Animals in group 2 are given asenapine at 30 mg/kg twice daily for eight weeks.
  • Animals in group 3 are given asenapine at 60 mg/kg twice daily for eight weeks.
  • Animals in group 4 are given an identical volume of vehicle (i.e., saline solution) twice daily for eight weeks. Spontaneous mobility in the lower paws and tail is tested in each animal weekly.
  • MSCs multipotential stem cells
  • Differentiation of the MSCs is monitored daily until more than 70% of cells observed in each well have sprouted neurites or shown other signs of differentiation. Cells are then washed with sterile Neurobasal medium, incubated with anti-NeuN antibody, which binds a neuron- specific antigen, and separated on a flow cytometer. Neurons are collected, washed to dissociate the antibody, and collected again in isotonic buffer for administration to paraplegic rats prepared as described above. One group of animals is treated with differentiated neurons, while the control group is treated with an equivalent volume of isotonic buffer. The differentiated neurons are implanted at the site of the spinal transection between T- 13 and L-3. Spontaneous mobility in the lower paws and tail is tested in each animal each week for eight weeks.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 11 Use of an in vivo model to determine the ability of the methods of the invention to treat experimental autoimmune encephalomyelitis ("EAE").
  • EAE experimental autoimmune encephalomyelitis
  • EAE Experimental Autoimmune Encephalomyelitis
  • MS multiple sclerosis
  • EAE has been induced in a number of different animal species including mice, rats, guinea pigs, rabbits, macaques, rhesus monkeys and marmosets.
  • mice and rats are the most commonly used species.
  • In-bred strains are used to reliably produce animals susceptible to EAE. As with humans and MS, not all mice or rats will have a natural propensity to acquire EAE.
  • Neurobasal medium supplemented with 2% B27 and 0.5 mM L-glutamine (all from GIBCO).
  • Cells are plated to an appropriate density in wells on poly-L-lysine-coated plates and incubated at 37 0 C in 5% CO 2 -95% air atmosphere. After the MSCs have adhered to the plates and are growing normally, the cells are treated daily with an effective amount of 10 nM asenapine in saline. Differentiation of the MSCs is monitored daily until more than 70% of cells observed in each well have sprouted neurites or shown other signs of differentiation.
  • MSCs from a desired source i.e., purified from skin, bone marrow or plasma
  • a desired source i.e., purified from skin, bone marrow or plasma
  • sterile Neurobasal medium incubated with anti-NeuN antibody, which binds a neuron- specific antigen, and separated on a flow cytometer.
  • Neurons are collected, washed to dissociate the antibody, and collected again in isotonic buffer for administration to rats having EAE.
  • One group is injected with differentiated neurons at an appropriate site, while the control group is injected with an equivalent volume of isotonic buffer at the same site used in Group I. Severity of EAE symptoms is evaluated weekly for four weeks according to standard clinical diagnostic criteria.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof
  • a second therapy comprising one or more additional compounds, such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 12 Use of an in vivo model to assay the ability of compounds of the invention to treat, prevent and/or delay the onset and/or the development of Huntington's disease.
  • Compounds of Formula I, Formula II or Formula III can be assayed for their ability to inhibit mutant huntingtin-induced neurodegeneration of photoreceptor neurons in Drosophila eyes (which reflect neurodegenerative changes in fly brains). Those compounds can be tested alone, or in combination with other compounds, such as hydrogenated pyrido[4,3-b]indoles ⁇ e.g., dimebon).
  • the insertion of the huntingtin gene responsible for Huntington's disease into the genomes of rodents and Drosophila fruit flies has been shown by others to induce many of the pathological and clinical signs of Huntington's disease seen in humans.
  • Huntington's disease or other related neurodegenerative diseases because it contains a fully functional nervous system with an architecture that separates specialized functions such as vision, smell, learning and memory in a manner not unlike that of mammalian nervous systems. Furthermore, the compound eye of the fruit fly is made up of hundreds of repeating constellations of specialized neurons which can be directly visualized through a microscope and upon which the ability of potential neuroprotective drugs to directly block neuronal cell death can easily be assessed. Finally, among human genes known to be associated with disease, approximately 75% have a Drosophila fruit fly counterpart.
  • mutant huntingtin protein in Drosophila fruit flies results in a fly phenotype that exhibits some of the features of human Huntington's disease.
  • the presumed etiologic agent in Huntington's disease is encoded by a repeated triplet of nucleotides (CAG) which are called polyglutamine or polyQ repeats.
  • CAG nucleotides
  • the severity of Huntington's disease correlates with the length of polyQ repeats inserted into the huntingtin protein. The same polyQ length dependency is seen in Drosophila.
  • a therapy of the invention e.g., a therapy that contains a therapeutic compound of Formula I, Formula II or Formula III (i.e., asenapine) at a dose of, for example, 0, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 100 ⁇ M, 100, 300 ⁇ M, or 1,000 ⁇ M
  • a therapy of the invention is administered to one group of transgenic Drosophila engineered to express the mutant huntingtin protein in all their neurons.
  • This is accomplished by cloning a foreign gene into transposable p-element DNA vectors under control of a yeast upstream activator sequence that is activated by the yeast GAL4 transcription factor.
  • yeast upstream activator sequence that is activated by the yeast GAL4 transcription factor.
  • Those promoter fusions are injected into fly embryos to produce transgenic animals.
  • the foreign gene is silent until crossed to another transgenic strain of flies expressing the GAL4 gene in a tissue specific manner.
  • the Elav>Gal4
  • Eggs are collected for about 20 hours at 25 0 C and dispensed into vials (expected about 70% lethality from Htt effects).
  • a therapy of the invention such as via food containing the desired concentration of a compound of Formula I, Formula II or Formula III (e.g., asenapine)(20 eclosed adults per vial).
  • Flies are scored when 7 days old. Compound-containing food is prepared just before tester flies begin to emerge.
  • the two types of transgenic animals are crossed in order to collect enough closely age-matched controls to study.
  • the crossed age-matched adults (about 20 per dosing group) are placed on compound-containing food for 7 days. Animals are transferred to fresh food daily to minimize any effects caused by instability of the compounds. Survival is scored daily.
  • the average number of photoreceptors at day zero is determined by scoring 7-10 of the newly eclosed tester siblings within six hours of eclosing. This establishes the baseline of degeneration at the time of exposure to therapy. At day 7, animals are sacrificed and the number of surviving photoreceptor neurons is counted.
  • Scoring is by the pseudopupil method where individual functioning photoreceptors are revealed by light focused on the back of the head and visualized as focused points of light under a compound microscope focused at the photoreceptor level of the eye.
  • flies are decapitated and the heads are mounted in a drop of nail polish on a microscopic slide.
  • the head is then covered with immersion oil and light is projected through the eye of the fly using a Nikon EFD-3/Optiphot-2 compound microscope with a 5OX oil objective.
  • the test may be split into multiple days. This allows time for the pseudopupil analysis. Since a difference may be observed between Elav>Gal4;UAS>HttQ93 adult flies that emerge on different days, no therapy controls are set up for each day. To analyze the data, the non-treated adults are compared to the therapy treated adults that emerged on the same day.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, for example a hydrogenated pyrido[4,3-b]indole such as dimebon or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine)
  • a second therapy comprising one or more additional compounds, for example a hydrogenated pyrido[4,3-b]indole such as dimebon or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 13 Use of an in vitro model to assay the ability of compounds of the invention to treat, prevent and/or delay the onset and/or the development of amyotrophic lateral sclerosis.
  • N2a cells e.g., the mouse neuroblastoma cell cline N2a sold by InPro Biotechnology, South San Francisco, CA, USA
  • a mutant SODl in the presence or absence of various concentrations of a compound of the invention (e.g., compounds of Formula I, Formula II or Formula III (e.g., asenapine)).
  • Standard methods can be used for this transfection, such as those described by Y. Wang et al, (J. Nucl. Med., 46(4):667-674, 2005).
  • Cell toxicity can be measured using any routine method, such as cell counting, immuno staining, and/or MTT (3-(4,5-dimethylthazol-2- yl)-2,5-diphenyltetrazolium bromide) assays to determine whether the therapy attenuates mutant SODl-mediated toxicity in N2a cells (see, e.g., U.S. Patent Number 7,030,126; Y. Zhang et al, Proc. Natl. Acad. ScL USA, 99(l l):7408-7413, 2002; or S. Fernaeus et al, Neurosci Letts. 389(3):133-6, 2005).
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, for example a hydrogenated pyrido[4,3-b]indole such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vitro model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine)
  • a second therapy comprising one or more additional compounds, for example a hydrogenated pyrido[4,3-b]indole such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vitro model system.
  • Example 14 Use of an in vivo model to assay the ability of compounds of the invention to treat, prevent and/or delay the onset and/or the development of amyotrophic lateral sclerosis.
  • Formula I, Formula II or Formula III e.g., asenapine described herein to treat, prevent and/or delay the onset and/or the development of ALS in mammals, such as humans.
  • ALS a progressive neuron degeneration
  • Several animal models of ALS or motor neuron degeneration have been developed by others, such as those described in U.S. Patent Nos. 7,030,126 and 6,723,315.
  • transgenic mice expressing mutated forms of SOD responsible for the familial forms of ALS have been constructed as murine models of ALS (U.S. Patent Number 6,723,315).
  • Transgenic mice overexpressing mutated human SOD carrying a substitution of glycine 93 by alanine have a progressive motor neuron degeneration expressing itself by a paralysis of the limbs, and die at the age of 4-6 months (Gurney et al, Science, 264, 1772-1775, 1994).
  • the first clinical signs consist of a trembling of the limbs at approximately 90 days, then a reduction in the length of the step at 125 days.
  • vacuoles of mitochondrial origin can be observed in the motor neurons from approximately 37 days, and a motor neurons loss can be observed from 90 days.
  • Attacks on the myelinated axons are observed principally in the ventral marrow and a little in the dorsal region. Compensatory collateral reinnervation phenomena are observed at the level of the motor plaques.
  • FALS G93A mice constitute a very good animal model for the study of the physiopathological mechanisms of ALS as well as for the development of therapeutic strategies. These mice exhibit a large number of histopathological and electromyographic characteristics of ALS.
  • the electromyographic performances of the FALS G93A mice indicate that they fulfill many of the criteria for ALS: (1) reduction in the number of motor units with a concomitant collateral reinnervation, (2) presence of spontaneous denervation activity (fibrillations) and of fasciculation in the hind and fore limbs, (3) modification of the speed of motor conduction correlated with a reduction in the motor response evoked, and (4) no sensory attack.
  • FALS G93A mice are available from Transgenic Alliance (L'Arbresle, France). Additionally, heterozygous transgenic mice carrying the human SODl (G93A) gene can be obtained from the Jackson Laboratory (Bar Harbor, ME, USA) (U.S. Patent Number 7,030,126). These mice have 25 copies of the human G93A SOD mutation that are driven by the endogenous promoter. Survival in the mouse is copy number dependent. Mouse heterozygotes developing the disease can be identified by PCR after taking a piece of tail and extracting DNA.
  • a line of Xt/pmn transgenic mice has also been used previously as another murine model of ALS (U.S. Patent Number 6,723,315). These mice are obtained by a first crossing between C57/B156 or DBA2 female mice and Xt pmn + /Xt + pmn male mice (strain 129), followed by a second between descendants Xt pmn + /Xt + pmn + heterozygous females (Nl) with initial males.
  • Xt pmn mice carrying an Xt allele (demonstrated by the Extra digit phenotype) and a pan allele (determined by PCR) are chosen for the future crossings.
  • mice (B6SJL) are purchased to breed with the transgenic males that overexpress a mutated SOD carrying a substitution of glycine 93 by alanine (e.g., FALS G93A mice).
  • Two females are put in each cage with one male and monitored at least daily for pregnancy. As each pregnant female is identified, it is removed from the cage and a new nonpregnant female is added. Since 40-50% of the pups are expected to be transgenic, a colony of, for example, at least 200 pups can be born at approximately the same time. After genotyping at three weeks of age, the transgenic pups are weaned and separated into different cages by sex.
  • At least 80 transgenic mice (40 male and 40 female) are randomized into four groups: 1) vehicle treated (20 mice); 2) dose 1 (3 mg/kg/day; 20 mice); 3) dose 2 (10 mg/kg/day; 20 mice); and 3) dose 3 (30 mg/kg/day; 20 mice). Mice are evaluated daily. This evaluation includes analysis of weight, appearance (fur coat, activities, etc.) and motor coordination. Treatment starts at approximate stage 3 and continues until mice are euthanized.
  • a compound of Formula I, Formula II or Formula III e.g., asenapine is administered to the mice in their food.
  • the neuroprotective effects of a compound of the invention may also be tested in this protocol at lower doses, including 0.01 mg/kg, 0.05 mg/kg, 0.10 mg/kg, 1 mg/kg, and 5 mg/kg, or using other models of ALS.
  • the onset of clinical disease is scored by examining the mouse for tremor of its limbs and for muscle strength. The mice are lifted gently by the base of the tail to note any muscle tremors, and the hind limb extension is measured. Muscle weakness is reflected in the inability of the mouse to extend its hind limbs.
  • mice are scored on a five point scale for symptoms of motor neuron dysfunction: 5 - no symptoms; 4 - weakness in one or more limbs; 3 - limping in one or more limbs; 2 - paralysis in one or more limbs; 1 - animal negative for reflexes, unable to right itself when placed on its back.
  • mice showing signs of paralysis moistened food pellets are placed inside the cage.
  • nutritional supplements are administered through assisted feeding (Ensure ® , p.o., twice daily).
  • Normal saline is supplemented by intraperitoneal administration of 1 ml saline twice daily if necessary.
  • mice are weighed daily. If necessary, mice are cleaned by the research personnel, and the cage bedding is changed frequently. At end-stage disease, mice lay on their sides in their cage. Mice are euthanized immediately if they cannot right themselves within 10 seconds, or if they lose 20% of their body weight.
  • the effect of compounds of Formula I, Formula II or Formula III ⁇ e.g., asenapine) in the ALS mouse model can be further characterized using standard methods to measure the size of the bicep muscles, the muscle morphology, the muscle response to electric stimulation, the number of spinal motor neurons, muscle function, and/or the amount of oxidative damage, e.g., as described in U.S. Patent Nos. 6,933,310 or 6,723,315.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, for example a hydrogenated pyrido[4,3-b]indole such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine)
  • a second therapy comprising one or more additional compounds, for example a hydrogenated pyrido[4,3-b]indole such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 15 Use of human clinical trials to determine the ability to compounds of the invention to treat, prevent and/or delay the onset and/or the development of Parkinson's disease
  • any compounds of Formulas I- III e.g., asenapine
  • combination therapies described herein can also be tested in humans to determine the ability of the compound or combination therapy to treat, prevent and/or delay the onset and/or the development of Parkinson's disease.
  • Standard methods are used for these clinical trials.
  • subjects with Parkinson's disease are enrolled in a tolerability, pharmacokinetics and pharmacodynamics phase I study of a hydrogenated pyrido [4,3-b] indole using standard protocols. Then a phase II, double-blind randomized controlled trial is performed to determine the efficacy of the hydrogenated pyrido [4,3-b] indole using standard protocols.
  • SH cells and SY-SH5Y cells are maintained in EMEM supplemented with 10% FBS, at 37°C, 5% CO 2 .
  • SH-SY5Y cells are maintained in a 1:1 mixture of EMEM and F12 medium, supplemented with 10% FBS at 37°C, 5% CO 2 .
  • Cells are seeded at 3x10 4 cells per well in 96-well plates containing 100 ⁇ l of the required medium. A day after seeding, cells are treated with different concentrations of ionomycin in MEM medium without serum (assay medium) in triplicate for 24 hours in a final volume of 100 ⁇ l. Cell viability is determined by the MTS reduction assay as follows. MTS (20 ⁇ l) is added to each well for at least 1 h at 37°C. Absorbance at 490 nm is measured using a microplate reader. Asenapine at various concentrations is used to study the effect on ionomycin- treated cells. Cells are seeded at the same density as previously detailed.
  • the cells are treated for 24 h with a solution containing 1.5 ⁇ M ionomycin and different concentrations of asenapine in a final volume of 100 ⁇ l.
  • Each experiment is performed in triplicate and the cell viability was determined by the MTS reduction assay. The results are graphed using control cells (incubated with assay medium only) as reference. Percent (%) viability is the percent of MTS signal for each sample relative to the control (no asenapine and no ionomycin treatment). Three independent experiments are considered for statistical analysis. A non-parametric ANOVA followed by a Dunnett Multiple Comparisons Post Test analysis is used.
  • Example 17 Use of an in vivo model to assay the ability of compounds of the invention to inhibit canine cognitive dysfunction syndrome
  • the following exemplary experimental parameters can be used to assay the ability of compounds of Formula I, Formula II or Formula III (e.g., asenapine) to inhibit canine cognitive dysfunction syndrome.
  • therapies that result in an increase in activity such as an increase in day time activity), an increase in locomotor activity, an increase in curiosity, or an increase in exploratory behavior are expected to be useful for inhibiting canine cognitive dysfunction syndrome (e.g., to cause symptomatic improvement of age-associated behavioral deficits in dogs).
  • An exemplary test facility contains 2 areas for dog housing.
  • the first consists of 32 stainless steel pens in opposing rows of 16. Each pen is 5 feet by 16 feet, with 2 foot by 4 foot perches. Some of the pens are divided in half (2.5 feet by 16 feet).
  • the second consists of 24 galvanized steel pens in opposing rows of 12. In both areas, the floors are epoxy painted and heated.
  • the exterior walls of the facility have windows near the ceiling (approximately 10 feet from ground level) that allow natural light to enter the facility.
  • Dogs are housed generally four per cage based on compatibility and sex. A natural light-dark schedule is used. The pens are cleaned daily with a power washer.
  • Dogs are allowed free access to well water via a wall-mounted automatic watering system or in bowls.
  • the dogs are fed a standard adult maintenance food (e.g., Purina Pro Plan® Chicken & Rice) once daily, with the amount adjusted to maintain a constant body weight.
  • a standard adult maintenance food e.g., Purina Pro Plan® Chicken & Rice
  • Housing temperature and humidity is held relatively constant by automated temperature control and continuous ventilation.
  • Room environmental conditions have design specifications as follows: single-pass air supply with a minimum of approximately 2100 c.f. filtered air changes per minute, relative humidity of 60 ⁇ 10%, temperature of 20 ⁇ 3 0 C, and a natural light- dark cycle.
  • Enrichment is provided by the presence of a pen mate and/or play toys. All dogs receive veterinary examinations prior to initiation in the study. Over the course of the study, trained personnel record all adverse events and contact the responsible veterinarian or study director when necessary.
  • Formula I, Formula II or Formula III are prepared for each dog according to weight.
  • the following doses of a therapy of the invention may be used: 2, 6 and 20 mg/kg.
  • the neuroprotective effects of a therapy of the invention may also be tested in this protocol at lower doses, including 0.01 mg/kg, 0.05 mg/kg, 0.10 mg/kg, 1 mg/kg, and 5 mg/kg, or using other models of canine cognitive dysfunction syndrome.
  • Technicians not otherwise involved in the study prepare the capsules.
  • subjects are administered empty gelatin capsules.
  • the test and control articles are administered to the dogs PO within meatballs of moist dog food once daily. Individual subjects are administered the capsule at the same time on each treatment day.
  • test block refers to the
  • the first test block is a control and no subject receives treatment during those seven days.
  • the study then follows a Latin-square design, in which all of the subjects are tested at all the three dose levels of the test article in a different order (see Table 3 below). To accomplish this, the twelve subjects are divided into six groups of two subjects balanced for sex and age to the extent possible.
  • Table 3 Canine Groups (Groups A-F refer to canine groups that each have two dogs) and Dose Order (A in the Dose Order column refers to dose of 2 mg/kg; B in the Dose Order column refers to dose of 6 mg/kg and C in the Dose Order column refers to dose of 20 mg/kg).
  • each group receives three doses of the test article in the order prescribed for that group.
  • subjects receive their respective treatment for the first four days.
  • subjects are tested on the curiosity test twice; the first test is administered one hour after article administration and the second test four hours after article administration. The remaining three days are considered washout days for each test block (Table 4).
  • an Actiwatch ® collar is placed on each dog. The collar remains on for the duration of the study. All behavioral testing follows previously established protocols. For behavioral tests conducted in the open field arena, data analyses are conducted using the DogAct behavioral software (CanCog Technologies Inc., Toronto, ON, Canada). Actiware-Rhythm ® software is used to obtain activity counts for the day-night measure. The Actiwatch ® data are analyzed to look at both changes in activity pattern temporally linked to treatment and changes in day/night activity.
  • each behavioral measure is analyzed individually using a repeated measures ANOVA with dose (control, 2, 6, and 20 mg/kg), test (first and second) as within-subject variables and order as a between- subject variable.
  • Activity is a marker associated with cognition. Activity is evaluated as a function of dose and time following treatment as well as a function of treatment day.
  • Post-dose activity patterns and twenty-four hour activity rhythms are assessed using the Actiwatch ® method, which detects alterations in activity and changes in phase of the activity cycle as described previously (Siwak et al., 2003, "Orcadian Activity Rhythms in Dogs Vary with Age and Cognitive Status," Behav. Neurosci., 111:813-824). Briefly, general activity patterns are monitored for 28 continuous days using the Mini-Mitter ® Actiwatch- 16 ® activity monitoring system (Mini-Mitter Co., Inc., Bend, OR) adapted for dogs. The Actiwatch- 16 ® contains an activity sensor that is programmed to provide counts of total activity at 5 minute intervals. Putting the Actiwatch-16 ® on a dog's collar allows for recording uninterrupted patterns of activity and rest.
  • the first analysis of the Actiwatch ® data is intended to provide an overall picture of the post-dosing effect of the therapy on behavioral activity. Accordingly, data for the 5-hour period following dosing is first segregated into 5 one-hour blocks. Thus, each subject's data for each treatment day consists of 5 consecutive one -hour activity scores. The data are then analyzed with a repeated measures analysis of variance, with time post dosing (1-5 hours), treatment days (1-4 for each condition) and dose (control, 2, 6, and 20 mg/kg) as within subject variables. Test order serves as between subject variables in the initial analysis.
  • day/night activity data are analyzed with repeated-measures ANOVA, with dose, wash-in day, and phase as within-subject variables and test order as a between- subject variable.
  • the open field activity arena consists of an empty test room (approximately 8 feet by 10 feet) with strips of electrical tape applied to the floor in a grid pattern of rectangles to facilitate tracking.
  • the floor of the test room is mopped prior to testing and between dogs to reduce olfactory cues from affecting testing.
  • the dogs are placed in the test room and their behavior is videotaped over a 5- or 10-minute period.
  • all dogs are tested on the control and 20 mg/kg dose and a separate analysis is carried out comparing control and high dose treatments.
  • the movement pattern of the dog within the test room is recorded.
  • keyboard keys are pressed to indicate the frequency of occurrence of the various behaviors including: sniffing, urinating, grooming, jumping, rearing, inactivity and vocalization.
  • the software also provides a total measure of distance for locomotor activity.
  • the interactions with the objects picking-up, contacting, sniffing and urinating on the objects) are assessed and used as measures of exploratory behavior.
  • Urination frequency indicates marking behavior.
  • Combination therapy comprising a method of administering to an individual in need thereof a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine) and a second therapy comprising one or more additional compounds, for example a hydrogenated pyrido[4,3-b]indole such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • a first therapy comprising a compound of Formula I, Formula II or Formula III (e.g., asenapine)
  • a second therapy comprising one or more additional compounds, for example a hydrogenated pyrido[4,3-b]indole such as dimebon, or a pharmaceutically acceptable salt thereof is also tested in this in vivo model system.
  • Example 18 Randomized, double-blinded, placebo-controlled Alzheimer's disease study using dimebon.
  • R 1 and R 3 are methyl, and R 2 is 2-(6-methyl-3-pyridyl)-ethyl.
  • ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the Neuropsychiatric Inventory measures the patients' behavior and psychiatric disturbance in 12 domains including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibitions, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating.
  • An ADL inventory assesses the impact of cognitive impairment on activities of daily living. Eighty four percent of patients completed the trial (dimebon 87.6; placebo 81.9). All subjects enrolled were included in the intention-to-treat analysis. Thus, the analysis includes all randomized patients, even those who discontinued the study prior to study completion.
  • MMSE was 18.3 (SD 3.3).
  • Treatment with dimebon also resulted in significant improvements in all 5 endpoints when the mean baseline scores were compare with the week 26 scores. Fewer dimebon-treated patients experienced serious adverse events than did placebo patients (2.2% vs. 7.4%). The most common adverse event in dimebon-treated patients was dry mouth (13.5%).
  • Dimebon-treated patients were significantly improved compared to placebo patients on all five endpoints.
  • dimebon-treated patients were significantly improved on all five endpoints at 6 months (i.e., week 26) and 12 months (i.e., week 52) as compared to mean baseline assessments at the beginning of the trial.
  • Dimebon is a well-tolerated drug that improved cognition, function and behavior in patients with mild-moderate Alzheimer's disease.
  • Example 19 Randomized, double-blinded, placebo-controlled Alzheimer's disease study using asenapine.
  • Example 18 A similar study as that shown in Example 18 may be conducted with asenapine, or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing.
  • Example 20 Use of an in vivo model to determine the ability of compounds of the invention to treat, prevent and/or delay the onset and/or the development of Alzheimer's disease
  • In vivo models of Alzheimer's disease can also be used to determine the ability of any of the compounds described herein to treat, prevent and/or delay the onset and/or the development of Alzheimer's disease in mammals, such as humans.
  • An exemplary animal model of Alzheimer's disease includes transgenic mice over-expressing the 'Swedish' mutant amyloid precursor protein (APP; Tg2576; K670N/M671L; Hsiao et al, 1996, Science, 274:99-102). The phenotype present in these mice has been well-characterized (Holcomb LA et al., 1998, Nat. Med., 4:97-100; Holcomb LA et al, 1999, Behav.
  • Standard methods can be used to determine whether any of the combination therapies of the invention decrease the amount of AB deposits in the brains of these mice (see, for example, WO 2004/032868, published April 22, 2004).
  • Example 21 Use of an in vivo model to evaluate the ability of asenapine to enhance cognition, learning and memory in scopolamine-treated rats.
  • the two-trial object recognition paradigm developed by Ennaceur and Delacour in the rat is used as a model of episodic memory.
  • the paradigm is based on spontaneous exploratory activity of rodents and does not involve rule learning or reinforcement.
  • the object recognition paradigm is sensitive to the effects of ageing and cholinergic dysfunction. See, e.g., Scali, C, et al., (1994), Neurosci. Letts. 170:117-120; and Bartolini, L., et al., (1996), Biochem. Behav. 53:277-283.
  • 220-300 grams are obtained from Centre d'Elevage (Rue Janvier, B. P. 55, Le Genest-Saint-Isle 53940, France).
  • the animals are housed in groups of 2 to 4 in polypropylene cages (with a floor area of 1032 cm 2 ) under standard conditions: at room temperature (22 ⁇ 2°C), under a 12 hour light/12 hour dark cycle, with food and water provided ad libitum. Animals are permitted to acclimate to environmental conditions for at least 5 days before therapy begins, and are numbered on their tails with indelible marker.
  • the experimental arena is a square wooden box (60 cm x 60 cm x 40 cm) painted dark blue, with 15 cm x 15 cm black squares under a clear plexiglass floor.
  • the arena and objects placed inside the arena are cleaned with water between each trial to eliminate any odor trails left by rats.
  • the arena is placed in a dark room illuminated only by halogen lamps directed towards the ceiling in order to produce a uniformly dim light in the box of approximately 60 lux.
  • the day before testing animals are allowed to freely explore the experimental arena for three minutes in the presence of two objects (habituation). Animals to be tested are placed in the experimental room at least 30 minutes before testing.
  • mice are submitted to two trials separated by an interval of 120 minutes.
  • first, or acquisition, trial (Ti) rats are placed in the arena, which is prepared with two identical objects. The time required for each animal to complete 15 seconds of object exploration is determined, with a cut-off time of four minutes. Exploration is considered to be directing the nose at a distance less than 2 centimeters ("cm") from the object and/or touching the object.
  • second, or testing, trial (T 2 ) one of the objects presented in the first trial is replaced with an unknown or novel object, while the second, familiar object is left in place. Rats are placed back in the arena for three minutes, and exploration of both objects is determined. Locomotor activity of rats (number of times rats cross grid lines visible under the clear plexiglass floor) is scored for during Ti and T 2 .
  • the rats are sacrificed by an overdose of pentobarbital given intraperitoneally.
  • Asenapine and scopolamine are administered simultaneously prepared freshly each day. Scopolamine is purchased from Sigma Chemical Co. (Catalog No.S-1875; St. Quentin Fallavier, France) and may be dissolved in saline to a concentration of 0.06 mg/mL.
  • Asenapine or its vehicle and scopolamine are administered forty minutes before the acquisition trial (Ti).
  • the volume of administration is 5 ml/kg body weight for compounds administered intraperitoneally or subcutaneously and 10 ml/kg for compounds administered orally.
  • the experiments may be repeated substantially as described using any of the compounds of Formulas I- III described herein or modified as needed for combination therapies described herein, such as dimebon and asenapine.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés, des trousses et des compositions pour le traitement, la prévention, le retardement de l’apparition et/ou le retardement du développement d’indications neurales et non neurales à l’aide d’asénapine ou d’un sel pharmaceutiquement acceptable de celle-ci, soit seul, soit conjointement avec un autre composé ou sel pharmaceutiquement acceptable de celui-ci. L’invention concerne également des procédés, des trousses et des compositions pour le traitement, la prévention, le retardement de l’apparition et/ou le retardement du développement d’indications neurales et non neurales qui entraînent la mort cellulaire et ou la baisse de la fonction cellulaire qui bénéficierait de l’activation, la différenciation et/ou la prolifération d’un ou plusieurs types cellulaires. L’invention concerne également des procédés, des trousses et une composition pour la stimulation de l’excroissance de neurites et/ou l’amélioration de la neurogénèse chez un individu présentant une indication neurale ou non neurale à l’aide d’asénapine ou d’un sel pharmaceutiquement acceptable de celle-ci.
PCT/US2009/042451 2008-04-30 2009-04-30 Utilisation d’asénapine et composés associés pour le traitement de maladies ou de conditions neurales ou non Ceased WO2009135091A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US4934608P 2008-04-30 2008-04-30
US61/049,346 2008-04-30
US6045208P 2008-06-10 2008-06-10
US6043808P 2008-06-10 2008-06-10
US61/060,438 2008-06-10
US61/060,452 2008-06-10

Publications (1)

Publication Number Publication Date
WO2009135091A1 true WO2009135091A1 (fr) 2009-11-05

Family

ID=41255440

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/042451 Ceased WO2009135091A1 (fr) 2008-04-30 2009-04-30 Utilisation d’asénapine et composés associés pour le traitement de maladies ou de conditions neurales ou non

Country Status (1)

Country Link
WO (1) WO2009135091A1 (fr)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110195049A1 (en) * 2008-10-13 2011-08-11 Biovista, Inc. Compositions and methods for treating multiple sclerosis
US8063032B2 (en) 2009-02-11 2011-11-22 Sunovion Pharmaceuticals Inc. Histamine H3 inverse agonists and antagonists and methods of use thereof
WO2011039675A3 (fr) * 2009-09-30 2011-12-29 Pfizer Inc. Formes posologiques thérapeutiques transdermiques de latrepirdine
EP2524919A1 (fr) 2011-05-17 2012-11-21 Sandoz AG Nouveaux sels cristallins d'asénapine avec des di-acides et des tri-acides cristallins
EP2524920A1 (fr) 2011-05-17 2012-11-21 Sandoz AG Nouvelles formes salines cristallines d'hydrochlorure d'asénapine
US8791132B2 (en) 2011-02-18 2014-07-29 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US8859561B2 (en) 2009-09-23 2014-10-14 Medivation Technologies, Inc. Pyrido[4,3-b]indoles and methods of use
US8906925B2 (en) 2008-10-31 2014-12-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles containing rigid moieties
US8927571B2 (en) 2009-04-29 2015-01-06 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8999977B2 (en) 2008-03-24 2015-04-07 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US8999978B2 (en) 2007-10-25 2015-04-07 Medivation Technologies, Inc. Tetracyclic compounds
US9006234B2 (en) 2009-09-23 2015-04-14 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US9035056B2 (en) 2011-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
US9034865B2 (en) 2010-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9040519B2 (en) 2010-02-18 2015-05-26 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9079904B2 (en) 2009-09-23 2015-07-14 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9115137B2 (en) 2008-01-25 2015-08-25 Medivation Technologies, Inc. 2,3,4,5-tetrahydro-1H-pyrido[4,3-B]indole compounds and methods of use thereof
US9187471B2 (en) 2010-02-19 2015-11-17 Medivation Technologies, Inc. Pyrido [4,3-b] indole and pyrido [3,4-b] indole derivatives and methods of use
US9193728B2 (en) 2010-02-18 2015-11-24 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9199985B2 (en) 2011-02-18 2015-12-01 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US9255094B2 (en) 2009-04-29 2016-02-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9260429B2 (en) 2008-03-24 2016-02-16 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9409910B2 (en) 2008-10-31 2016-08-09 Medivation Technologies, Inc. Azepino[4,5-B]indoles and methods of use
US9434747B2 (en) 2011-02-18 2016-09-06 Medivation Technologies, Inc. Methods of treating diabetes
CN107802823A (zh) * 2017-10-27 2018-03-16 胡军 Sh2b衔接蛋白1在治疗帕金森病中的功能应用
US10172854B2 (en) 2012-02-27 2019-01-08 Biovista, Inc. Compositions and methods for treating mitochondrial diseases
CN109952291A (zh) * 2016-09-12 2019-06-28 纽若斯丹公司 与糖尿病相关的神经缺陷的改善
US20190224322A1 (en) * 2016-09-23 2019-07-25 Delpor, Inc. Compositions for small molecule therapeutic agent compounds
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
CN112704672A (zh) * 2018-06-20 2021-04-27 罗曼治疗系统股份公司 含有阿塞那平的透皮治疗系统
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
CN113209068A (zh) * 2013-01-22 2021-08-06 维斯塔津治疗公司 L-4-氯犬尿氨酸的剂型和治疗用途
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11389435B2 (en) 2008-09-15 2022-07-19 Biovista, Inc. Compositions and methods for treating epilepsy
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032108A1 (fr) * 1997-12-19 1999-07-01 Akzo Nobel N.V. Traitement pour la depression
US20060019968A1 (en) * 2004-07-24 2006-01-26 Laboratorios Dr. Esteve S.A. Use of compounds active on the sigma receptor for the treatment of neuropathic pain
US20060052386A1 (en) * 2003-06-12 2006-03-09 Tadeusz Wieloch Sigma ligands for neuronal regeneration and functional recovery
US20060084692A1 (en) * 2004-10-15 2006-04-20 Pfizer Inc. Treatment of bipolar disorders and associated symptoms
US20080064671A1 (en) * 2006-09-08 2008-03-13 Braincells, Inc. Combinations containing a 4-acylaminopyridine derivative

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032108A1 (fr) * 1997-12-19 1999-07-01 Akzo Nobel N.V. Traitement pour la depression
US20060052386A1 (en) * 2003-06-12 2006-03-09 Tadeusz Wieloch Sigma ligands for neuronal regeneration and functional recovery
US20060019968A1 (en) * 2004-07-24 2006-01-26 Laboratorios Dr. Esteve S.A. Use of compounds active on the sigma receptor for the treatment of neuropathic pain
US20060084692A1 (en) * 2004-10-15 2006-04-20 Pfizer Inc. Treatment of bipolar disorders and associated symptoms
US20080064671A1 (en) * 2006-09-08 2008-03-13 Braincells, Inc. Combinations containing a 4-acylaminopyridine derivative

Cited By (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8999978B2 (en) 2007-10-25 2015-04-07 Medivation Technologies, Inc. Tetracyclic compounds
US9181240B2 (en) 2007-10-25 2015-11-10 Medivation Technologies, Inc. Tetracyclic compounds
US9096591B2 (en) 2007-10-25 2015-08-04 Medivation Technologies, Inc. Tetracyclic compounds
US9034880B2 (en) 2007-10-25 2015-05-19 Medivation Technologies, Inc. Tetracyclic compounds
US9115137B2 (en) 2008-01-25 2015-08-25 Medivation Technologies, Inc. 2,3,4,5-tetrahydro-1H-pyrido[4,3-B]indole compounds and methods of use thereof
US9034869B2 (en) 2008-03-24 2015-05-19 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US9051314B2 (en) 2008-03-24 2015-06-09 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US9469641B2 (en) 2008-03-24 2016-10-18 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9260429B2 (en) 2008-03-24 2016-02-16 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US8999977B2 (en) 2008-03-24 2015-04-07 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US11389435B2 (en) 2008-09-15 2022-07-19 Biovista, Inc. Compositions and methods for treating epilepsy
US20110195049A1 (en) * 2008-10-13 2011-08-11 Biovista, Inc. Compositions and methods for treating multiple sclerosis
US8906925B2 (en) 2008-10-31 2014-12-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles containing rigid moieties
US8907097B2 (en) 2008-10-31 2014-12-09 Medivation Technologies, Inc. Pyrido[4,3-b]indoles containing rigid moieties
US9409910B2 (en) 2008-10-31 2016-08-09 Medivation Technologies, Inc. Azepino[4,5-B]indoles and methods of use
US9481676B2 (en) 2008-10-31 2016-11-01 Medivation Technologies, Inc. Azepino[4,5-B]indoles and methods of use
US9458155B2 (en) 2008-10-31 2016-10-04 Medivation Technologies, Inc Pyrido[4,3-b]indoles containing rigid moieties
US8063032B2 (en) 2009-02-11 2011-11-22 Sunovion Pharmaceuticals Inc. Histamine H3 inverse agonists and antagonists and methods of use thereof
US8404670B2 (en) 2009-02-11 2013-03-26 Sunovion Pharmaceuticals Inc. Histamine H3 inverse agonists and antagonists and methods of use thereof
US9255094B2 (en) 2009-04-29 2016-02-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8927571B2 (en) 2009-04-29 2015-01-06 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8859561B2 (en) 2009-09-23 2014-10-14 Medivation Technologies, Inc. Pyrido[4,3-b]indoles and methods of use
US9580425B2 (en) 2009-09-23 2017-02-28 Medivation Technologies, Inc. Pyrido[3,4-b] indoles and methods of use
US9199996B2 (en) 2009-09-23 2015-12-01 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9045482B2 (en) 2009-09-23 2015-06-02 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9271971B2 (en) 2009-09-23 2016-03-01 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9079904B2 (en) 2009-09-23 2015-07-14 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9085580B2 (en) 2009-09-23 2015-07-21 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9006234B2 (en) 2009-09-23 2015-04-14 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
WO2011039675A3 (fr) * 2009-09-30 2011-12-29 Pfizer Inc. Formes posologiques thérapeutiques transdermiques de latrepirdine
US9193728B2 (en) 2010-02-18 2015-11-24 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9034865B2 (en) 2010-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9040519B2 (en) 2010-02-18 2015-05-26 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9433626B2 (en) 2010-02-18 2016-09-06 Medivation Technologies, Inc. Pyrido[4,3-B]indole and pyrido[3,4-B]indole derivatives and methods of use
US9187471B2 (en) 2010-02-19 2015-11-17 Medivation Technologies, Inc. Pyrido [4,3-b] indole and pyrido [3,4-b] indole derivatives and methods of use
US9550782B2 (en) 2011-02-18 2017-01-24 Medivation Technologies, Inc. Compounds and methods for treating diabetes
US9035056B2 (en) 2011-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
US9006263B2 (en) 2011-02-18 2015-04-14 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US8815843B2 (en) 2011-02-18 2014-08-26 Medivation Technologies, Inc. Compounds and methods of treating diabetes
US9434747B2 (en) 2011-02-18 2016-09-06 Medivation Technologies, Inc. Methods of treating diabetes
US9211287B2 (en) 2011-02-18 2015-12-15 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
US8791132B2 (en) 2011-02-18 2014-07-29 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US9527854B2 (en) 2011-02-18 2016-12-27 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US9199985B2 (en) 2011-02-18 2015-12-01 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
WO2012156383A1 (fr) 2011-05-17 2012-11-22 Sandoz Ag Nouveaux sels cristallins d'asénapine contenant des diacides et triacides organiques
WO2012156382A1 (fr) 2011-05-17 2012-11-22 Sandoz Ag Nouvelles formes de sels de chlorhydrate d'asénapine cristallins
EP2524919A1 (fr) 2011-05-17 2012-11-21 Sandoz AG Nouveaux sels cristallins d'asénapine avec des di-acides et des tri-acides cristallins
EP2524920A1 (fr) 2011-05-17 2012-11-21 Sandoz AG Nouvelles formes salines cristallines d'hydrochlorure d'asénapine
US10172854B2 (en) 2012-02-27 2019-01-08 Biovista, Inc. Compositions and methods for treating mitochondrial diseases
CN113209068A (zh) * 2013-01-22 2021-08-06 维斯塔津治疗公司 L-4-氯犬尿氨酸的剂型和治疗用途
US12036198B2 (en) 2013-01-22 2024-07-16 Vistagen Therapuetics, Inc. Dosage forms and therapeutic uses of L-4-chlorokynurenine
CN109952291A (zh) * 2016-09-12 2019-06-28 纽若斯丹公司 与糖尿病相关的神经缺陷的改善
EP3497082A4 (fr) * 2016-09-12 2020-04-29 Neuralstem, Inc. Amélioration de déficits neuronaux associés au diabète
CN109952291B (zh) * 2016-09-12 2022-09-23 纽若斯丹公司 与糖尿病相关的神经缺陷的改善
US20190224322A1 (en) * 2016-09-23 2019-07-25 Delpor, Inc. Compositions for small molecule therapeutic agent compounds
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12138353B2 (en) 2016-12-20 2024-11-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
CN107802823A (zh) * 2017-10-27 2018-03-16 胡军 Sh2b衔接蛋白1在治疗帕金森病中的功能应用
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
CN112704672A (zh) * 2018-06-20 2021-04-27 罗曼治疗系统股份公司 含有阿塞那平的透皮治疗系统
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Similar Documents

Publication Publication Date Title
WO2009135091A1 (fr) Utilisation d’asénapine et composés associés pour le traitement de maladies ou de conditions neurales ou non
US20100178277A1 (en) Methods and compositions for stimulating cells
JP7082186B2 (ja) プリドピジンによる筋萎縮性側索硬化症の治療方法
EP2254598B1 (fr) Agonistes nicotiniques alpha-7 et antipsychotiques
US11197856B2 (en) Bicyclic compounds and methods for their use in treating autism
CN101600461B (zh) 通过干细胞营养物进行的器官的形成和复壮以及酒精损伤的器官的再生
JP2010504338A (ja) 筋萎縮性側索硬化症（ＡＬＳ）の治療のための水素化ピリド［４，３−ｂ］インドール
US7132287B2 (en) Method for neural stem cell differentiation using 5HT-1A agonists
KR20080093453A (ko) 4-아실아미노피리딘 유도체 매개된 신경조직발생
JP2010530371A (ja) 神経学的機能を増強するための作用物質、組成物および方法
US20230340407A1 (en) Method for differentiating pluripotent stem cells into dopaminergic nerve cells in midbrain substantia nigra
JP2022511266A (ja) 陰性症状および障害を処置するため、神経可塑性を増大するため、ならびに神経保護を促進するためのロルペリドンの使用
JPWO2018043476A1 (ja) 筋萎縮性側索硬化症治療剤及び治療用組成物
US20230149355A1 (en) Compositions and methods for modulating trp channel activity
Gingras et al. Synaptic transmission is impaired at neuronal autonomic synapses in agrin‐null mice
CA3195622A1 (fr) Procedes de generation de cellules ciliees de l'oreille interne
Yoon Zic2 to Alx1: Genetic Regulators for Vertebrate Craniofacial and Ocular Morphogenesis
US20200085819A1 (en) Application of 5-ht6 receptor antagonists for the alleviation of cognitive deficits of down syndrome
WO2020186217A1 (fr) Méthodes et compositions de traitement de troubles d'entreposage lysosomial
Sigulinsky Defining the relationship between the homeobox gene Vsx2 and extrinsic signaling in the regulation of retinal progenitor cell properties
HK1147954B (en) Combination of alpha 7 nicotinic agonists and antipsychotics
HK1185794A (en) Combination of alpha 7 nicotinic agonists and antipsychotics

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09739893

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09739893

Country of ref document: EP

Kind code of ref document: A1