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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P25/08—Antiepileptics; Anticonvulsants
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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Definitions

• the instant invention relates to methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis via modulation of angiotensin activity.
• the invention includes methods based on the application of an agent which modulates angiotensin action to stimulate or activate the formation of new nerve cells.
• the angiotensin modulator can be used alone or in combination with another angiotensin modulator, a neurogenic agent, including a neurogenic sensitizing agent, or an anti-astrogenic agent.
• Neurogenesis is a vital process in the brains of animals and humans, whereby new nerve cells are continuously generated throughout the life span of the organism.
• the newly born cells are able to differentiate into functional cells of the central nervous system and integrate into existing neural circuits in the brain.
• Neurogenesis is known to persist throughout adulthood in two regions of the mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus. In these regions, multipotent neural progenitor cells (NPCs) continue to divide and give rise to new functional neurons and glial cells (for review Gage MoI Psychiatry. 2000 May;5(3):262-9).
• SVZ subventricular zone
• NPCs multipotent neural progenitor cells
• Renin and angiotensin are components of the renin-angiotensin system (RAS) and the renin-angiotensin-aldosterone system (RAAS).
• RAS renin-angiotensin system
• RAAS renin-angiotensin-aldosterone system
• Both systems have renin and angiotensin in common, where renin proteolytically cleaves inactive angiotensinogen to form the decapeptide angiotensin I (AI).
• Angiotensin-converting enzyme (ACE) then cleaves AI to form the octapeptide angiotensin II (All).
• All has been observed to be more potent. All acts as a vasoconstrictor to raise arterial blood pressure and decrease blood flow. All also acts on the adrenal cortex, which leads to the release of aldosterone. In turn, aldosterone acts in the kidney to cause resorption of sodium and water from urine. The result in an increase in the fluid volume of blood.
• Angiotensin receptors are G protein-coupled receptors which bind All as a ligand. Subtypes of the receptors include ATj and AT 2 , both of which bind All, and the AT 3 and AT 4 receptors. Both the receptors and ACE have been the targets of manipulation to treat hypertension (high blood pressure) and other conditions. All receptor antagonists, also referred to as angiotensin receptor blockers or ARBs, ATI -receptor antagonists, or saltans, are used to antagonize All activity by preventing All interactions with All receptor(s). ACE inhibitors are used to lower All formation. Additional information is available, for example, in the review by Jackson, et al. in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, pp. 733-754 (New York: McGraw-Hill, 1996).
• aspects of the invention include increasing neurogenesis in cases of a disease, disorder, or condition of the nervous system.
• Embodiments of the invention include methods of treating a neurodegenerative disorder, neurological trauma including brain or central nervous system trauma and/or recovery therefrom, depression, anxiety, psychosis, learning and memory disorders, and ischemia of the central and/or peripheral nervous systems.
• the invention includes methods of stimulating or increasing neurogenesis.
• the neurogenesis may be at the level of a cell or tissue.
• the cell or tissue may be present in an animal subject or a human being, or alternatively be in an in vitro or ex vivo setting.
• neurogenesis is stimulated or increased in a neural cell or tissue, such as that of the central or peripheral nervous system of an animal or human being.
• the methods may be practiced in connection with one or more disease, disorder, or condition of the nervous system as present in the animal or human subject.
• embodiments of the invention include compositions or methods of treating a disease, disorder, or condition by administering one or more modulators of angiotensin activity as described herein.
• a modulator is an aldosterone receptor inhibitor, ACE inhibitor, or rennin inhibitor.
• the modulator is an angiotensin receptor antagonist (also known as angiotensin receptor blockers or ARBs, ATl- receptor antagonists, or saltans).
• angiotensin receptor antagonist also known as angiotensin receptor blockers or ARBs, ATl- receptor antagonists, or saltans.
• antagonists of the ATi, AT 2 , AT 3 , and/or AT 4 receptors are used.
• the invention includes methods of using chemical or biological entities as modulators of angiotensin activity to increase neurogenesis.
• a chemical entity used as a modulator is a sulfhydryl-containing (or mercapto- containing) agent, such as alacepril or captopril (Capoten®) as non-limiting examples.
• the chemical entity is a dicarboxylate-containing agent, such as enalapril (Vasotec® or Renitec®) or enalaprilat; ramipril (Altace® or Tritace® or Ramace®); quinapril (Accupril®); perindopril (Coversyl®) or perindopril erbumine (Aceon®); and lisinopril (Lisodur® or Prinivil® or Zestril®) as non-limiting examples.
• the chemical entity is a phosphonate-containing (or phosphate-containing) agent, such as fosinopril (Monopril®).
• a modulator of angiotensin activity examples include benazepril (Lotensin®), imidapril, moexipril (Univasc®), and trandolapril (Mavik®).
• a modulator is administered in an alternative form such as an ester, that increases biovavailability upon oral administration with subsequent conversion into metabolites with greater activity.
• angiotensin receptor antagonists include candesartan (Atacand® or Ratacand®); eprosartan (Teveten®); irbesartan (Aprovel® or Karvea® or Avapro®); losartan (Cozaar® or Hyzaar®); olmesartan (Benicar®); telmisartan (Micardis® or Pritor®); and valsartan (Diovan®).
• candesartan Alacand® or Ratacand®
• eprosartan Teveten®
• irbesartan Aprovel® or Karvea® or Avapro®
• losartan Cozaar® or Hyzaar®
• olmesartan Benicar®
• telmisartan Micardis® or Pritor®
• valsartan Diovan®
• the invention includes the use of other modulators as well as a combination with one or more than one of the neuro
• the methods include identifying a patient suffering from one or more diseases, disorders, or conditions, or a symptom thereof, and administering to the patient at least one modulator of angiotensin activity as described herein.
• the modulator is alacepril, candesartan, telmisartan, enalapril, lisinopril, and/or captopril.
• the invention provides a method including identification of a subject as in need of an increase in neurogenesis, and administering to the subject one or more modulators as described herein.
• the subject is a patient, such as a human patient.
• the invention further provides a method including administering one or more modulators of angiotensin activity to a subject exhibiting the effects of insufficient amounts of, or inadequate levels of, neurogenesis.
• the subject may be one that has been subjected to an agent that decreases or inhibits neurogenesis.
• an inhibitor of neurogenesis includes opioid receptor agonists, such as a mu receptor subtype agonist like morphine.
• the invention provides for administering one or more modulators to a subject or person that will be subjected to an agent that decreases or inhibits neurogenesis.
• the subject or person may be one that is about to be administered morphine or other opioid receptor agonist, like another opiate, and so about to be subject to a decrease or inhibition of neurogenesis.
• Non-limiting examples include administering a modulator to a subject before, simultaneously with, or after, the subject is administered morphine or other opiate in connection with a surgical procedure.
• Also disclosed are methods for preparing a population of neural stem cells suitable for transplantation comprising culturing a population of neural stem cells (NSCs) in vitro, and contacting the cultured neural stem cells with at least one modulator of angiotensin activity.
• the stem cells are prepared and then transferred to a recipient host animal or human.
• preparation include 1) contact with a modulator until the cells have undergone neurogenesis, such as that which is detectable by visual inspection, marker, or cell counting, or 2) contact with a modulator until the cells have been sufficiently stimulated or induced toward or into neurogenesis.
• the cells prepared in such a non-limiting manner may be transplanted to a subject, optionally with simultaneous, nearly simultaneous, or subsequent administration of a neurogenic agent, or a modulator of angiotensin activity to the subject.
• a neurogenic agent or a modulator of angiotensin activity to the subject.
• the neural stem cells may be in the form of an in vitro culture or cell line, in other embodiments, the cells may be part of a tissue which is subsequently transplanted into a subject, based upon the cell morphology.
• the invention includes methods of stimulating or increasing neurogenesis in a subject by administering a modulator of angiotensin activity.
• the neurogenesis occurs in combination with the stimulation of angiogenesis which provides new cells with access to the circulatory system.
• the invention includes the use of a modulator of angiotensin activity in combination with a neurogenic agent, such as, but not limited to, a PDE inhibitor, such as to PDE3, 4, or 5; or GABA inhibitor.
• a neurogenic agent such as, but not limited to, a PDE inhibitor, such as to PDE3, 4, or 5; or GABA inhibitor.
• PDE inhibitor such as to PDE3, 4, or 5
• GABA inhibitor such as to PDE3, 4, or 5
• certain combinations include candesartan, captopril or telmisartan with ibudilast, enoximone, baclofen, donepezil, vardenafil, rolipram or theophylline.
• the combination of agents may be administered in one formulation, or concurrently or sequentially in more than one formulation.
• FIG. l is a dose-response curve showing effect of the neurogenic agent alacepril on neuronal differentiation. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted. EC 50 was observed at an alacepril concentration of 13 ⁇ M in test cells, compared to 4.7 ⁇ M for the positive control compound.
• FIG. 2 is a dose-response curve showing effect of the neurogenic agent enalapril on neuronal differentiation. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted. EC 5O was observed at an enalapril concentration of 0.5 ⁇ M in test cells, compared to 4.7 ⁇ M for the positive control compound.
• FIG. 3 is a dose-response curve showing effect of the neurogenic agent lisinopril on neuronal differentiation. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted. EC 50 was observed at a lisinopril concentration of 9.1 ⁇ M in test cells, compared to 4.7 ⁇ M for the positive control compound.
• FIG. 4 is a dose-response curve showing effect of the neurogenic agent captopril on neuronal differentiation. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted. EC 50 was observed at a captopril concentration of 3.8 ⁇ M in test cells, compared to 4.7 ⁇ M for the positive control compound.
• FIG. 5 is a dose-response curve showing effect of the neurogenic agent losartan on neuronal differentiation. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted. EC 50 was observed at a losartan concentration of 0.9 ⁇ M in test cells, compared to 4.7 ⁇ M for the positive control compound.
• FIG. 6 is a dose-response curve showing effect of the neurogenic agent benazepril (ACE inhibitor) on neuronal differentiation of human neural stem cells.
• the agent was tested in a concentration response curve ranging from 0.01 uM to 31.6 uM. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted. Benazepril promoted neuronal differentiation of human neural stem cells with an EC 5 o of 3.3 uM in test cells.
• FIG. 7 is a dose-response curve showing effect of the neurogenic agent trandolapril (ACE inhibitor) on neuronal differentiation of human neural stem cells.
• the agent was tested in a concentration response curve ranging from 0.01 uM to 31.6 uM. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted. Trandolapril promoted neuronal differentiation of human neural stem cells with an EC 5 o of approximately 35 uM in test cells.
• FIG. 8 is a dose-response curve showing effect of the neurogenic agent candesartan (angiotensin receptor blocker) on neuronal differentiation of human neural stem cells.
• the agent was tested in a concentration response curve ranging from 0.01 uM to 31.6 uM. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted. Candesartan promoted neuronal differentiation of human neural stem cells with an EC50 of approximately 0.84 uM in test cells.
• FIG. 9 is a dose-response curve showing effect of the neurogenic agent telmisartan (angiotensin receptor blocker) on neuronal differentiation of human neural stem cells.
• the agent was tested in a concentration response curve ranging from 0.001 uM to 3.16 uM. Data is presented as the percentage of the neuronal positive control, with basal media values subtracted.
• Telmisartan promoted neuronal differentiation of human neural stem cells with an EC 50 of approximately 0.03 uM in test cells.
• FIG. 10 is a dose-response curve showing the effect of the neurogenic agents captopril (angiotensin converting enzyme, or ACE, inhibitor) and ibudilast (PDE inhibitor) in combination on neuronal differentiation compared to the effect of either agent alone.
• captopril angiotensin converting enzyme, or ACE, inhibitor
• PDE inhibitor ibudilast
• ibudilast was tested in a CRC ranging from 0.003 ⁇ M to 10.0 ⁇ M and captopril was added at a concentration 3.16-fold higher at each point (for example, the first point in the combined curve reflects a combination of 0.003 ⁇ M ibudilast and 0.01 ⁇ M captopril). Data is presented as the percentage of the neuronal positive control, with basal media values subtracted.
• EC 50 was observed at a captopril concentration of 3.8 ⁇ M or an ibudilast concentration of 6.2 ⁇ M in test cells.
• EC 5O was observed in a combination of captopril at a concentration of 0.15 ⁇ M and ibudilast at a concentration of 0.05 ⁇ M, resulting in a synergistic combination index of 0.05.
• FIG. 11 is a dose-response curve showing the effect of the neurogenic agents captopril (ACE inhibitor) and enoximone (PDE-3 inhibitor) in combination on neuronal differentiation compared to the effect of either agent alone.
• ACE inhibitor neurogenic agents captopril
• PDE-3 inhibitor enoximone
• EC 50 When used alone, EC 50 was observed at a captopril concentration of 3.8 ⁇ M or an enoximone concentration of 6.8 ⁇ M in test cells. When used in combination, EC 5O was observed at a combination of captopril and enoximone at concentrations of 1.1 ⁇ M each, resulting in a synergistic combination index of 0.5.
• FIG. 12 is a dose-response curve showing the effect of the neurogenic agents candesartan (angiotensin II ATI receptor antagonist) and ibudilast (PDE inhibitor) in combination on neuronal differentiation compared to the effect of either agent alone.
• ibudilast was tested in a concentration response curve (CRC) ranging from 0.01 ⁇ M to 10.0 ⁇ M and candesartan was tested in a CRC ranging from 0.01 ⁇ M to 31.6 ⁇ M.
• CRC concentration response curve
• ibudilast was tested in a CRC ranging from 0.003 ⁇ M to 10.0 ⁇ M and candesartan was added at a concentration 3.16-fold higher at each point (for example, the first point in the combined curve reflects a combination of 0.003 ⁇ M ibudilast and 0.01 ⁇ M captopril). Data is presented as the percentage of the neuronal positive control, with basal media values subtracted.
• EC 50 was observed at a candesartan concentration of 2.2 ⁇ M or an ibudilast concentration of 6.2 ⁇ M in test cells.
• EC 50 was observed at the combination of candesartan at a concentration of 0.35 ⁇ M and ibudilast at a concentration of 0.11 ⁇ M, resulting in a synergistic combination index of 0.07.
• FIG. 13 is a dose-response curve showing the effect of the neurogenic agents captopril (ACE inhibitor) and baclofen (GABA agonist) in combination on neuronal differentiation compared to the effect of either agent alone.
• ACE inhibitor neurogenic agents captopril
• baclofen GABA agonist
• EC 50 When used alone, EC 50 was observed at a captopril concentration of 3.8 ⁇ M or a baclofen concentration of 3.2 ⁇ M in test cells. When used in combination, EC 50 was observed at a combination of captopril and baclofen at concentrations of 1.3 ⁇ M each, resulting in a synergistic combination index of 0.88.
• FIG. 14 is a dose-response curve showing the effect of the neurogenic agents captopril (ACE inhibitor) and donepezil (acetylcholinesterase inhibitor) in combination on neuronal differentiation compared to the effect of either agent alone.
• ACE inhibitor acetylcholinesterase inhibitor
• each compound was tested in a concentration response curve ranging from 0.01 ⁇ M to 31.6 ⁇ M.
• the compounds were combined at equal concentrations at each point (for example, the first point in the combined curve consisted of a test of 0.01 ⁇ M captopril and 0.01 ⁇ M donepezil). Data is presented as the percentage of the neuronal positive control, with basal media values subtracted.
• EC 50 When used alone, EC 50 was observed at a captopril concentration of 3.8 ⁇ M or a donepezil concentration of 2.0 ⁇ M in test cells. When used in combination, EC 50 was observed at a combination of captopril and donepezil at concentrations of 0.16 ⁇ M each, resulting in a synergistic combination index of 0.13.
• FIG. 15 is a dose-response curve showing the effect of the neurogenic agents captopril (ACE inhibitor) and vardenafil (ACE, PDE5 inhibitor) in combination on neuronal differentiation compared to the effect of either agent alone.
• ACE inhibitor neurogenic agent
• vardenafil ACE inhibitor
• PDE5 inhibitor PDE5 inhibitor
• each compound was tested in a concentration response curve ranging from 0.01 ⁇ M to 31.6 ⁇ M.
• the compounds were combined at equal concentrations at each point (for example, the first point in the combined curve consisted of a test of 0.01 ⁇ M captopril and 0.01 ⁇ M vardenafil). Data is presented as the percentage of the neuronal positive control, with basal media values subtracted.
• EC 50 When used alone, EC 50 was observed at a captopril concentration of 3.8 ⁇ M or a vardenafil concentration of 8.6 ⁇ M in test cells. When used in combination, EC 50 was observed at a combination of captopril and vardenafil at concentrations of 1.6 ⁇ M each, resulting in a synergistic combination index of 0.69.
• FIG. 16 is a dose-response curve showing the effect of the neurogenic agents telmisartan (angiotensin II ATI receptor antagonist) and rolipram (PDE4 inhibitor) in combination on neuronal differentiation compared to the effect of either agent alone.
• telmisartan angiotensin II ATI receptor antagonist
• PDE4 inhibitor rolipram
• telmisartan was tested in a CRC ranging from 0.001 ⁇ M to 3.16 ⁇ M and rolipram was added at a concentration 10-fold higher at each point (for example, the first point in the combined curve reflects a combination of 0.001 ⁇ M telmisartan and 0.01 ⁇ M rolipram). Data is presented as the percentage of the neuronal positive control, with basal media values subtracted.
• EC 50 was observed at a telmisartan concentration of 0.06 ⁇ M or a rolipram concentration of 2.3 ⁇ M in test cells.
• EC 50 was observed at a concentration of 0.027 ⁇ M telmisartan and 0.27 ⁇ M rolipram, resulting in a synergistic combination index of 0.62.
• FIG. 17 is a dose-response curve showing the effect of the neurogenic agents captopril (ACE inhibitor) and theophylline (PDE inhibitor) in combination on neuronal differentiation compared to the effect of either agent alone.
• ACE inhibitor neurogenic agents captopril
• PDE inhibitor theophylline
• EC 50 When used alone, EC 50 was observed at a captopril concentration of 3.8 ⁇ M or a theophylline concentration of 16.4 ⁇ M in test cells. When used in combination, EC 50 was observed at a combination of captopril and donepezil at concentrations of 0.0.22 ⁇ M each, resulting in a synergistic combination index of 0.07.
• Neurogenesis is defined herein as proliferation, differentiation, migration and/or survival of a neural cell in vivo or in vitro.
• the neural cell is an adult, fetal, or embryonic neural stem cell or population of cells.
• the cells may be located in the central nervous system or elsewhere in an animal or human being.
• the cells may also be in a tissue, such as neural tissue.
• the neural cell is an adult, fetal, or embryonic progenitor cell or population of cells, or a population of cells comprising a mixture of stem cells and progenitor cells.
• Neural cells include all brain stem cells, all brain progenitor cells, and all brain precursor cells.
• Neurogenesis includes neurogenesis as it occurs during normal development, as well as neural regeneration that occurs following disease, damage or therapeutic intervention, such as by the treatment described herein.
• a “neurogenic agent” is defined as a chemical or biological agent or reagent that can promote, stimulate, or otherwise increase the amount or degree or nature of neurogenesis in vivo or ex vivo or in vitro relative to the amount, degree, or nature of neurogenesis in the absence of the agent or reagent.
• treatment with a neurogenic agent increases neurogenesis if it promotes neurogenesis by at least about 5%, at least about 10%, at least about 25%, at least about 50%, at least about 100%, at least about 500%, or more in comparison to the amount, degree, and/or nature of neurogenesis in the absence of the agent, under the conditions of the method used to detect or determine neurogenesis.
• a neurogenic agent is a modulator of angiotensin activity, such as an ACE inhibitor or angiotensin receptor antagonist.
• astrogenic is defined in relation to "astrogenesis” which refers to the activation, proliferation, differentiation, migration and/or survival of an astrocytic cell in vivo or in vitro.
• astrocytic cells include astrocytes, activated microglial cells, astrocyte precursors and potentiated cells, and astrocyte progenitor and derived cells.
• the astrocyte is an adult, fetal, or embryonic astrocyte or population of astrocytes.
• the astrocytes may be located in the central nervous system or elsewhere in an animal or human being.
• the astrocytes may also be in a tissue, such as neural tissue.
• the astrocyte is an adult, fetal, or embryonic progenitor cell or population of cells, or a population of cells comprising a mixture of stem and/or progenitor cells, that is/are capable of developing into astrocytes.
• Astrogenesis includes the proliferation and/or differentiation of astrocytes as it occurs during normal development, as well as astrogenesis that occurs following disease, damage or therapeutic intervention.
• stem cell or neural stem cell (NSC)
• NSC neural stem cell
• progenitor cell e.g., neural progenitor cell
• neural progenitor cell refers to a cell derived from a stem cell that is not itself a stem cell. Some progenitor cells can produce progeny that are capable of differentiating into more than one cell type.
• an "angiotensin receptor antagonist” is a ligand that binds the angiotensin receptor and has All receptor antagonist activity that may be greater than, or similar to, antagonist activity at other All receptor subtypes.
• Non-limiting examples of receptor subtypes include ATi and AT 2 , both of which bind All, as well as AT 3 and AT 4 .
• antagonist activity at one All receptor subtype may be approximately equal to antagonist activity at another All receptor subtype.
• the antagonist activity at an All receptor subtype is "selective" by being at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, or at least about 500% or more than antagonist activity at another receptor subtype.
• antagonist activity relative to All may be the same at one receptor subtype as at one or more other subtypes.
• Antagonists that lack agonist activity at any of the All receptor subtypes may be advantageously used in the practice of the invention.
• the present invention includes compositions and methods of increasing neurogenesis by contacting cells with one or more modulators of angiotensin activity.
• the amount of a modulator of the invention may be selected to be effective to produce an improvement in a treated subject, or detectable neurogenesis in vitro. In some embodiments, the amount is one that also minimizes clinical side effects seen with administration of the agent to a subject.
• the amount of a modulator used in vivo may be about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 18%, about 16%, about 14%, about 12%, about 10%, about 8%, about 6%, about 4%, about 2%, or about 1% or less of the maximum tolerated dose for a subject. This is readily determined for each modulator that has been in clinical use or testing, such as in humans.
• the invention includes compositions and methods of using one or more All receptor antagonists, at a level at which neurogenesis occur.
• the amount of antagonist may be any that is effective to produce neurogenesis.
• the cells may be in vitro or in vivo.
• the cells are present in a tissue or organ of a subject animal or human being.
• the All receptor antagonist may be any that has All receptor selective antagonist activity as described herein.
• the cells are those capable of neurogenesis, such as to result, whether by direct differentiation or by proliferation and differentiation, in differentiated neuronal or glial cells. Representative, and non-limiting examples of other All receptor antagonist compounds for use in the present invention are provided below.
• the invention in applications to an animal or human being, relates to a method of bringing cells into contact with a modulator of angiotensin activity in effective amounts to result in an increase in neurogenesis in comparison to the absence of the modulator.
• a modulator of angiotensin activity in effective amounts to result in an increase in neurogenesis in comparison to the absence of the modulator.
• a non- limiting example is in the administration of the modulator to the animal or human being.
• Such contacting or administration may also be described as exogenously supplying the modulator to a cell or tissue.
• the term "animal” or "animal subject” refers to a non- human mammal, such as a primate, canine, or feline.
• the terms refer to an animal that is domesticated (e.g. livestock) or otherwise subject to human care and/or maintenance (e.g. zoo animals and other animals for exhibition).
• the terms refer to ruminants or carnivores, such as dogs, cats, birds, horses, cattle, sheep, goats, marine animals and mammals, penguins, deer, elk, and foxes.
• the present invention also relates to methods of treating diseases, disorders, and conditions of the central and/or peripheral nervous systems (CNS and PNS, respectively) by administering one or more modulators of angiotensin activity.
• treating includes prevention, amelioration, alleviation, and/or elimination of the disease, disorder, or condition being treated or one or more symptoms of the disease, disorder, or condition being treated, as well as improvement in the overall well being of a patient, as measured by objective and/or subjective criteria.
• treating is used for reversing, attenuating, minimizing, suppressing, or halting undesirable or deleterious effects of, or effects from the progression of, a disease, disorder, or condition of the central and/or peripheral nervous systems, hi other embodiments, the method of treating may be advantageously used in cases where additional neurogenesis would replace, replenish, or increase the numbers of cells lost due to injury or disease as non-limiting examples.
• the amount of the modulator of angiotensin activity may be any that results in a measurable relief of a disease condition like those described herein.
• an improvement in the Hamilton depression scale (HAM-D) score for depression may be used to determine (such as quantitatively) or detect (such as qualitatively) a measurable level of improvement in the depression of a subject.
• Non-limiting examples of symptoms that may be treated with the methods described herein include abnormal behavior, abnormal movement, hyperactivity, hallucinations, acute delusions, combativeness, hostility, negativism, withdrawal, seclusion, memory defects, sensory defects, cognitive defects, and tension.
• abnormal behavior include irritability, poor impulse control, distractibility, and aggressiveness.
• an angiotensin agent as used herein includes a neurogenesis modulating agent, as defined herein, that elicits an observable neurogenic response by producing, generating, stabilizing, or increasing the retention of an intermediate agent which, when contacted with an angiotensin agent, results in the neurogenic response.
• a neurogenesis modulating agent as defined herein, that elicits an observable neurogenic response by producing, generating, stabilizing, or increasing the retention of an intermediate agent which, when contacted with an angiotensin agent, results in the neurogenic response.
• “increasing the retention of or variants of that phrase or the term “retention” refer to decreasing the degradation of, or increasing the stability of, an intermediate agent.
• an angiotensin agent optionally in combination with one or more other neurogenic agents, results in improved efficacy, fewer side effects, lower effective dosages, less frequent dosing, and/or other desirable effects relative to use of the neurogenesis modulating agents individually (such as at higher doses), due, e.g., to synergistic activities and/or the targeting of molecules and/or activities that are differentially expressed in particular tissues and/or cell-types.
• neurogenesis modulating agents refers to a combination of neurogenesis modulating agents.
• administering a neurogenic, or neuromodulating, combination according to methods provided herein modulates neurogenesis in a target tissue and/or cell-type by at least about 20%, about 25%, about 30%, about 40%, about 50%, at least about 75%, or at least about 90% or more in comparison to the absence of the combination.
• neurogenesis is modulated by at least about 95% or by at least about 99% or more.
• a neuromodulating combination may be used to inhibit a neural cell's proliferation, division, or progress through the cell cycle.
• a neuromodulating combination may be used to stimulate survival and/or differentiation in a neural cell.
• a neuromodulating combination may be used to inhibit, reduce, or prevent astrocyte activation and/or astrogenesis or astrocyte differentiation.
• IC 5 o and “EC 50” values are concentrations of an agent, in a combination of an angiotensin agent with one or more other neurogenic agents, that reduce and promote, respectively, neurogenesis or another physiological activity (e.g., the activity of a receptor) to a half-maximal level.
• IC 50 and EC 5O values can be assayed in a variety of environments, including cell-free environments, cellular environments (e.g., cell culture assays), multicellular environments (e.g., in tissues or other multicellular structures), and/or in vivo.
• one or more neurogenesis modulating agents in a combination or method disclosed herein individually have IC 50 or EC 5O values of less than about 10 ⁇ M, less than about 1 ⁇ M, or less than about 0.1 ⁇ M or lower.
• an agent in a combination has an IC 50 or EC 50 of less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.1 nM, or lower.
• selectivity of one or more agents, in a combination of a an angiotensin agent with one or more other neurogenic agents is individually measured as the ratio of the IC 50 or EC 50 value for a desired effect (e.g., modulation of neurogenesis) relative to the IC 50 ZEC 5O value for an undesired effect.
• a "selective" agent in a combination has a selectivity of less than about 1 :2, less than about 1:10, less than about 1 :50, or less than about 1 : 100.
• one or more agents in a combination individually exhibits selective activity in one or more organs, tissues, and/or cell types relative to another organ, tissue, and/or cell type.
• an agent in a combination selectively modulates neurogenesis in a neurogenic region of the brain, such as the hippocampus (e.g., the dentate gyrus), the subventricular zone, and/or the olfactory bulb.
• modulation by a combination of agents is in a region containing neural cells affected by disease or injury, region containing neural cells associated with disease effects or processes, or region containing neural cells affect other event injurious to neural cells.
• Non-limiting examples of such events include stroke or radiation therapy of the region.
• a neuromodulating combination substantially modulates two or more physiological activities or target molecules, while being substantially inactive against one or more other molecules and/or activities.
• cognitive function refers to mental processes of an animal or human subject relating to information gathering and/or processing; the understanding, reasoning, and/or application of information and/or ideas; the abstraction or specification of ideas and/or information; acts of creativity, problem-solving, and possibly intuition; and mental processes such as learning, perception, and/or awareness of ideas and/or information.
• the mental processes are distinct from those of beliefs, desires, and the like, hi some embodiments, cognitive function may be assessed, and thus optionally defined, via one or more tests or assays for cognitive function.
• Non-limiting examples of a test or assay for cognitive function include CANTAB (see for example Fray et al. "CANTAB battery: proposed utility in neurotoxicology.” Neurotoxicol Teratol.
• a modulator may be a rennin inhibitor, such as aliskerin. Also provided herein, a modulator may be a sulfhydryl-containing agent, such as alacepril, captopril (Capoten®), fentiapril, pivopril, pivalopril, or zofenopril.
• a rennin inhibitor such as aliskerin.
• a modulator may be a sulfhydryl-containing agent, such as alacepril, captopril (Capoten®), fentiapril, pivopril, pivalopril, or zofenopril.
• Alacepril also known as l-(D-3-acetylthio-2-methylpropanoyl)-L-prolyl-L- phenylalanine or l-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine
• CAS Registry Number CAS RN 74258-86-9.
• This modulator is described, for example, in Onoyama et al., Clin Pharmacol Ther, 38(4): 462-8 (1985)) and is represented by the following structure:
• Captopril or l-[(2S)-3-mercapto-2-methylpropionyl]-l-proline (or D-3- mercapto-2-methylpropanoyl-L-proline or 1 -(2-methyl-3-sulfanyl-propanoyl)pyrrolidine-2- carboxylic acid) is referenced by CAS RN 62571-86-2, and is also disclosed in U.S. Pat. 4,046,889, which is hereby incorporated by reference in its entirety as if fully set forth.
• Captopril is represented by the following structure:
• a modulator may be a substituted acyl derivative of amino acids, disclosed as ACE inhibitors, in U.S. Pat. Nos. 4,129,571 and 4,154,960, which are hereby incorporated by reference in its entirety as if fully set forth.
• Fentiapril, or rentiapril is another sulfhydryl-containing modulator disclosed herein and in Clin. Exp. Pharmacol. Physiol. 10:131 (1983), which is incorporated by reference as if fully set forth. It is referenced by CAS RN 80830-42-8 and has a structure represented by the following:
• rentiapril isomers represented as follows, may also be used as a modulator of angiotensin activity as disclosed herein:
• Pivopril or (S)-N-cyclopentyl-N-[3-[(2,2-dimethyl-l -oxopropyl)thio]-2- methyl-1-oxopropyl] glycine, is another a sulfhydryl-containing modulator of angiotensin activity. It is referenced by CAS RN 81045-50-3 and discussed by Suh et al. ("Angiotensin- converting enzyme inhibitors. New orally active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl] glycine derivatives.” J Med Chem. 28(l):57-66, 1985). Its structure is represented as follows:
• Pivalopril, or Rhc 3659 or N-cyclopentyl-N-(3-((2,2-dimethyl-l- oxopropyl)thio)-2-methyl-l-oxypropyl) glycine is referenced by CAS RN 76963-39-8. It has a structure represented by the following:
• Zofenopril referenced by CAS RN 81872-10-8, is a pro-drug that is converted to the related sulfhydryl-containing compound zofenoprilat, referenced by CAS Registry Number 75176-37-3, which is an ACE for use as described herein.
• Studies on the conversion in humans are described by Dal Bo et al. ("Assay of zofenopril and its active metabolite zofenoprilat by liquid chromatography coupled with tandem mass spectrometry.” J Chromatogr B Biomed Sci Appl. 749(2):287-94, 2000). It has a structure represented by the following:
• the metabolite zofenoprilat (CAS RN 75176-37-3) may also be used as a modulator of angiotensin activity as described herein. Its structure is represented as follows:
• the chemical entity is a dicarboxylate-containing agent, such as enalapril (Vasotec® or Renitec®) or enalaprilat; ramipril (Altace® or Tritace® or Ramace®); quinapril (Accupril®); perindopril (Coversyl®); lisinopril (Lisodur® or Prinivil® or Zestril®); benazepril; and moexipril (Univasc®) as non-limiting examples.
• enalapril Vasotec® or Renitec®
• ramipril Altace® or Tritace® or Ramace®
• quinapril Accupril®
• perindopril Coversyl®
• lisinopril Liodur® or Prinivil® or Zestril®
• benazepril benazepril
• moexipril Univasc
• Enalapril or (S)-I- [N- [l-(ethoxycarbonyl)-3-phenylpropyl] -l-alanyl]-l- proline or l-[2-(l-ethoxycarbonyl-3-phenyl-propyl)aminopropanoyl]pyrrolidine-2-carboxylic acid or enalapril maleate, is referenced by CAS RN 75847-73-3 and Patchett et al, Nature 288, 280 (1980). It is represented by the following structure:
• the related metabolite compound called enalaprilat, referenced by CAS RN 76420-72-9, may also be used as a modulator of angiotensin activity as disclosed herein. It has a structure represented by the following:
• Ramipril or 4- [2-( 1 -ethoxycarbonyl-3 -phenyl -propyl)aminopropanoyl] -A- azabicyclo[3.3.0]octane-3-carboxylic acid, is referenced by CAS RN 87333-19-5. It is also disclosed in U.S. Pat. 4,587,258, which is hereby incorporated by reference in its entirety as if fully set forth. Its structure is represented by the following:
• Ramiprilat (CAS RN 87269-97-4) is the metabolite of ramipril and may also be used as a modulator of angiotensin activity as described herein. Its structure is represented as follows:
• Quinaprilat (CAS RN 85441-60-7 or 82768-85-2) is the metabolite of quinapril and may also be used as a modulator of angiotensin activity as described herein. Its structure is represented as follows:
• Perindopril or perindopril erbumine
• perindopril erbumine is also known as l-[2-(l- ethoxycarbonylbutylamino)propanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid. It is referenced by CAS RN 82834-16-0 and has a structure represented by the following:
• Perindoprilat (CAS RN 95153-31-4) is the metabolite of perindopril and may also be used as a modulator of angiotensin activity as described herein. Its structure is represented as follows:
• Lisinopril (CAS RN 76547-98-3) or (S)-l-(N(sup 2)-(l-carboxy-3- phenylpropyl)-L-lysyl)-L-proline is also known as l-[6-amino-2-(l-carboxy-3-phenyl- propyl)amino-hexanoyl]pyrrolidine-2-carboxylic acid dihydrate (CAS RN 83915-83-7). Its structure, and the structure of the dihydrate, are represented by the following:
• Benazepril or 2-[4-(l-ethoxycarbonyl-3-phenyl-propyl)amino-5-oxo-6- azabicyclo[5.4.0]undeca-7,9,l l-trien-6-yl] acetic acid, is referenced by CAS RN 86541-75-5 and disclosed in U.S. Patent 4,410,520, which is hereby incorporated by reference in its entirety as if fully set forth. Its structure, and the structure of the dihydrate, are represented by the following:
• Benazepril or Cgs 14831 (referenced as CAS RN 86541-78-8 or 89747-91-
• Moexipril or 2-[2-[(l-ethoxycarbonyl-3-phenyl-propyl)amino]propanoyl]-6,7- dimethoxy-3,4-dihydro-lH-isoquinoline-3-carboxylic acid, is referenced by CAS RN 103775-10-6 and its structure is represented by the following:
• Moexiprilat (CAS RN 103775-14-0) is the metabolite of moexipril and may also be used as a modulator of angiotensin activity as described herein. Its structure is represented as follows:
• Non-limiting embodiments of angiotensin receptor antagonists include candesartan (Atacand® or Ratacand®); eprosartan (Teveten®); irbesartan (Aprovel® or Karvea® or Avapro®); losartan (Cozaar® or Hyzaar®); olmesartan (Benicar®); telmisartan (Micardis® or Pritor®); and valsartan (Diovan®).
• Candesartan or 2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]- 3H-benzoimidazole-4-carboxylic acid, is referenced as CAS RN 139481-59-7.
• the structure of candesartan is represented by the following:
• Eprosartan or 4-[[2-butyl-5-(2-carboxy-3-thiophen-2-yl-prop-l -enyl)- imidazol-l-yl]methyl]benzoic acid, is referenced by CAS RN 133040-01-4 and represented by the following structure:
• Irbesartan or 3-butyl-2-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]-2,4- diazaspiro[4.4]non-3-en-l-one, is referenced by CAS RN 138402-11-6.
• the structure of irbesartan is represented by the following:
• Losartan also known as [2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5- yl)phenyl]phenyl]methyl]-3H-imidazol-4-yl] methanol or 2-butyl-4-chloro-l-[p-(O-lH- tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, is referenced by CAS RN 114798-26-4 and disclosed in U.S. Patent 5,138,069, which is hereby incorporated by reference in its entirety as if fully set forth.
• Losartan potassium (CAS RN 124750-99-8) may also be used as a modulator and described herein.
• the structure of losartan is represented by the following:
• Olmesartan or 4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 -((2'-( 1 H-tetrazol-5 -yl) (l,r-biphenyl)-4-yl)methyl)-lH-imidazole-5-carboxylic acid, is referenced by CAS RN 144689-24-7 and has a structure represented by the following:
• Olmesartan medoxomil (CAS RN 144689-63-4), metabolically converted to olmesartan via ester hydrolysis, may also be used as described herein.
• the structure of olmesartan medoxomil is represented by the following:
• Telmisartan or 2-[4-[[4-methyl-6-(l -methylbenzoimidazol-2-yl)-2-propyl- benzoimidazol-l-yl]methyl]phenyl]benzoic acid, is referenced by CAS RN 144701-48-4 and has a structure represented by the following:
• Valsartan or 3-methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5- yl)phenyl]phenyl]methyl]amino]-butanoic acid, is referenced by CAS RN 137862-53-4 and disclosed in U.S. Pat. 5,399,578, which is hereby incorporated by reference in its entirety as if fully set forth.
• Valsartan has a structure represented by the following:
• the chemical entity is a phosphonate-containing (or phosphate-containing) agent, such as fosinopril (Monopril®), fosinoprilat, fosinopril sodium (CAS RN 88889-14-9), or a structurally related ACE inhibitor.
• the structure of fosinopril is represented by the following:
• Fosinoprilat (CAS RN 95399-71-6) is the metabolite of fosinopril and may also be used as a modulator of angiotensin activity as described herein. Its structure is represented as follows:
• Imidapril or (S)-3-(N-((S)-l-ethoxycarbonyl-3-phenylpropyl)-L-alanyl)-l - methyl-2-oxoimidazoline-4-carboxylic acid, is another modulator of angiotensin activity for use as described herein. It is referenced by CAS RN 89371-37-9 and has a structure represented by the following:
• Imidaprilat (CAS RN 89371-44-8) is the metabolite of imidapril and may also be used as a modulator of angiotensin activity as described herein. Its structure is represented as follows:
• Trandolapril or l-[2-[(l-ethoxycarbonyl-3-phenyl-propyl)amino]propanoyl]- 2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid, is another modulator of angiotensin activity for use as described herein. It is referenced by CAS RN 87679-37-6 and represented by the following:
• Trandolaprilat referenced as CAS RN 87679-71-8 or 83601-86-9, is the metabolite of trandolapril and may also be used as a modulator of angiotensin activity as described herein. Its structure is represented as the following:
• Methods described herein can be used to treat any disease or condition for which it is beneficial to promote or otherwise stimulate or increase neurogenesis.
• One focus of the methods described herein is to achieve a therapeutic result by stimulating or increasing neurogenesis via modulation of angiotensin activity.
• certain methods described herein can be used to treat any disease or condition susceptible to treatment by increasing neurogenesis.
• a disclosed method is applied to modulating neurogenesis in vivo, in vitro, or ex vivo.
• the cells may be present in a tissue or organ of a subject animal or human being.
• Non-limiting examples of cells include those capable of neurogenesis, such as to result, whether by differentiation or by a combination of differentiation and proliferation, in differentiated neural cells.
• neurogenesis includes the differentiation of neural cells along different potential lineages.
• the differentiation of neural stem or progenitor cells is along a neuronal cell lineage to produce neurons.
• the differentiation is along both neuronal and glial cell lineages.
• the disclosure further includes differentiation along a neuronal cell lineage to the exclusion of one or more cell types in a glial cell lineage.
• glial cell types include oligodendrocytes and radial glial cells, as well as astrocytes, which have been reported as being of an "astroglial lineage".
• embodiments of the disclosure include differentiation along a neuronal cell lineage to the exclusion of one or more cell types selected from oligodendrocytes, radial glial cells, and astrocytes.
• the disclosure includes a method of bringing cells into contact with an angiotensin agent, optionally in combination with one or more other neurogenic agents, in effective amounts to result in an increase in neurogenesis in comparison to the absence of the agent or combination.
• angiotensin agent optionally in combination with one or more other neurogenic agents
• a non-limiting example is in the administration of the agent or combination to the animal or human being.
• Such contacting or administration may also be described as exogenously supplying the combination to a cell or tissue.
• Embodiments of the disclosure include a method to treat, or lessen the level of, a decline or impairment of cognitive function. Also included is a method to treat a mood disorder.
• a disease or condition treated with a disclosed method is associated with pain and/or addiction, but in contrast to known methods, the disclosed treatments are substantially mediated by increasing neurogenesis.
• a method described herein may involve increasing neurogenesis ex vivo, such that a composition containing neural stem cells, neural progenitor cells, and/or differentiated neural cells can subsequently be administered to an individual to treat a disease or condition.
• methods described herein allow treatment of diseases characterized by pain, addiction, and/or depression by directly replenishing, replacing, and/or supplementing neurons and/or glial cells. In further embodiments, methods described herein enhance the growth and/or survival of existing neural cells, and/or slow or reverse the loss of such cells in a neurodegenerative condition.
• a method comprises contacting a neural cell with an angiotensin agent
• the result may be an increase in neurodifferentiation.
• the method may be used to potentiate a neural cell for proliferation, and thus neurogenesis, via the one or more other agents used with the angiotensin agent in combination.
• the disclosure includes a method of maintaining, stabilizing, stimulating, or increasing neurodifferentiation in a cell or tissue by use of an angiotensin agent, optionally in combination with one or more other neurogenic agents that also increase neurodifferentiation.
• the method may comprise contacting a cell or tissue with an angiotensin agent, optionally in combination with one or more other neurogenic agents, to maintain, stabilize, stimulate, or increase neurodifferentiation in the cell or tissue.
• the disclosure also includes a method comprising contacting the cell or tissue with an angiotensin agent in combination with one or more other neurogenic agents where the combination stimulates or increases proliferation or cell division in a neural cell.
• the increase in neuroproliferation may be due to the one or more other neurogenic agents and/or to an angiotensin agent.
• a method comprising such a combination may be used to produce neurogenesis (in this case both neurodifferentiation and/or proliferation) in a population of neural cells.
• the cell or tissue is in an animal subject or a human patient as described herein. Non-limiting examples include a human patient treated with chemotherapy and/or radiation, or other therapy or condition which is detrimental to cognitive function; or a human patient diagnosed as having epilepsy, a condition associated with epilepsy, or seizures associated with epilepsy.
• Administration of an angiotensin agent, optionally in combination with one or more other neurogenic agents, may be before, after, or concurrent with, another agent, condition, or therapy.
• the overall combination may be of an angiotensin agent, optionally in combination with one or more other neurogenic agents.
• Embodiments include a method of modulating neurogenesis by contacting one or more neural cells with one or more angiotensin agents, optionally in combination with one or more other neurogenic agents.
• the amount of an angiotensin agent, or a combination thereof with one or more other neurogenic agents may be selected to be effective to produce an improvement in a treated subject, or detectable neurogenesis in vitro. In some embodiments, the amount is one that also minimizes clinical side effects seen with administration of the inhibitor to a subject.
• a method of the invention may be for enhancing or improving the reduced cognitive function in a subject or patient.
• the method may comprise administering an angiotensin agent, optionally in combination with one or more other neurogenic agents, to a subject or patient to enhance, or improve a decline or decrease, of cognitive function due to a therapy and/or condition that reduces cognitive function.
• Other methods of the disclosure include treatment to affect or maintain the cognitive function of a subject or patient.
• the maintenance or stabilization of cognitive function may be at a level, or thereabouts, present in a subject or patient in the absence of a therapy and/or condition that reduces cognitive function.
• the maintenance or stabilization may be at a level, or thereabouts, present in a subject or patient as a result of a therapy and/or condition that reduces cognitive function.
• a method of the invention may be for enhancing or improving the reduced cognitive function in a subject or patient.
• the method may comprise administering an angiotensin agent, or a combination thereof with one or more other neurogenic agents, to a subject or patient to enhance or improve a decline or decrease of cognitive function due to the therapy or condition.
• the administering may be in combination with the therapy or condition.
• a methods may comprise i) treating a subject or patient that has been previously assessed for cognitive function and ii) reassessing cognitive function in the subject or patient during or after the course of treatment.
• the assessment may measure cognitive function for comparison to a control or standard value (or range) in subjects or patients in the absence of an angiotensin agent, or a combination thereof with one or more other neurogenic agents. This may be used to assess the efficacy of an angiotensin agent, alone or in a combination, in alleviating the reduction in cognitive function.
• a disclosed method may be used to moderate or alleviate a mood disorder in a subject or patient as described herein.
• the disclosure includes a method of treating a mood disorder in such a subject or patient.
• Non-limiting examples of the method include those comprising administering an angiotensin agent, or a combination thereof with one or more other neurogenic agents, to a subject or patient that is under treatment with a therapy and/or condition that results in a mood disorder.
• the administration may be with any combination and/or amount that is effective to produce an improvement in the mood disorder.
• Non-limiting examples of mood disorders include depression, anxiety, hypomania, panic attacks, excessive elation, seasonal mood (or affective) disorder, schizophrenia and other psychoses, lissencephaly syndrome, anxiety syndromes, anxiety disorders, phobias, stress and related syndromes, aggression, non-senile dementia, post-pain depression, and combinations thereof.
• the disclosure includes methods comprising identification of an individual suffering from one or more disease, disorders, or conditions, or a symptom thereof, and administering to the subject or patient an angiotensin agent, optionally in combination with one or more other neurogenic agents, as described herein.
• angiotensin agent optionally in combination with one or more other neurogenic agents, as described herein.
• identification of a patient in need of neurogenesis modulation comprises identifying a patient who has or will be exposed to a factor or condition known to inhibit neurogenesis, including but not limited to, stress, aging, sleep deprivation, hormonal changes (e.g., those associated with puberty, pregnancy, or aging (e.g., menopause), lack of exercise, lack of environmental stimuli (e.g., social isolation), diabetes and drugs of abuse (e.g., alcohol, especially chronic use; opiates and opioids; psychostimulants).
• a factor or condition known to inhibit neurogenesis including but not limited to, stress, aging, sleep deprivation, hormonal changes (e.g., those associated with puberty, pregnancy, or aging (e.g., menopause), lack of exercise, lack of environmental stimuli (e.g., social isolation), diabetes and drugs of abuse (e.g., alcohol, especially chronic use; opiates and opioids; psychostimulants).
• the patient has been identified as non-responsive to treatment with primary medications for the condition(s) targeted for treatment (e.g., non- responsive to antidepressants for the treatment of depression), and an angiotensin agent, optionally in combination with one or more other neurogenic agents, is administered in a method for enhancing the responsiveness of the patient to a co-existing or pre-existing treatment regimen.
• the method or treatment comprises administering a combination of a primary medication or therapy for the condition(s) targeted for treatment and an angiotensin agent, optionally in combination with one or more other neurogenic agents.
• a combination in the treatment of depression or related neuropsychiatric disorders, may be administered in conjunction with, or in addition to, electroconvulsive shock treatment, a monoamine oxidase modulator, and/or a selective reuptake modulators of serotonin and/or norepinephrine.
• the patient in need of neurogenesis modulation suffers from premenstrual syndrome, post-partum depression, or pregnancy-related fatigue and/or depression, and the treatment comprises administering a therapeutically effective amount of an angiotensin agent, optionally in combination with one or more other neurogenic agents.
• angiotensin agent such as estrogen
• the patient is a user of a recreational drug including, but not limited to, alcohol, amphetamines, PCP, cocaine, and opiates.
• an angiotensin agent optionally in combination with one or more other neurogenic agents, to treat patients suffering from substance abuse and/or mood disorders.
• an angiotensin agent optionally in combination with one or more other neurogenic agents, can used in combination with one or more additional agents selected from an antidepressant, an antipsychotic, a mood stabilizer, or any other agent known to treat one or more symptoms exhibited by the patient.
• an angiotensin agent exerts a synergistic effect with the one or more additional agents in the treatment of substance abuse and/or mood disorders in patients suffering from both conditions.
• the patient is on a co-existing and/or pre-existing treatment regimen involving administration of one or more prescription medications having a modulatory effect on neurogenesis.
• the patient suffers from chronic pain and is prescribed one or more opiate/opioid medications; and/or suffers from ADD, ADHD, or a related disorder, and is prescribed a psychostimulant, such as Ritalin®, dexedrine, adderall, or a similar medication which inhibits neurogenesis.
• a psychostimulant such as Ritalin®, dexedrine, adderall, or a similar medication which inhibits neurogenesis.
• an angiotensin agent is administered to a patient who is currently or has recently been prescribed a medication that exerts a modulatory effect on neurogenesis, in order to treat depression, anxiety, and/or other mood disorders, and/or to improve cognition.
• the patient suffers from chronic fatigue syndrome; a sleep disorder; lack of exercise (e.g., elderly, infirm, or physically handicapped patients); and/or lack of environmental stimuli (e.g., social isolation); and the treatment comprises administering a therapeutically effective amount of an angiotensin agent, optionally in combination with one or more other neurogenic agents.
• a sleep disorder e.g., elderly, infirm, or physically handicapped patients
• environmental stimuli e.g., social isolation
• the patient is an individual having, or who is likely to develop, a disorder relating to neural degeneration, neural damage and/or neural demyelination.
• a subject or patient includes human beings and animals in assays for behavior linked to neurogenesis.
• exemplary human and animal assays are known to the skilled person in the field.
• identifying a patient in need of neurogenesis modulation comprises selecting a population or sub-population of patients, or an individual patient, that is more amenable to treatment and/or less susceptible to side effects than other patients having the same disease or condition.
• identifying a patient amenable to treatment with an angiotensin agent, optionally in combination with one or more other neurogenic agents comprises identifying a patient who has been exposed to a factor known to enhance neurogenesis, including but not limited to, exercise, hormones or other endogenous factors, and drugs taken as part of a pre-existing treatment regimen, hi some embodiments, a sub-population of patients is identified as being more amenable to neurogenesis modulation with an angiotensin agent, optionally in combination with one or more other neurogenic agents, by taking a cell or tissue sample from prospective patients, isolating and culturing neural cells from the sample, and determining the effect of the combination on the degree or nature of neurogenesis of the cells, thereby allowing selection of patients for which
• the selection of a patient or population of patients in need of or amenable to treatment with an angiotensin agent, optionally in combination with one or more other neurogenic agents, of the disclosure allows more effective treatment of the disease or condition targeted for treatment than known methods using the same or similar compounds.
• the patient has suffered a CNS insult, such as a CNS lesion, a seizure (e.g., electroconvulsive seizure treatment; epileptic seizures), radiation, chemotherapy and/or stroke or other ischemic injury.
• an angiotensin agent is administered to a patient who has suffered, or is at risk of suffering, a CNS insult or injury to stimulate neurogenesis.
• stimulation of the differentiation of neural stem cells with an angiotensin agent activates signaling pathways necessary for progenitor cells to effectively migrate and incorporate into existing neural networks or to block inappropriate proliferation.
• Neurogenesis includes the differentiation of neural cells along different potential lineages.
• the differentiation of neural stem or progenitor cells is along a neuronal and/or glial cell lineage, optionally to the exclusion of differentiation along an astrocyte lineage.
• a modulator of angiotensin activity as described herein includes pharmaceutically acceptable salts, derivatives, prodrugs, and metabolites of the modulator. Methods for preparing and administering salts, derivatives, prodrugs, and metabolites of various agents are well known in the art.
• compositions described herein that contain a chiral center include all possible stereoisomers of the compound, including compositions comprising the racemic mixture of the two enantiomers, as well as compositions comprising each enantiomer individually, substantially free of the other enantiomer.
• contemplated herein is a composition comprising the S enantiomer of a compound substantially free of the R enantiomer, or the R enantiomer substantially free of the S enantiomer.
• compositions comprising mixtures of varying proportions between the diastereomers, as well as compositions comprising one or more diastereomers substantially free of one or more of the other diastereomers.
• substantially free it is meant that the composition comprises less than 25%, 15%, 10%, 8%, 5%, 3%, or less than 1% of the minor enantiomer or diastereomer(s).
• the disease or condition being treated is associated with pain and/or addiction, but in contrast to known methods, the treatments of the invention are substantially mediated by increasing neurogenesis.
• methods described herein involve increasing neurogenesis ex vivo, such that a composition containing neural stem cells, neural progenitor cells, and/or differentiated neural cells can subsequently be administered to an individual to treat a disease or condition.
• methods described herein allow treatment of diseases characterized by pain, addiction, and/or depression to be treated by directly replenishing, replacing, and/or supplementing neurons and/or glial cells, hi further embodiments, methods described herein enhance the growth and/or survival of existing neural cells, and/or slow or reverse the loss of such cells in a neurodegenerative condition.
• diseases and conditions treatable by the methods described herein include, but are not limited to, neurodegenerative disorders, such as senile dementia, Alzheimer's Disease, memory disturbances/memory loss, Parkinson's disease, Parkinson's disorders, Huntingdon's disease (Huntington's Chorea), Lou Gehrig's disease, multiple sclerosis, Pick's disease, Parkinsonism dementia syndrome, progressive subcortical gliosis, progressive supranuclear palsy, thalmic degeneration syndrome, hereditary aphasia, amyotrophic lateral sclerosis, Shy-Drager syndrome, and Lewy body disease.
• neurodegenerative disorders such as senile dementia, Alzheimer's Disease, memory disturbances/memory loss, Parkinson's disease, Parkinson's disorders, Huntingdon's disease (Huntington's Chorea), Lou Gehrig's disease, multiple sclerosis, Pick's disease, Parkinsonism dementia syndrome, progressive subcortical gliosis, progressive supranuclear pals
• the invention also provides for the treatment of a nervous system disorder related to cellular degeneration, a psychiatric condition, cellular trauma and/or injury, or other neurologically related conditions, hi practice, the invention may be applied to a subject or patient afflicted with, or diagnosed with, one or more central or peripheral nervous system disorders in any combination. Diagnosis may be performed by a skilled person in the applicable fields using known and routine methodologies which identify and/or distinguish these nervous system disorders from other conditions.
• Non-limiting examples of nervous system disorders related to cellular degeneration include neurodegenerative disorders, neural stem cell disorders, neural progenitor cell disorders, degenerative diseases of the retina, and ischemic disorders.
• an ischemic disorder comprises an insufficiency, or lack, of oxygen or angiogenesis, and non-limiting example include spinal ischemia, ischemic stroke, cerebral infarction, multi-infarct dementia. While these conditions may be present individually in a subject or patient, the invention also provides for the treatment of a subject or patient afflicted with, or diagnosed with, more than one of these conditions in any combination.
• Non-limiting embodiments of nervous system disorders related to a psychiatric condition include neuropsychiatric disorders and affective disorders.
• an affective disorder refers to a disorder of mood such as, but not limited to, depression, post-traumatic stress disorder (PTSD), hypomania, panic attacks, excessive elation, bipolar depression, bipolar disorder (manic-depression), and seasonal mood (or affective) disorder.
• Other non-limiting embodiments include schizophrenia and other psychoses, lissencephaly syndrome, anxiety syndromes, anxiety disorders, phobias, stress and related syndromes, cognitive function disorders, aggression, drug and alcohol abuse, obsessive compulsive behavior syndromes, borderline personality disorder, non-senile dementia, post-pain depression, post-partum depression, and cerebral palsy.
• nervous system disorders related to cellular or tissue trauma and/or injury include, but are not limited to, neurological traumas and injuries, surgery related trauma and/or injury, retinal injury and trauma, injury related to epilepsy, spinal cord injury, brain injury, brain surgery, trauma related brain injury, trauma related to spinal cord injury, brain injury related to cancer treatment, spinal cord injury related to cancer treatment, brain injury related to infection, brain injury related to inflammation, spinal cord injury related to infection, spinal cord injury related to inflammation, brain injury related to environmental toxin, and spinal cord injury related to environmental toxin.
• Non-limiting examples of nervous system disorders related to other neurologically related conditions include learning disorders, memory disorders, age-associated memory impairment (AAMI) or age-related memory loss, autism, attention deficit disorders, narcolepsy, sleep disorders, cognitive disorders, epilepsy, and temporal lobe epilepsy.
• AAMI age-associated memory impairment
• autism attention deficit disorders
• narcolepsy sleep disorders
• cognitive disorders epilepsy
• temporal lobe epilepsy lobe epilepsy
• the invention provides for the application of a modulator of angiotensin activity to treat a subject or patient for a condition due to the anti-neuro genie effects of an opiate or opioid based analgesic.
• the administration of an opiate or opioid based analgesic such as an opiate like morphine or other opioid receptor agonist
• results in a decrease in, or inhibition of, neurogenesis results in a decrease in, or inhibition of, neurogenesis.
• the administration of a modulator of the invention in combination with an opiate or opioid based analgesic would reduce the anti-neurogenic effect.
• administration of a modulator of the invention in combination with an opioid receptor agonist after surgery such as for the treating post-operative pain).
• the invention includes a method of treating post operative pain in a subject or patient by combining administration of an opiate or opioid based analgesic with a modulator of the invention.
• the analgesic may have been administered before, simultaneously with, or after a modulator.
• the analgesic or opioid receptor agonist is morphine or another opiate.
• methods of treatment disclosed herein comprise the step of administering to a mammal a modulator of angiotensin activity for a time and at a concentration sufficient to treat the condition targeted for treatment.
• Methods of the invention can be applied to individuals having, or who are likely to develop, disorders relating to neural degeneration, neural damage and/or neural demyelination.
• a method comprises selecting a population or sub-population of patients, or selecting an individual patient, that is more amenable to treatment and/or less susceptible to side effects than other patients having the same disease or condition.
• a sub-population of patients is identified as being more amenable to neurogenesis with a modulator of angiotensin activity by taking a cell or tissue sample from prospective patients, isolating and culturing neural cells from the sample, and determining the effect of one or more modulators on the degree or nature of neurogenesis, thereby allowing selection of patients for which one or more modulators have a substantial effect on neurogenesis.
• the selection step(s) results in more effective treatment for the disease or condition that known methods using the same or similar compounds.
• methods described herein involve modulating neurogenesis in vitro or ex vivo with an angiotensin agent, optionally in combination with one or more other neurogenic agents, such that a composition containing neural stem cells, neural progenitor cells, and/or differentiated neural cells can subsequently be administered to an individual to treat a disease or condition.
• the method of treatment comprises the steps of contacting a neural stem cell or progenitor cell with an angiotensin agent, optionally in combination with one or more other neurogenic agents, to modulate neurogenesis, and transplanting the cells into a patient in need of treatment.
• Methods for transplanting stem and progenitor cells are known in the art, and are described, e.g., in U.S.
• methods described herein allow treatment of diseases or conditions by directly replenishing, replacing, and/or supplementing damaged or dysfunctional neurons.
• methods described herein enhance the growth and/or survival of existing neural cells, and/or slow or reverse the loss of such cells in a neurodegenerative or other condition.
• the method of treatment comprises identifying, generating, and/or propagating neural cells in vitro or ex vivo in contact with an angiotensin agent, optionally in combination with one or more other neurogenic agents, and transplanting the cells into a subject.
• the method of treatment comprises the steps of contacting a neural stem cell of progenitor cell with an angiotensin agent, optionally in combination with one or more other neurogenic agents, to stimulate neurogenesis or neurodifferentiation, and transplanting the cells into a patient in need of treatment.
• Also disclosed are methods for preparing a population of neural stem cells suitable for transplantation comprising culturing a population of neural stem cells (NSCs) in vitro, and contacting the cultured neural stem cells with an angiotensin agent, optionally in combination with one or more other neurogenic agents, as described herein.
• the disclosure further includes methods of treating the diseases, disorders, and conditions described herein by transplanting such treated cells into a subject or patient.
• the method of treatment comprises identifying, generating, and/or propagating neural cells ex vivo in contact with one or more modulators of angiotensin activity and transplanting the cells into a subject.
• the method of treatment comprises the steps of contacting a neural stem cell of progenitor cell with one or more modulators to stimulate neurogenesis, and transplanting the cells into a patient in need of treatment.
• methods for preparing a population of neural stem cells suitable for transplantation comprising culturing a population of neural stem cells (NSCs) in vitro, and contacting the cultured neural stem cells with at least one modulator described herein.
• the invention further includes methods of treating the diseases, disorders, and conditions described herein by transplanting such cells into a subject or patient. Methods described herein may comprise administering to the subject an effective amount of a modulator compound or pharmaceutical composition thereof.
• an effective amount of modulator compound(s) according to the invention is an amount sufficient, when used as described herein, to stimulate or increase neurogenesis in the subject targeted for treatment when compared to the absence of the compound.
• An effective amount of a composition may vary based on a variety of factors, including but not limited to, the activity of the active compound(s), the physiological characteristics of the subject, the nature of the condition to be treated, and the route and/or method of administration.
• the methods of the invention typically involve the administration of an agent of the invention in a dosage range of 0.001 ng/kg/day to 500 ng/kg/day, preferably in a dosage range of 0.05 to 200 ng/kg/day.
• methods described herein allow treatment of indications with reductions in side effects, dosage levels, dosage frequency, treatment duration, tolerability, and/or other factors.
• the use of a modulator of angiotensin activity having selective activity may allow effective treatment with substantially fewer and/or less severe side effects compared to existing treatments.
• All receptor antagonists with selectivity within the CNS can reduce side effects associated with activity at receptors outside the intended target tissue/organ.
• Established methods of treating various conditions of the CNS and PNS with compounds having activity against opioid receptors have been known to cause side effects including, but not limited to, sweating, diarrhea, flushing, hypotension, bradycardia, bronchoconstriction, urinary bladder contraction, nausea, vomiting, parkinsonism, and increased mortality risk.
• methods described herein allow treatment of certain conditions with doses that minimize these side effects.
• the disclosed modulators or pharmaceutical compositions are administered by any means suitable for achieving a desired effect.
• Various delivery methods are known in the art and can be used to deliver a modulator to a subject or to NSCs or progenitor cells within a tissue of interest. The delivery method will depend on factors such as the tissue of interest, the nature of the compound (e.g., its stability and ability to cross the blood-brain barrier), and the duration of the experiment, among other factors.
• an osmotic minipump can be implanted into a neurogenic region, such as the lateral ventricle.
• compounds can be administered by direct injection into the cerebrospinal fluid of the brain or spinal column, or into the eye.
• Compounds can also be administered into the periphery (such as by intravenous or subcutaneous injection, or oral delivery), and subsequently cross the blood-brain barrier.
• the modulators and pharmaceutical compositions of the invention are administered in a manner that allows them to contact the sub ventricular zone (SVZ) of the lateral ventricles and/or the dentate gyrus of the hippocampus.
• routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
• Intranasal administration generally includes, but is not limited to, inhalation of aerosol suspensions for delivery of compositions to the nasal mucosa, trachea and bronchioli.
• the disclosed combinations are administered so as to either pass through or by-pass the blood-brain barrier.
• Methods for allowing factors to pass through the blood-brain barrier are known in the art, and include minimizing the size of the factor, providing hydrophobic factors which facilitate passage, and conjugating a modulator of the invention to a carrier molecule that has substantial permeability across the blood brain barrier.
• the combination of compounds can be administered by a surgical procedure implanting a catheter coupled to a pump device.
• the pump device can also be implanted or be extracorporally positioned.
• Administration of the modulator can be in intermittent pulses or as a continuous infusion. Devices for injection to discrete areas of the brain are known in the art.
• the modulator is administered locally to the ventricle of the brain, substantia nigra, striatum, locus ceruleous, nucleus basalis Meynert, pedunculopontine nucleus, cerebral cortex, and/or spinal cord by, e.g., injection.
• Methods, compositions, and devices for delivering therapeutics, including therapeutics for the treatment of diseases and conditions of the CNS and PNS, are known in the art.
• the delivery or targeting of an AChE inhibitor, optionally in combination with another AChE inhibitor and/or another neurogenic agent, to a neurogenic region, such as the dentate gyrus or the subventricular zone enhances efficacy and reduces side effects compared to known methods involving administration with the same or similar compounds.
• the methods include identifying a patient suffering from one or more disease, disorders, or conditions, or a symptom thereof, and administering to the subject or patient an AChE inhibitor, optionally in combination with another AChE inhibitor and/or another neurogenic agent, as described herein.
• the identification of a subject or patient as having one or more disease, disorder or condition, or a symptom thereof may be made by a skilled practitioner using any appropriate means known in the field.
• the methods may be used to treat a cell, tissue, or subject which is exhibiting decreased neurogenesis or increased neurodegeneration. In some cases, the cell, tissue, or subject is, or has been, subjected to, or contacted with, an agent that decreases or inhibits neurogenesis.
• Non-limiting example is a human subject that has been administered morphine or other agent which decreases or inhibits neurogenesis.
• Non-limiting examples of other agents include opiates and opioid receptor agonists, such as mu receptor subtype agonists, that inhibit or decrease neurogenesis.
• the methods may be used to treat subjects having, or diagnosed with, depression or other withdrawal symptoms from morphine or other agents which decrease or inhibit neurogenesis. This is distinct from the treatment of subjects having, or diagnosed with, depression independent of an opiate, such as that of a psychiatric nature, as disclosed herein.
• the methods may be used to treat a subject with one or more chemical addiction or dependency, such as with morphine or other opiates, where the addiction or dependency is ameliorated or alleviated by an increase in neurogenesis.
• the methods may optionally further comprise use of one or more anti-depressant agents.
• a method may comprise treatment with one or more antidepressant agents as known to the skilled person.
• anti-depressant agents include an SSRI, such as fluoxetine (Prozac®), citalopram, escitalopram, fluvoxamine, paroxetine (Paxil®), and sertraline (Zoloft®) as well as the active ingredients of known medications including Luvox® and Serozone®; selective norepinephrine reuptake inhibitors (SNRI) such as reboxetine (Edronax®) and atomoxetine (Strattera®); selective serotonin & norepinephrine reuptake inhibitor (SSNRI) such as venlafaxine (Effexor) and duloxetine (Cymbalta); and agents like baclofen, dehydro
• SNRI selective norepinephrine reuptake inhibitors
• the combination therapy may be of one of the above with an AChE inhibitor, optionally in combination with another AChE inhibitor and/or another neurogenic agent, as described herein to improve the condition of the subject or patient.
• Non-limiting examples of combination therapy include the use of lower dosages of the above which reduce side effects of the anti-depressant agent when used alone.
• an anti-depressant agent like fluoxetine or paroxetine or sertraline may be administered at a reduced or limited dose, optionally also reduced in frequency of administration, in combination with an AChE inhibitor.
• the reduced dose mediates a sufficient anti-depressant effect so that the side effects of the anti-depressant agent alone are reduced or eliminated.
• an AChE inhibitor in embodiments for treating weight gain and/or to induce weight loss, may be used in combination with another agent for treating weight gain and/or inducing weight loss.
• another agent for treating weight gain and/or inducing weight loss include various diet pills that are commercially available.
• the disclosed embodiments include combination therapy, where an AChE inhibitor and one or more other compounds are used together to produce neurogenesis.
• the therapeutic compounds can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic compounds can be given as a single composition.
• the invention is not limited in the sequence of administration.
• the invention includes methods wherein treatment with an AChE inhibitor and another neurogenic agent occurs over a period of more than about 48 hours, more than about 72 hours, more than about 96 hours, more than about 120 hours, more than about 144 hours, more than about 7 days, more than about 9 days, more than about 11 days, more than about 14 days, more than about 21 days, more than about 28 days, more than about 35 days, more than about 42 days, more than about 49 days, more than about 56 days, more than about 63 days, more than about 70 days, more than about 77 days, more than about 12 weeks, more than about 16 weeks, more than about 20 weeks, or more than about 24 weeks or more.
• treatment by administering an AChE inhibitor occurs at least about 12 hours, such as at least about 24, or at least about 36 hours, before administration of another neurogenic agent.
• further administrations may be of only the other neurogenic agent in some embodiments.
• the first administration may be of another neurogenic agent, such as a non- AChE inhibitor neurogenic agent, and further administrations may be of only an AChE inhibitor.
• an angiotensin agent optionally in combination with one or more other neurogenic agents, to treat a subject or patient for a condition due to the anti-neurogenic effects of an opiate or opioid based analgesic.
• the administration of an opiate or opioid based analgesic, such as an opiate like morphine or other opioid receptor agonist, to a subject or patient results in a decrease in, or inhibition of, neurogenesis.
• the administration of an angiotensin agent, optionally in combination with one or more other neurogenic agents, with an opiate or opioid based analgesic would reduce the anti-neurogenic effect.
• One non- limiting example is administration of such a combination with an opioid receptor agonist after surgery (such as for the treating post-operative pain).
• the disclosed embodiments include a method of treating post operative pain in a subject or patient by combining administration of an opiate or opioid based analgesic with an angiotensin agent, optionally in combination with one or more other neurogenic agents.
• the analgesic may have been administered before, simultaneously with, or after the combination.
• the analgesic or opioid receptor agonist is morphine or another opiate.
• Other disclosed embodiments include a method to treat or prevent decreases in, or inhibition of, neurogenesis in other cases involving use of an opioid receptor agonist.
• the methods comprise the administration of an angiotensin agent, optionally in combination with one or more other neurogenic agents, as described herein.
• Non-limiting examples include cases involving an opioid receptor agonist, which decreases or inhibits neurogenesis, and drug addiction, drug rehabilitation, and/or prevention of relapse into addiction.
• the opioid receptor agonist is morphine, opium or another opiate.
• the disclosure includes methods to treat a cell, tissue, or subject which is exhibiting decreased neurogenesis or increased neurodegeneration.
• the cell, tissue, or subject is, or has been, subjected to, or contacted with, an agent that decreases or inhibits neurogenesis.
• an agent that decreases or inhibits neurogenesis is a human subject that has been administered morphine or other agent which decreases or inhibits neurogenesis.
• Non-limiting examples of other agents include opiates and opioid receptor agonists, such as mu receptor subtype agonists, that inhibit or decrease neurogenesis.
• the methods may be used to treat subjects having, or diagnosed with, depression or other withdrawal symptoms from morphine or other agents which decrease or inhibit neurogenesis. This is distinct from the treatment of subjects having, or diagnosed with, depression independent of an opiate, such as that of a psychiatric nature, as disclosed herein, hi further embodiments, the methods may be used to treat a subject with one or more chemical addiction or dependency, such as with morphine or other opiates, where the addiction or dependency is ameliorated or alleviated by an increase in neurogenesis.
• the neurogenic agent may be an opioid or non-opioid (acts independently of an opioid receptor) agent.
• the neurogenic agent is one that antagonizes one or more opioid receptors or is an inverse agonist of at least one opioid receptor.
• An opioid receptor antagonist or inverse agonist of the invention may be specific or selective (or alternatively non-specific or non-selective) for opioid receptor subtypes. So an antagonist may be non-specific or non-selective such that it antagonizes more than one of the three known opioid receptor subtypes, identified as OPi, OP 2 , and OP 3 (also know as delta, or ⁇ , kappa, or K, and mu, or ⁇ , respectively).
• an opioid that antagonizes any two, or all three, of these subtypes, or an inverse agonist that is specific or selective for any two or all three of these subtypes may be used as the non- AChE inhibitor neurogenic agent.
• an antagonist or inverse agonist may be specific or selective for one of the three subtypes, such as the kappa subtype as a non-limiting example.
• the neurogenic agent used in the methods described herein has "selective" activity (such as in the case of an antagonist or inverse agonist) under certain conditions against one or more opioid receptor subtypes with respect to the degree and/or nature of activity against one or more other opioid receptor subtypes.
• the neurogenic agent has an antagonist effect against one or more subtypes, and a much weaker effect or substantially no effect against other subtypes.
• an additional neurogenic agent used in the methods described herein may act as an agonist at one or more opioid receptor subtypes and as antagonist at one or more other opioid receptor subtypes.
• a neurogenic agent has activity against kappa opioid receptors, while having substantially lesser activity against one or both of the delta and mu receptor subtypes.
• a neurogenic agent has activity against two opioid receptor subtypes, such as the kappa and delta subtypes.
• the agents naloxone and naltrexone have nonselective antagonist activities against more than one opioid receptor subtypes.
• selective activity of one or more opioid antagonists results in enhanced efficacy, fewer side effects, lower effective dosages, less frequent dosing, or other desirable attributes.
• An opioid receptor antagonist is an agent able to inhibit one or more characteristic responses of an opioid receptor or receptor subtype.
• an antagonist may competitively or non-competitively bind to an opioid receptor, an agonist or partial agonist (or other ligand) of a receptor, and/or a downstream signaling molecule to inhibit a receptor's function.
• An inverse agonist able to block or inhibit a constitutive activity of an opioid receptor may also be used.
• An inverse agonist may competitively or non-competitively bind to an opioid receptor and/or a downstream signaling molecule to inhibit a receptor's function.
• Non-limiting examples of inverse agonists for use in the practice of the invention include ICI- 174864 ( ⁇ TV-diallyl-Tyr-Aib-Aib-Phe-Leu), RTI-5989-1, RTI-5989-23, and RTI-5989-25 (see Zaki et al. J. Pharmacol. Exp. Therap. 298(3): 1015-1020, 2001).
• the disclosure includes a method of stimulating or increasing neurogenesis in a subject or patient with stimulation of angiogenesis in the subject or patient.
• the co-stimulation may be used to provide the differentiating and/or proliferating cells with increased access to the circulatory system.
• the neurogenesis is produced by modulation of angiotensin activity, such as with an angiotensin agent, optionally in combination with one or more other neurogenic agents, as described herein.
• An increase in angiogenesis may be mediated by a means known to the skilled person, including administration of a angiogenic factor or treatment with an angiogenic therapy.
• Non-limiting examples of angiogenic factors or conditions include vascular endothelial growth factor (VEGF), angiopoietin-1 or -2, erythropoietin, exercise, or a combination thereof.
• VEGF vascular endothelial growth factor
• the disclosure includes a method comprising administering i) an angiotensin agent, optionally in combination with one or more other neurogenic agents, and ii) one or more angiogenic factors to a subject or patient.
• the disclosure includes a method comprising administering i) an angiotensin agent, optionally in combination with one or more other neurogenic agents, to a subject or patient with ii) treating said subject or patient with one or more angiogenic conditions.
• the subject or patient may be any as described herein.
• the co-treatment of a subject or patient includes simultaneous treatment or sequential treatment as non-limiting examples, hi cases of sequential treatment, the administration of an angiotensin agent, optionally with one or more other neurogenic agents, may be before or after the administration of an angiogenic factor or condition.
• the angiotensin agent may be administered separately from the one or more other agents, such that the one or more other agent is administered before or after administration of an angiogenic factor or condition.
• the disclosed embodiments include methods of treating diseases, disorders, and conditions of the central and/or peripheral nervous systems (CNS and PNS, respectively) by administering an angiotensin agent, optionally in combination with one or more other neurogenic agents.
• treating includes prevention, amelioration, alleviation, and/or elimination of the disease, disorder, or condition being treated or one or more symptoms of the disease, disorder, or condition being treated, as well as improvement in the overall well being of a patient, as measured by objective and/or subjective criteria.
• treating is used for reversing, attenuating, minimizing, suppressing, or halting undesirable or deleterious effects of, or effects from the progression of, a disease, disorder, or condition of the central and/or peripheral nervous systems.
• the method of treating may be advantageously used in cases where additional neurogenesis would replace, replenish, or increase the numbers of cells lost due to injury or disease as non-limiting examples.
• the amount of an angiotensin agent, optionally in combination with one or more other neurogenic agents may be any that results in a measurable relief of a disease condition like those described herein.
• an improvement in the Hamilton depression scale (HAM-D) score for depression may be used to determine (such as quantitatively) or detect (such as qualitatively) a measurable level of improvement in the depression of a subject.
• Non-limiting examples of symptoms that may be treated with the methods described herein include abnormal behavior, abnormal movement, hyperactivity, hallucinations, acute delusions, combativeness, hostility, negativism, withdrawal, seclusion, memory defects, sensory defects, cognitive defects, and tension.
• Non-limiting examples of abnormal behavior include irritability, poor impulse control, distractibility, and aggressiveness. Outcomes from treatment with the disclosed methods include improvements in cognitive function or capability in comparison to the absence of treatment.
• diseases and conditions treatable by the methods described herein include, but are not limited to, neurodegenerative disorders and neural disease, such as dementias (e.g., senile dementia, memory disturbances/memory loss, dementias caused by neurodegenerative disorders (e.g., Alzheimer's, Parkinson's disease, Parkinson's disorders, Huntington's disease (Huntington's Chorea), Lou Gehrig's disease, multiple sclerosis, Pick's disease, Parkinsonism dementia syndrome), progressive subcortical gliosis, progressive supranuclear palsy, thalmic degeneration syndrome, hereditary aphasia, amyotrophic lateral sclerosis, Shy-Drager syndrome, and Lewy body disease; vascular conditions (e.g., infarcts, hemorrhage, cardiac disorders); mixed vascular and Alzheimer's; bacterial meningitis; Creutzfeld- Jacob Disease; and Cushing's disease).
• dementias e.g., senile dementia, memory disturbances/
• the disclosed embodiments also provide for the treatment of a nervous system disorder related to neural damage, cellular degeneration, a psychiatric condition, cellular (neurological) trauma and/or injury (e.g., subdural hematoma or traumatic brain injury), toxic chemicals (e.g., heavy metals, alcohol, some medications), CNS hypoxia, or other neurologically related conditions, hi practice, the disclosed compositions and methods may be applied to a subject or patient afflicted with, or diagnosed with, one or more central or peripheral nervous system disorders in any combination. Diagnosis may be performed by a skilled person in the applicable fields using known and routine methodologies which identify and/or distinguish these nervous system disorders from other conditions.
• Non-limiting examples of nervous system disorders related to cellular degeneration include neurodegenerative disorders, neural stem cell disorders, neural progenitor cell disorders, degenerative diseases of the retina, and ischemic disorders.
• an ischemic disorder comprises an insufficiency, or lack, of oxygen or angiogenesis, and non-limiting example include spinal ischemia, ischemic stroke, cerebral infarction, multi-infarct dementia. While these conditions may be present individually in a subject or patient, the disclosed methods also provide for the treatment of a subject or patient afflicted with, or diagnosed with, more than one of these conditions in any combination.
• Non-limiting embodiments of nervous system disorders related to a psychiatric condition include neuropsychiatric disorders and affective disorders.
• an affective disorder refers to a disorder of mood such as, but not limited to, depression, post-traumatic stress disorder (PTSD), hypomania, panic attacks, excessive elation, bipolar depression, bipolar disorder (manic-depression), and seasonal mood (or affective) disorder.
• Non-limiting embodiments include schizophrenia and other psychoses, lissencephaly syndrome, anxiety syndromes, anxiety disorders, phobias, stress and related syndromes (e.g., panic disorder, phobias, adjustment disorders, migraines), cognitive function disorders, aggression, drug and alcohol abuse, drug addiction, and drug-induced neurological damage, obsessive compulsive behavior syndromes, borderline personality disorder, non-senile dementia, post-pain depression, post-partum depression, and cerebral palsy.
• nervous system disorders related to cellular or tissue trauma and/or injury include, but are not limited to, neurological traumas and injuries, surgery related trauma and/or injury, retinal injury and trauma, injury related to epilepsy, cord injury, spinal cord injury, brain injury, brain surgery, trauma related brain injury, trauma related to spinal cord injury, brain injury related to cancer treatment, spinal cord injury related to cancer treatment, brain injury related to infection, brain injury related to inflammation, spinal cord injury related to infection, spinal cord injury related to inflammation, brain injury related to environmental toxin, and spinal cord injury related to environmental toxin.
• Non-limiting examples of nervous system disorders related to other neurologically related conditions include learning disorders, memory disorders, age-associated memory impairment (AAMI) or age-related memory loss, autism, learning or attention deficit disorders (ADD or attention deficit hyperactivity disorder, ADHD), narcolepsy, sleep disorders and sleep deprivation (e.g., insomnia, chronic fatigue syndrome), cognitive disorders, epilepsy, injury related to epilepsy, and temporal lobe epilepsy.
• AAMI age-associated memory impairment
• ADD attention deficit hyperactivity disorder
• narcolepsy sleep disorders and sleep deprivation (e.g., insomnia, chronic fatigue syndrome), cognitive disorders, epilepsy, injury related to epilepsy, and temporal lobe epilepsy.
• diseases and conditions treatable by the methods described herein include, but are not limited to, hormonal changes (e.g., depression and other mood disorders associated with puberty, pregnancy, or aging (e.g., menopause)); and lack of exercise (e.g., depression or other mental disorders in elderly, paralyzed, or physically handicapped patients); infections (e.g., HIV); genetic abnormalities (down syndrome); metabolic abnormalities (e.g., vitamin B12 or folate deficiency); hydrocephalus; memory loss separate from dementia, including mild cognitive impairment (MCI), age- related cognitive decline, and memory loss resulting from the use of general anesthetics, chemotherapy, radiation treatment, post-surgical trauma, or therapeutic intervention; and diseases of the of the peripheral nervous system (PNS), including but not limited to, PNS neuropathies (e.g., vascular neuropathies, diabetic neuropathies, amyloid neuropathies, and the like), neuralgias, neoplasms, myelin-related diseases, etc.
• an angiotensin agent is in the form of a single or multiple compositions that includes at least one pharmaceutically acceptable excipient.
• pharmaceutically acceptable excipient includes any excipient known in the field as suitable for pharmaceutical application. Suitable pharmaceutical excipients and formulations are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (19th ed.) (Genarro, ed. (1995) Mack Publishing Co., Easton, Pa.).
• pharmaceutical carriers are chosen based upon the intended mode of administration of an angiotensin agent, optionally in combination with one or more other neurogenic agents.
• the pharmaceutically acceptable carrier may include, for example, disintegrants, binders, lubricants, glidants, emollients, humectants, thickeners, silicones, flavoring agents, and water.
• An angiotensin agent may be incorporated with excipients and administered in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or any other form known in the pharmaceutical arts.
• the pharmaceutical compositions may also be formulated in a sustained release form. Sustained release compositions, enteric coatings, and the like are known in the art. Alternatively, the compositions may be a quick release formulation.
• the amount of a combination of an angiotensin agent, or a combination thereof with one or more other neurogenic agents may be an amount that also potentiates or sensitizes, such as by activating or inducing cells to differentiate, a population of neural cells for neurogenesis.
• the degree of potentiation or sensitization for neurogenesis may be determined with use of the combination in any appropriate neurogenesis assay, including, but not limited to, a neuronal differentiation assay described herein.
• the amount of a combination of an angiotensin agent, optionally in combination with one or more other neurogenic agents is based on the highest amount of one agent in a combination, which amount produces no detectable neuroproliferation in vitro but yet produces neurogenesis, or a measurable shift in efficacy in promoting neurogenesis in vitro, when used in the combination.
• an effective amount of an angiotensin agent, optionally in combination with one or more other neurogenic agents, in the described methods is an amount sufficient, when used as described herein, to stimulate or increase neurogenesis in the subject targeted for treatment when compared to the absence of the combination.
• An effective amount of an angiotensin agent alone or in combination may vary based on a variety of factors, including but not limited to, the activity of the active compounds, the physiological characteristics of the subject, the nature of the condition to be treated, and the route and/or method of administration. General dosage ranges of certain compounds are provided herein and in the cited references based on animal models of CNS diseases and conditions.
• the disclosed methods typically involve the administration of an angiotensin agent, optionally in combination with one or more other neurogenic agents, in a dosage range of from about 0.001 ng/kg/day to about 200 mg/kg/day.
• Other non-limiting dosages include from about 0.001 to about 0.01 ng/kg/day, about 0.01 to about 0.1 ng/kg/day, about 0.1 to about 1 ng/kg/day, about 1 to about 10 ng/kg/day, about 10 to about 100 ng/kg/day, about 100 ng/kg/day to about 1 ⁇ g/kg/day, about 1 to about 2 ⁇ g/kg/day, about 2 ⁇ g/kg/day to about 0.02 mg/kg/day, about 0.02 to about 0.2 mg/kg/day, about 0.2 to about 2 mg/kg/day, about 2 to about 20 mg/kg/day, or about 20 to about 200 mg/kg/day.
• an angiotensin agent optionally in combination with one or more other neurogenic agents, used to treat a particular condition will vary in practice due to a wide variety of factors. Accordingly, dosage guidelines provided herein are not limiting as the range of actual dosages, but rather provide guidance to skilled practitioners in selecting dosages useful in the empirical determination of dosages for individual patients.
• methods described herein allow treatment of one or more conditions with reductions in side effects, dosage levels, dosage frequency, treatment duration, safety, tolerability, and/or other factors. So where suitable dosages for an angiotensin agent are known to a skilled person, the disclosure includes the use of about 75%, about 50%, about
• the amount of an angiotensin agent used in vivo may be about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 18%, about 16%, about 14%, about 12%, about 10%, about 8%, about 6%, about 4%, about 2%, or about 1% or less than the maximum tolerated dose for a subject, including where one or more other neurogenic agents is used in combination with an angiotensin agent. This is readily determined for each muscarinic agent that has been in clinical use or testing, such as in humans.
• the amount of an angiotensin agent may be an amount selected to be effective to produce an improvement in a treated subject based on detectable neurogenesis in vitro as described above.
• the amount is one that minimizes clinical side effects seen with administration of the agent to a subject.
• the amount of an agent used in vivo may be about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 18%, about 16%, about 14%, about 12%, about 10%, about 8%, about 6%, about 4%, about 2%, or about 1% or less of the maximum tolerated dose in terms of acceptable side effects for a subject. This is readily determined for each angiotensin agent or other agent(s) of a combination disclosed herein as well as those that have been in clinical use or testing, such as in humans.
• the amount of an additional neurogenic sensitizing agent in a combination with an angiotensin agent of the disclosure is the highest amount which produces no detectable neurogenesis when the sensitizing agent is used, alone in vitro, or in vivo, but yet produces neurogenesis, or a measurable shift in efficacy in promoting neurogenesis, when used in combination with an angiotensin agent.
• Embodiments include amounts which produce about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, about 18%, about 20%, about 25%, about 30%, about 35%, or about 40% or more of the neurogenesis seen with the amount that produces the highest level of neurogenesis in an in vitro assay.
• the amount may be the lowest needed to produce a desired, or minimum, level of detectable neurogenesis or beneficial effect.
• the administered angiotensin agent alone or in a combination disclosed herein, may be in the form of a pharmaceutical composition.
• the amount of an angiotensin agent may be any that is effective to produce neurogenesis, optionally with reduced or minimized amounts of astrogenesis.
• the levels of astrogenesis observed with the use of certain angiotensin agents alone may be reduced or suppressed when an angiotensin agent is used in combination with a second agent such as baclofen (or other GABA modulator with the same anti-astrogenesis activity) or melatonin.
• a second agent such as baclofen (or other GABA modulator with the same anti-astrogenesis activity) or melatonin.
• the methods of the disclosure further include a method of decreasing the level of astrogenesis in a cell or cell population by contacting the cell or population with an angiotensin agent and a second agent that reduces or suppresses the amount or level of astrogenesis caused by said angiotensin agent.
• the reduction or suppression of astrogenesis may be readily determined relative to the amount or level of astrogenesis in the absence of the second agent.
• the second agent is baclofen or melatonin.
• an effective, neurogenesis modulating amount of a combination of an angiotensin agent is an amount of an angiotensin agent (or of each agent in a combination) that achieves a concentration within the target tissue, using the particular mode of administration, at or above the IC 5O or EC 50 for activity of target molecule or physiological process.
• an angiotensin agent optionally in combination with one or more other neurogenic agents, is administered in a manner and dosage that gives a peak concentration of about 1, about 1.5, about 2, about 2.5, about 5, about 10, about 20 or more times the IC 50 or EC 50 concentration of an angiotensin agent (or each agent in the combination).
• IC 50 and EC 50 values and bioavailability data for an angiotensin agent and other agent(s) described herein are known in the art, and are described, e.g., in the references cited herein or can be readily determined using established methods.
• methods for determining the concentration of a free compound in plasma and extracellular fluids in the CNS, as well pharmacokinetic properties are known in the art, and are described, e.g., in de Lange et al., AAPS Journal, 7(3): 532-543 (2005).
• an angiotensin agent optionally in combination with one or more other neurogenic agents, described herein is administered, as a combination or separate agents used together, at a frequency of at least about once daily, or about twice daily, or about three or more times daily, and for a duration of at least about 3 days, about 5 days, about 7 days, about 10 days, about 14 days, or about 21 days, or about 4 weeks, or about 2 months, or about 4 months, or about 6 months, or about 8 months, or about 10 months, or about 1 year, or about 2 years, or about 4 years, or about 6 years or longer.
• an effective, neurogenesis modulating amount is a dose that produces a concentration of an angiotensin agent (or each agent in a combination) in an organ, tissue, cell, and/or other region of interest that includes the ED 50 (the pharmacologically effective dose in 50% of subjects) with little or no toxicity.
• IC 50 and EC50 values for the modulation of neurogenesis can be determined using methods described in PCT Application US06/026677, filed July 7, 2006, incorporated by reference, or by other methods known in the art.
• the IC 50 or EC 5O concentration for the modulation of neurogenesis is substantially lower than the IC 50 or ECs 0 concentration for activity of an angiotensin agent and/or other agent(s) at non-targeted molecules and/or physiological processes.
• an angiotensin agent in combination with one or more other neurogenic agents may allow effective treatment with substantially fewer and/or less severe side effects compared to existing treatments.
• combination therapy with an angiotensin agent and one or more additional neurogenic agents allows the combination to be administered at dosages that would be subtherapeutic when administered individually or when compared to other treatments.
• each agent in a combination of agents may be present in an amount that results in fewer and/or less severe side effects than that which occurs with a larger amount.
• methods described herein allow treatment of certain conditions for which treatment with the same or similar compounds is ineffective using known methods due, for example, to dose-limiting side effects, toxicity, and/or other factors.
• the methods of the disclosure comprise contacting a cell with an angiotensin agent, optionally in combination with one or more other neurogenic agents, or administering such an agent or combination to a subject, to result in neurogenesis.
• angiotensin agent such as buspirone, tandospirone, azasetron, granisetron, ondansetron, mosapride, cisapride, or sumatriptan, in combination with one or more other neurogenic agents.
• a combination of two or more agents such as two or more of buspirone, tandospirone, azasetron, granisetron, ondansetron, mosapride, cisapride, and sumatriptan, is used in combination with one or more other neurogenic agents.
• methods of treatment disclosed herein comprise the step of administering to a mammal an angiotensin agent, optionally in combination with one or more other neurogenic agents, for a time and at a concentration sufficient to treat the condition targeted for treatment.
• the disclosed methods can be applied to individuals having, or who are likely to develop, disorders relating to neural degeneration, neural damage and/or neural demyelination.
• the disclosed agents or pharmaceutical compositions are administered by any means suitable for achieving a desired effect.
• Various delivery methods are known in the art and can be used to deliver an agent to a subject or to NSCs or progenitor cells within a tissue of interest.
• the delivery method will depend on factors such as the tissue of interest, the nature of the compound (e.g., its stability and ability to cross the blood-brain barrier), and the duration of the experiment or treatment, among other factors.
• an osmotic minipump can be implanted into a neurogenic region, such as the lateral ventricle.
• compounds can be administered by direct injection into the cerebrospinal fluid of the brain or spinal column, or into the eye.
• Compounds can also be administered into the periphery (such as by intravenous or subcutaneous injection, or oral delivery), and subsequently cross the blood-brain barrier.
• the disclosed agents or pharmaceutical compositions are administered in a manner that allows them to contact the sub ventricular zone (SVZ) of the lateral ventricles and/or the dentate gyrus of the hippocampus.
• SVZ sub ventricular zone
• the delivery or targeting of an angiotensin agent, optionally in combination with one or more other neurogenic agents, to a neurogenic region, such as the dentate gyrus or the subventricular zone, may enhances efficacy and reduces side effects compared to known methods involving administration with the same or similar compounds.
• routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
• Intranasal administration generally includes, but is not limited to, inhalation of aerosol suspensions for delivery of compositions to the nasal mucosa, trachea and bronchioli.
• a combination of an angiotensin agent, optionally in combination with one or more other neurogenic agents, is administered so as to either pass through or by-pass the blood-brain barrier.
• Methods for allowing factors to pass through the blood-brain barrier are known in the art, and include minimizing the size of the factor, providing hydrophobic factors which facilitate passage, and conjugation to a carrier molecule that has substantial permeability across the blood brain barrier.
• an agent or combination of agents can be administered by a surgical procedure implanting a catheter coupled to a pump device.
• the pump device can also be implanted or be extracorporally positioned.
• an angiotensin agent can be in intermittent pulses or as a continuous infusion.
• Devices for injection to discrete areas of the brain are known in the art.
• the combination is administered locally to the ventricle of the brain, substantia nigra, striatum, locus ceruleous, nucleus basalis of Meynert, pedunculopontine nucleus, cerebral cortex, and/or spinal cord by, e.g., injection.
• Methods, compositions, and devices for delivering therapeutics, including therapeutics for the treatment of diseases and conditions of the CNS and PNS are known in the art.
• an angiotensin agent and/or other agent(s) in a combination is modified to facilitate crossing of the gut epithelium.
• an angiotensin agent or other agent(s) is a prodrug that is actively transported across the intestinal epithelium and metabolized into the active agent in systemic circulation and/or in the CNS.
• an angiotensin agent and/or other agent(s) of a combination is conjugated to a targeting domain to form a chimeric therapeutic, where the targeting domain facilitates passage of the blood-brain barrier (as described above) and/or binds one or more molecular targets in the CNS.
• the targeting domain binds a target that is differentially expressed or displayed on, or in close proximity to, tissues, organs, and/or cells of interest.
• the target is preferentially distributed in a neurogenic region of the brain, such as the dentate gyrus and/or the SVZ.
• an angiotensin agent and/or other agent(s) of a combination is conjugated or complexed with the fatty acid docosahexaenoic acid (DHA), which is readily transported across the blood brain barrier and imported into cells of the CNS.
• DHA fatty acid docosahexaenoic acid
• a method may comprise use of a combination of an angiotensin agent and one or more agents reported as anti-depressant agents.
• a method may comprise treatment with an angiotensin agent and one or more reported anti-depressant agents as known to the skilled person.
• agents include an SSRI (selective serotonine reuptake inhibitor), such as fluoxetine (Prozac®; described, e.g., in U.S. Pat. 4,314,081 and 4,194,009), citalopram (Celexa®; described, e.g., in U.S. Pat.
• nefazodone Serozone®; described, e.g., in U.S. Pat. 4,338,317
• SNRI selective norepinephrine reuptake inhibitor
• reboxetine Edronax®
• atomoxetine Strattera®
• milnacipran described, e.g., in U.S. Pat.
• sibutramine or its primary amine metabolite BTS 54 505
• amoxapine or maprotiline
• SSNRI selective serotonin and norepinephrine reuptake inhibitor
• venlafaxine effexor®; described, e.g., in U.S. Pat. 4,761,501
• Cymbalta® reported metabolite desvenlafaxine, or duloxetine
• serotonin, noradrenaline, and dopamine "triple uptake inhibitor” such as
• DOV 102,677 see Popik et al. "Pharmacological Profile of the "Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677.” Cell MoI Neurobiol. 2006 Apr 25; Epub ahead of print
• DOV 216,303 see Beer et al. "DOV 216,303, a “triple” reuptake inhibitor: safety, tolerability, and pharmacokinetic profile.” J Clin Pharmacol. 2004 44(12): 1360-7)
• DOV 21 ,947 ((+)- 1 -(3 ,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride), see Skolnick et al. "Antidepressant-like actions of DOV 21,947: a "triple” reuptake inhibitor.” Eur J Pharmacol. 2003 461(2-3):99-104), NS-2330 or tesofensine (CAS RN 402856-42-2), or NS 2359 (CAS RN
• DHEA dehydroepiandrosterone
• DHEAS DHEA sulfate
• agents include a tricyclic compound such as clomipramine, dosulepin or dothiepin, lofepramine (described, e.g., in U.S. Pat. 4,172,074), trimipramine, protriptyline, amitriptyline, desipramine(described, e.g., in U.S. Pat.
• doxepin imipramine, or nortriptyline
• a psychostimulant such as dextroamphetamine and methylphenidate
• an MAO inhibitor such as selegiline (Emsam®); an ampakine such as CX516 (or Ampalex®, CAS RN: 154235-83-3), CX546 (or 1-(1,4- benzodioxan-6-ylcarbonyl)piperidine), and CX614 (CAS RN 191744-13-5) from Cortex Pharmaceuticals
• a VIb antagonist such as SSR149415 ((2S,4R)-l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide),
• CP- 154,526 a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors. Proc Natl Acad Sci U S A. 1996 93(19):10477-82), NBI 30775 (also known as R121919 or 2,5-dimethyl-3-(6-dimethyl- 4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[l,5-a]pyrimidine), astressin (CAS RN 170809-51-5), or a photoactivatable analog thereof as described in Bonk et al. "Novel high- affinity photoactivatable antagonists of corticotropin-releasing factor (CRF)" Eur. J. Biochem.
• MCH melanin concentrating hormone
• Such agents include a tetracyclic compound such as mirtazapine (described, e.g., in U.S. Pat. 4,062,848; see CAS RN 61337-67-5; also known as Remeron®, or CAS RN 85650-52-8), mianserin (described, e.g., in U.S. Pat. 3,534,041), or setiptiline.
• mirtazapine described, e.g., in U.S. Pat. 4,062,848; see CAS RN 61337-67-5; also known as Remeron®, or CAS RN 85650-52-8
• mianserin described, e.g., in U.S. Pat. 3,534,041
• setiptiline a tetracyclic compound such as mirtazapine (described, e.g., in U.S. Pat. 4,062,848; see CAS RN 61337-67-5; also known as Remer
• Such agents include agomelatine (CAS RN 138112-76-2), pindolol (CAS RN 13523-86-9), antalarmin (CAS RN 157284-96-3), mifepristone (CAS RN 84371-65-3), nemifitide (CAS RN 173240-15-8) or nemifitide ditriflutate (CAS RN 204992-09-6), YKP-IOA or R228060 (CAS RN 561069-23-6), trazodone (CAS RN 19794-93-5), bupropion (CAS RN 34841-39-9 or 34911-55-2) or bupropion hydrochloride (or Wellbutrin®, CAS RN 31677-93-7) and its reported metabolite radafaxine (CAS RN 192374-14-4), NS2359 (CAS RN 843660-54-8), Org 34517 (CAS RN 189035-07-2), Org 34850 (CAS RN 162607-84-3
• Such agents include CX717 from Cortex Pharmaceuticals, TGBAOlAD (a serotonin reuptake inhibitor, 5-HT2 agonist, 5- HTlA agonist, and 5-HT1D agonist) from Fabre-Kramer Pharmaceuticals, Inc., ORG 4420 (an NaSSA (noradrenergic/specific serotonergic antidepressant) from Organon, CP-316,311 (a CRFl antagonist) from Pfizer, BMS-562086 (a CRFl antagonist) from Bristol-Myers
• Squibb, GW876008 (a CRFl antagonist) from Neurocrine/GlaxoSmithKline, ONO-2333Ms (a CRFl antagonist) from Ono Pharmaceutical Co., Ltd., JNJ-19567470 or TS-041 (a CRFl antagonist) from Janssen (Johnson & Johnson) and Taisho, SSR 125543 or SSR 126374 (a CRFl antagonist) from Sanofi-Aventis, Lu AA21004 and Lu AA24530 (both from H.
• ND7001 (a PDE2 inhibitor) from Neuro3d
• SSR 411298 or SSR 101010 (a fatty acid amide hydrolase, or FAAH, inhibitor) from Sanofi- Aventis
• 163090 (a mixed serotonin receptor inhibitor) from Glaxo SmithKline
• SSR 241586 an NK2 and NK3 receptor antagonist
• SAR 102279 an NK2 receptor antagonist
• YKP581 from SK Pharmaceuticals (Johnson & Johnson)
• Rl 576 (a GPCR modulator) from Roche
• ND1251 (a PDE4 inhibitor) from Neuro3d.
• a method may comprise use of a combination of an angiotensin agent and one or more agents reported as anti-psychotic agents.
• a reported anti -psychotic agent as a member of a combination include olanzapine, quetiapine (Seroquel®), clozapine (CAS RN 5786-21-0) or its metabolite ACP- 104 (N-desmethylclozapine or norclozapine, CAS RN 6104-71-8), reserpine, aripiprazole, risperidone, ziprasidone, sertindole, trazodone, paliperidone (CAS RN 144598-75-4), mifepristone (CAS RN 84371-65-3), bifeprunox or DU-127090 (CAS RN 350992-10-8), asenapine or ORG 5222 (CAS RN 65576-45-6), iloperidone (CAS RN
• a phosphodiesterase 1OA (PDElOA) inhibitor such as papaverine (CAS RN 58-74-2) or papaverine hydrochloride (CAS RN 61 -25-6), paliperidone (CAS RN 144598-75-4), trifluoperazine (CAS RN 117-89-5), or trifluoperazine hydrochloride (CAS RN 440-17-5).
• Such agents include trifluoperazine, fluphenazine, chlorpromazine, perphenazine, thioridazine, haloperidol, loxapine, mesoridazine, molindone, pimoxide, or thiothixene, SSR 146977 (see Emonds-Alt et al. "Biochemical and pharmacological activities of SSR 146977, a new potent nonpeptide tachykinin NK3 receptor antagonist.” Can J Physiol Pharmacol.
• Such agents include Lu-35-138 (a D4/5-HT antagonist) from Lundbeck, AVE 1625 (a CBl antagonist) from Sanofi-Aventis, SLV 310,313 (a 5-HT2A antagonist) from Solvay, SSR 181507 (a D2/5-HT2 antagonist) from Sanofi-Aventis, GW07034 (a 5-HT6 antagonist) or GW773812 (a D2, 5-HT antagonist) from GlaxoSmithKline, YKP 1538 from SK Pharmaceuticals, SSR 125047 (a sigma receptor antagonist) from Sanofi-Aventis, MEMl 003 (a L-type calcium channel modulator) from Memory Pharmaceuticals, JNJ-17305600 (a GLYTl inhibitor) from Johnson & Johnson, XY 2401 (a glycine site specific NMDA modulator) from Xytis, PNU 170413 from Pfizer, RGH- 188 (a D2, D3 antagonist) from Forrest, S
• a reported anti-psychotic agent may be one used in treating schizophrenia.
• Non-limiting examples of a reported anti-schizophrenia agent as a member of a combination with an angiotensin agent include molindone hydrochloride (MOB AN®) and TC- 1827 (see Bohme et al. "In vitro and in vivo characterization of TC- 1827, a novel brain ⁇ 4 ⁇ 2 nicotinic receptor agonist with pro-cognitive activity.” Drug Development Research 2004 62(l):26-40).
• a method may comprise use of a combination of an angiotensin agent and one or more agents reported for treating weight gain, metabolic syndrome, or obesity, and/or to induce weight loss or prevent weight gain.
• agents reported for treating weight gain, metabolic syndrome, or obesity include various diet pills that are commercially or clinically available.
• the reported agent is orlistat (CAS RN 96829-58-2), sibutramine (CAS RN 106650-56-0) or sibutramine hydrochloride (CAS RN 84485-00-7), phetermine (CAS RN 122-09-8) or phetermine hydrochloride (CAS RN 1197-21-3), diethylpropion or amfepramone (CAS RN 90-84-6) or diethylpropion hydrochloride, benzphetamine (CAS RN 156-08-1) or benzphetamine hydrochloride, phendimetrazine (CAS RN 634-03-7 or 21784-30-5) or phendimetrazine hydrochloride (CAS RN 17140-98-6) or phendimetrazine tartrate, rimonabant (CAS RN 168273-06-1), bupropion hydrochloride (CAS RN: 31677-93-7), topiramate (CAS RN 97240
• the agent may be fenfluramine or Pondimin® (CAS RN 458-24-2), dexfenfluramine or Redux® (CAS RN 3239-44-9), or levofenfluramine (CAS RN 37577-24-5); or a combination thereof or a combination with phentermine.
• Non-limiting examples include a combination of fenfluramine and phentermine (or "fen-phen") and of dexfenfluramine and phentermine (or "dexfen-phen”).
• the combination therapy may be of one of the above with an angiotensin agent as described herein to improve the condition of the subject or patient.
• Non-limiting examples of combination therapy include the use of lower dosages of the above additional agents, or combinations thereof, which reduce side effects of the agent or combination when used alone.
• an anti-depressant agent like fluoxetine or paroxetine or sertraline may be administered at a reduced or limited dose, optionally also reduced in frequency of administration, in combination with an angiotensin agent.
• a combination of fenfluramine and phentermine, or phentermine and dexfenfluramine may be administered at a reduced or limited dose, optionally also reduced in frequency of administration, in combination with an angiotensin agent.
• the reduced dose or frequency may be that which reduces or eliminates the side effects of the combination.
• a description of the whole of a plurality of alternative agents necessarily includes and describes subsets of the possible alternatives, such as the part remaining with the exclusion of one or more of the alternatives or exclusion of one or more classes.
• the disclosure includes combination therapy, where an angiotensin agent in combination with one or more other neurogenic agents is used to produce neurogenesis.
• the therapeutic compounds can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic compounds can be given as a single composition.
• the methods of the disclosure are not limited in the sequence of administration.
• the disclosure includes methods wherein treatment with an angiotensin agent and another neurogenic agent occurs over a period of more than about 48 hours, more than about 72 hours, more than about 96 hours, more than about 120 hours, more than about 144 hours, more than about 7 days, more than about 9 days, more than about 11 days, more than about 14 days, more than about 21 days, more than about 28 days, more than about 35 days, more than about 42 days, more than about 49 days, more than about 56 days, more than about 63 days, more than about 70 days, more than about 77 days, more than about 12 weeks, more than about 16 weeks, more than about 20 weeks, or more than about 24 weeks or more.
• treatment by administering an angiotensin agent occurs at least about 12 hours, such as at least about 24, or at least about 36 hours, before administration of another neurogenic agent.
• further administrations may be of only the other neurogenic agent in some embodiments of the disclosure.
• further administrations may be of only an angiotensin agent.
• combination therapy with an angiotensin agent and one or more additional agents results in a enhanced efficacy, safety, therapeutic index, and/or tolerability, and/or reduced side effects (frequency, severity, or other aspects), dosage levels, dosage frequency, and/or treatment duration. Examples of compounds useful in combinations described herein are provided above and below.
• Dosages of compounds administered in combination with an angiotensin agent can be, e.g., a dosage within the range of pharmacological dosages established in humans, or a dosage that is a fraction of the established human dosage, e.g., 70%, 50%, 30%, 10%, or less than the established human dosage.
• the neurogenic agent combined with an angiotensin agent may be a reported opioid or non-opioid (acts independently of an opioid receptor) agent.
• the neurogenic agent is one reported as antagonizing one or more opioid receptors or as an inverse agonist of at least one opioid receptor.
• a opioid receptor antagonist or inverse agonist may be specific or selective (or alternatively nonspecific or non-selective) for opioid receptor subtypes.
• an antagonist may be non-specific or non-selective such that it antagonizes more than one of the three known opioid receptor subtypes, identified as OP 1 , OP 2 , and OP 3 (also know as delta, or ⁇ , kappa, or K, and mu, or ⁇ , respectively).
• an opioid that antagonizes any two, or all three, of these subtypes, or an inverse agonist that is specific or selective for any two or all three of these subtypes may be used as the neurogenic agent in the practice.
• an antagonist or inverse agonist may be specific or selective for one of the three subtypes, such as the kappa subtype as a non- limiting example.
• Non-limiting examples of reported opioid antagonists include naltrindol, naloxone, naloxene, naltrexone, JDTic (Registry Number 785835-79-2; also known as 3- isoquinolinecarboxamide, l,2,3,4-tetrahydro-7-hydroxy-N-[(lS)-l-[[(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethyl-l-piperidinyl]methyl]-2-methylpropyl]-dihydrochloride, (3R)- (9CI)), nor-binaltorphimine, and buprenorphine.
• a reported selective kappa opioid receptor antagonist compound as described in US 20020132828, U.S. Patent 6,559,159, and/or WO 2002/053533, may be used. All three of these documents are herein incorporated by reference in their entireties as if fully set forth. Further non-limiting examples of such reported antagonists is a compound disclosed in U.S. Patent 6,900,228 (herein incorporated by reference in its entirety), arodyn (Ac[Phe(l ,2,3),Arg(4),d-Ala(8)]Dyn A-(I-11)NH(2), as described in Bennett, et al. (2002) J. Med. Chem.
• the neurogenic agent used in the methods described herein has "selective" activity (such as in the case of an antagonist or inverse agonist) under certain conditions against one or more opioid receptor subtypes with respect to the degree and/or nature of activity against one or more other opioid receptor subtypes.
• the neurogenic agent has an antagonist effect against one or more subtypes, and a much weaker effect or substantially no effect against other subtypes.
• an additional neurogenic agent used in the methods described herein may act as an agonist at one or more opioid receptor subtypes and as antagonist at one or more other opioid receptor subtypes.
• a neurogenic agent has activity against kappa opioid receptors, while having substantially lesser activity against one or both of the delta and mu receptor subtypes.
• a neurogenic agent has activity against two opioid receptor subtypes, such as the kappa and delta subtypes.
• the agents naloxone and naltrexone have nonselective antagonist activities against more than one opioid receptor subtypes.
• selective activity of one or more opioid antagonists results in enhanced efficacy, fewer side effects, lower effective dosages, less frequent dosing, or other desirable attributes.
• An opioid receptor antagonist is an agent able to inhibit one or more characteristic responses of an opioid receptor or receptor subtype.
• an antagonist may competitively or non-competitively bind to an opioid receptor, an agonist or partial agonist (or other ligand) of a receptor, and/or a downstream signaling molecule to inhibit a receptor's function.
• An inverse agonist able to block or inhibit a constitutive activity of an opioid receptor may also be used.
• An inverse agonist may competitively or non-competitively bind to an opioid receptor and/or a downstream signaling molecule to inhibit a receptor's function.
• Non-limiting examples of inverse agonists for use in the disclosed methods include ICI- 174864 ( ⁇ yV-diallyl-Tyr-Aib-Aib-Phe-Leu), RTI-5989-1, RTI-5989-23, and RTI-5989-25 (see Zaki et al. J Pharmacol. Exp. Therap. 298(3): 1015-1020, 2001).
• Additional embodiments of the disclosure include a combination of an angiotensin agent with an additional agent such as acetylcholine or a reported modulator of an androgen receptor.
• additional agent such as acetylcholine or a reported modulator of an androgen receptor.
• Non-limiting examples include the androgen receptor agonists ehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS).
• the neurogenic agent in combination with an angiotensin agent may be an enzymatic inhibitor, such as a reported inhibitor of HMG CoA reductase.
• enzymatic inhibitors include atorvastatin (CAS RN 134523-00-5), cerivastatin (CAS RN 145599-86-6), crilvastatin (CAS RN 120551-59-9), fluvastatin (CAS RN 93957- 54-1) and fluvastatin sodium (CAS RN 93957-55-2), simvastatin (CAS RN 79902-63-9), lovastatin (CAS RN 75330-75-5), pravastatin (CAS RN 81093-37-0) or pravastatin sodium, rosuvastatin (CAS RN 287714-41-4), and simvastatin (CAS RN 79902-63-9).
• Formulations containing one or more of such inhibitors may also be used in a combination.
• Non-limiting examples include formulations comprising lovastatin such as Advicor® (an extended-release, niacin containing formulation) or Altocor® (an extended release formulation); and formulations comprising simvastatin such as Vytorin® (combination of simvastatin and ezetimibe).
• the neurogenic agent in combination with an angiotensin agent may be a reported Rho kinase inhibitor.
• Non-limiting examples of such an inhibitor include fasudil (CAS RN 103745-39-7); fasudil hydrochloride (CAS RN 105628- 07-7); the metabolite of fasudil, which is hydroxyfasudil (see Shimokawa et al. "Rho-kinase- mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm.” Cardiovasc Res.
• Y 27632 (CAS RN 138381- 45-0); a fasudil analog thereof such as (S)-Hexahydro-l-(4-ethenylisoquinoline-5-sulfonyl)- 2-methyl- IH-1 ,4-diazepine, (S)-hexahydro-4-glycyl-2-methyl- 1 -(4-methylisoquinoline-5- sulfonyl)-lH-l,4-diazepine, or (S)-(+)-2-methyl-l-[(4-methyl-5-isoquinoline)sulfonyl]- homopiperazine (also known as H-1152P; see Sasaki et al.
• Rho-kinase inhibitor S-(+)-2-methyl-l-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho-kinase-involved pathway.
• Pharmacol Ther. 2002 93(2-3):225- 32) or a substituted isoquinolinesulfonamide compound as disclosed in U.S. Patent 6,906,061.
• the neurogenic agent in combination with an angiotensin agent may be a reported GSK-3 inhibitor or modulator, m some non-limiting embodiments, the reported GSK3-beta modulator is a paullone, such as alsterpaullone, kenpaullone (9-bromo- 7,12-dihydroindolo[3,2-d][l]benzazepin-6(5H)-one), gwennpaullone (see Knockaert et al. "Intracellular Targets of Paullones. Identification following affinity purification on immobilized inhibitor.” J Biol Chem. 2002 277(28):25493-501), azakenpaullone (see Kunick et al.
• WO-00144206 WO0144246; or WO- 2005035532; a thiadiazole or thiazole, such as TDZD-8 (benzyl-2-methyl- 1,2,4- thiadiazolidine-3,5-dione); OTDZT (4-dibenzyl-5-oxothiadiazolidine-3-thione); or a related compound described, e.g., in U.S. Patent Nos. 6645990 or 6762179; U.S. Publication No.
• the neurogenic agent used in combination with an angiotensin agent may be a reported glutamate modulator or metabotropic glutamate (mGlu) receptor modulator.
• the reported mGlu receptor modulator is a Group II modulator, having activity against one or more Group II receptors (mGlu 2 and/or mGlu 3 ).
• mGlu 2 and/or mGlu 3 Group II receptors
• Embodiments include those where the Group II modulator is a Group II agonist.
• Non- limiting xamples of Group II agonists include: (i) (lS,3R)-l-aminocyclopentane-l,3- dicarboxylic acid (ACPD), a broad spectrum mGlu agonist having substantial activity at Group I and II receptors; (ii) (-)-2-thia-4-aminobicyclo-hexane-4,6-dicarboxylate (LY389795), which is described in Monn et al., J. Med. Chem., 42(6): 1027-40 (1999); (iii) compounds described in US App. No. 20040102521 and Pellicciari et al., J. Med.
• Non-limiting examples of reported Group II antagonists include: (i) phenylglycine analogues, such as (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG), (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), and (RS)-alpha-methyl-4- tetrazolylphenylglycine (MTPG), described in Jane et al., Neuropharmacology 34: 851-856 (1995); (ii) LY366457, which is described in O'Neill et al., NeuropharmacoL, 45(5): 565-74 (2003); (iii) compounds described in US App Nos. 20050049243, 20050119345 and 20030157647; and (iv) the Group Il-specific modulators described below.
• the reported Group II modulator is a Group II-selective modulator, capable of modulating mGlu 2 and/or mGlu 3 under conditions where it is substantially inactive at other mGlu subtypes (of Groups I and III).
• Group II-selective modulators include compounds described in Monn, et al., J. Med. Chem., 40, 528-537 (1997); Schoepp, et al., Neuropharmacol., 36, 1-11 (1997) (e.g., lS,2S,5R,6S-2- aminobicyclohexane-2,6-dicarboxylate); and Schoepp, Neurochem. Int., 24, 439 (1994).
• Non-limiting examples of reported Group II-selective agonists include (i) (+)- 2-aminobicyclohexane-2,6-dicarboxylic acid (LY354740), which is described in Johnson et al., Drug Metab. Disposition, 30(1): 27-33 (2002) and Bond et al., NeuroReport 8: 1463- 1466 (1997), and is systemically active after oral administration (e.g., Grillon et al., Psychopharmacol. (Berl), 168: 446-454 (2003)); (ii) (-)-2-oxa-4-aminobicyclohexane-4,6- dicarboxylic acid (LY379268), which is described in Monn et al., J. Med.
• LY379268 is readily permeable across the blood- brain barrier, and has EC 50 values in the low nanomolar range (e.g., below about 10 nM, or below about 5 nM) against human mGlu 2 and mGlu 3 receptors in vitro; (iii) (2R,4R)-4- aminopyrrolidine-2,4-dicarboxylate ((2R,4R)- APDC), which is described in Monn et al., J. Med. Chem.
• Non-limiting examples of reported Group II-selective antagonists useful in methods provided herein include the competitive antagonist (2S)-2-amino-2-(lS,2S-2- carboxycycloprop-l-yl)-3-(xanth-9-yl) propanoic acid (LY341495), which is described, e.g., in Springfield et al., Neuropharmacology 37: 1-12 (1998) and Monn et al., J Med Chem 42: 1027-1040 (1999).
• LY341495 is readily permeably across the blood-brain barrier, and has IC 5O values in the low nanomolar range (e.g., below about 10 nM, or below about 5 nM) against cloned human InGIu 2 and mGlu 3 receptors.
• LY341495 has a high degree of selectivity for Group II receptors relative to Group I and Group III receptors at low concentrations (e.g., nanomolar range), whereas at higher concentrations (e.g., above l ⁇ M), LY341495 also has antagonist activity against mGlu 7 and mGlug, in addition to mGlu 2 / 3 .
• LY341495 is substantially inactive against KA, AMPA, and NMDA iGlu receptors.
• Group II-selective antagonists include the following compounds, indicated by chemical name and/or described in the cited references: (i) ⁇ -methyl-L-(carboxycyclopropyl) glycine (CCG); (ii) (2S,3S,4S)-2-methyl-2- (carboxycyclopropyl) glycine (MCCG); (iii) (lR,2R,3R,5R,6R)-2-amino-3-(3,4- dichlorobenzyloxy)-6 fluorobicyclohexane-2,6-dicarboxylic acid (MGS0039), which is described inNakazato et al., J. Med.
• APICA has an IC 50 value of approximately 30 ⁇ M against mGluR 2 and mGluR 3 , with no appreciable activity against Group I or Group III receptors at sub-mM concentrations.
• a reported Group II-selective modulator is a subtype-selective modulator, capable of modulating the activity of InGIu 2 under conditions in which it is substantially inactive at mGlu 3 (mGlu 2 -selective), or vice versa (mGlu 3 - selective).
• subtype-selective modulators include compounds described in US Pat Nos. 6,376,532 (mGlu 2 -selective agonists) and US App No. 20040002478 (mGlu 3 -selective agonists).
• subtype- selective modulators include allosteric mGlu receptor modulators (mGlu 2 and mGlu 3 ) and NAAG-related compounds (mGlu 3 ), such as those described below.
• a reported Group II modulator is a compound with activity at Group I and/or Group III receptors, in addition to Group II receptors, while having selectivity with respect to one or more mGlu receptor subtypes.
• Non- limiting examples of such compounds include: (i) (2 1 S',35',45)-2-(carboxycyclopropyl)glycine (L-CCG-I) (Group I/Group II agonist), which is described in Nicoletti et al., Trends Neurosci.
• the reported mGlu receptor modulator comprises (S)-MCPG (the active isomer of the Group I/Group II competitive antagonist (RS)- MCPG) substantially free from (R)-MCPG.
• S)-MCPG is described, e.g., in Sekiyama et al, Br. J. Pharmacol, 117: 1493 (1996) and Collingridge and Watkins, TiPS, 15: 333 (1994).
• mGlu modulators useful in methods disclosed herein include compounds described in US Pat Nos. 6,956,049, 6,825,211, 5,473,077, 5,912,248, 6,054,448, and 5,500,420; US App Nos. 20040077599, 20040147482, 20040102521, 20030199533 and 20050234048; and Intl Pub/App Nos. WO 97/19049, WO 98/00391, and EP0870760.
• the reported mGlu receptor modulator is a prodrug, metabolite, or other derivative of N-acetylaspartylglutamate (NAAG), a peptide neurotransmitter in the mammalian CNS that is a highly selective agonist for mGluR 3 receptors, as described in Wroblewska et al, J. Neurochem., 69(1): 174-181 (1997).
• NAAG N-acetylaspartylglutamate
• the mGlu modulator is a compound that modulates the levels of endogenous NAAG, such as an inhibitor of the enzyme N-acetylated-alpha-linked-acidic dipeptidase (NAALADase), which catalyzes the hydrolysis of NAAG to N-acetyl-aspartate and glutamate.
• NAALADase inhibitors include 2-PMPA (2- (phosphonomethyl)pentanedioic acid), which is described in Slusher et al, Nat. Med., 5(12): 1396-402 (1999); and compounds described in J. Med. Chem. 39: 619 (1996), US Pub. No. 20040002478, and US PatNos.
• the mGlu modulator is the mGlu 3 -selective antagonist, beta-NAAG.
• Additional non-limiting examples of reported glutamate modulators include memantine (CAS RN 19982-08-2), memantine hydrochloride (CAS RN 41100-52-1), and riluzole (CAS RN 1744-22-5).
• a reported Group II modulator is administered in combination with one or more additional compounds reported as active against a Group I and/or a Group III mGlu receptor.
• methods comprise modulating the activity of at least one Group I receptor and at least one Group II mGlu receptor (e.g., with a compound described herein).
• compounds useful in modulating the activity of Group I receptors include Group I-selective agonists, such as (i) trans-azetidine-2,4,-dicarboxylic acid (tADA), which is described in Kozikowski et al., J. Med.
• Group I agonists such as (RS)-3,5-dihydroxyphenylglycine, described in Brabet et al., Neuropharmacology, 34, 895-903, 1995; and compounds described in US Pat Nos. 6,399,641 and 6,589,978, and US Pub No. 20030212066;
• Group I antagonists such as (S)-4- carboxy-3 -hydroxyphenylglycine; 7-(hydroxyimino)cyclopropa- ⁇ -chromen-l ⁇ - carboxylate ethyl ester; (RS)-l-aminoindan-l,5-dicarboxylic acid (AIDA); 2-methyl-6
• mGlu 5 - selective agonists such as (RS)-2-chloro-5-hydroxyphenylglycine (CHPG); and
• mGlus- selective antagonists such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP); and compounds described in US Pat No. 6,660,753; and US Pub Nos. 20030195139, 20040229917, 20050153986, 20050085514, 20050065340, 20050026963, 20050020585, and 20040259917.
• Non-limiting examples of compounds reported to modulate Group III receptors include (i) the Group Ill-selective agonists (L)-2-arnino-4-phosphonobutyric acid (L-AP4), described in Knopfel et al., J. Med Chem., 38, 1417-1426 (1995); and (S)-2-amino- 2-methyl-4-phosphonobutanoic acid; (ii) the Group Ill-selective antagonists (RS)- ⁇ - cyclopropyl-4-phosphonophenylglycine; (RS)- ⁇ -methylserine-O-phosphate (MSOP); and compounds described in US App. No. 20030109504; and (iii) (15,3/2,45)- 1 - aminocyclopentane-l,2,4-tricarboxylic acid (ACPT-I).
• L-AP4 the Group Ill-selective agonists
• L-AP4 the Group Ill-selective agonists
• the neurogenic agent used in combination with an angiotensin agent may be a reported alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulator.
• AMPA alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
• Non-limiting examples include CX-516 or ampalex (CAS RN 154235-83-3), Org-24448 (CAS RN 211735-76-1), LY451395 (2-propanesulfonamide, N- [(2R)-2-[4'-[2-[methylsulfonyl)amino]ethyl][l,r-biphenyl]-4-yl]propyl]-), LY-450108 (see Jhee et al.
• AMPA receptor antagonists for use in combinations include YM90K (CAS RN 154164-30-4), YM872 or zonampanel (CAS RN 210245-80-0), NBQX (or 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; CAS RN 118876-58-7), PNQX (l,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3, 4-fJquinoxaline- 2,3-dione), and ZK200775 ([l,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(fluoromethyl) quinoxalin- 1 -yl] methylphosphonate).
• a neurogenic agent used in combination with an angiotensin agent may be a reported muscarinic agent.
• a reported muscarinic agent include a muscarinic agonist such as milameline (CI-979), or a structurally or functionally related compound disclosed in U.S. Patent Nos. 4,786,648, 5,362,860, 5,424,301, 5,650,174, 4,710,508, 5,314,901, 5,356,914, or 5,356,912; or xanomeline, or a structurally or functionally related compound disclosed in U.S. Patent Nos. 5,041,455, 5,043,345, or 5,260,314.
• Other non-limiting examples include a muscarinic agent such as alvameline
• clozapine 689,660, S-9977-2, AF- 102, thiopilocarpine, or an analog of clozapine, such as a pharmaceutically acceptable salt, ester, amide, or prodrug form thereof, or a diaryl[a,d]cycloheptene, such as an amino substituted form thereof, or N-desmethylclozapine, which has been reported to be a metabolite of clozapine, or an analog or related compound disclosed in US 2005/0192268 or WO 05/63254.
• the muscarinic agent is an mi receptor agonist selected from 55-LH-3B, 55-LH-25A, 55-LH-30B, 55-LH-4-1A, 40-LH-67, 55-LH-15A, 55-LH-16B, 55-LH-l 1C, 55-LH-31A, 55-LH-46, 55-LH-47, 55-LH-4-3A, or a compound that is functionally or structurally related to one or more of these agonists disclosed in US 2005/0130961 or WO 04/087158.
• the muscarinic agent is a benzimidazolidinone derivative, or a functionally or structurally compound disclosed in U.S. Patent 6,951,849, US 2003/0100545, WO 04/089942, or WO 03/028650; a spiroazacyclic compound, or a functionally or structurally related related compound like l-oxa-3,8-diaza-spiro[4,5]decan-2- one or a compound disclosed in U.S. Patent 6,911,452 or WO 03/057698; or a tetrahydroquinoline analog, or a functionally or structurally compound disclosed in US 2003/0176418, US 2005/0209226, or WO 03/057672.
• the neurogenic agent in combination with an angiotensin agent is a reported HDAC inhibitor.
• HDAC refers to any one of a family of enzymes that remove acetyl groups from the epsilon-amino groups of lysine residues at the N-terminus of a histone.
• An HDAC inhibitor refers to compounds capable of inhibiting, reducing, or otherwise modulating the deacetylation of histones mediated by a histone deacetylase.
• Non-limiting examples of a reported HDAC inhibitor include a short- chain fatty acid, such as butyric acid, phenylbutyrate (PB), 4-phenylbutyrate (4-PBA), pivaloyloxymethyl butyrate (Pivanex, AN-9), isovalerate, valerate, valproate, valproic acid, propionate, butyramide, isobutyramide, phenylacetate, 3-bromopropionate, or tributyrin; a compound bearing a hydroxyamic acid group, such as suberoylanlide hydroxamic acid (SAHA), trichostatin A (TSA), trichostatin C (TSC), salicylhydroxamic acid, oxamflatin, suberic bishydroxamic acid (SBHA), m-carboxy-cinnamic acid bishydroxamic acid (CBHA), pyroxamide (CAS RN 382180-17-8), diethyl
• Additional non-limiting examples include a reported HDac inhibitor selected from ONO-2506 or arundic acid (CAS RN 185517-21-9); MGCDO 103 (see Gelmon et al. "Phase I trials of the oral histone deacetylase (HDAC) inhibitor MGCDO 103 given either daily or 3x weekly for 14 days every 3 weeks in patients (pts) with advanced solid tumors.” Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. 23(16S, June 1 Supplement), 2005: 3147 and Kalita et al.
• HDAC histone deacetylase
• MGCD0103 an oral isotype-selective histone deacetylase (HDAC) inhibitor, on HDAC enzyme inhibition and histone acetylation induction in Phase I clinical trials in patients (pts) with advanced solid tumors or non-Hodgkin's lymphoma (NHL)" Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. 23(16S, Part I of II, June 1 Supplement), 2005: 9631), a reported thiophenyl derivative of benzamide HDac inhibitor as presented at the 97th American Association for Cancer Research (AACR) Annual Meeting in Washington, DC.
• HDAC histone deacetylase
• the neurogenic agent in combination with an angiotensin agent is a reported GABA modulator which modulates GABA receptor activity at the receptor level (e.g., by binding directly to GABA receptors), at the transcriptional and/or translational level (e.g., by preventing GABA receptor gene expression), and/or by other modes (e.g., by binding to a ligand or effector of a GABA receptor, or by modulating the activity of an agent that directly or indirectly modulates GABA receptor activity).
• Non- limiting examples of GABA-A receptor modulators useful in methods described herein include triazolophthalazine derivatives, such as those disclosed in WO 99/25353, and WO/98/04560; tricyclic pyrazolo-pyridazinone analogues, such as those disclosed in WO 99/00391; fenamates, such as those disclosed in 5,637,617; triazolo-pyridazine derivatives, such as those disclosed in WO 99/37649, WO 99/37648, and WO 99/37644; pyrazolo- pyridine derivatives, such as those disclosed in WO 99/48892; nicotinic derivatives, such as those disclosed in WO 99/43661 and 5,723,462; muscimol, thiomuscimol, and compounds disclosed in 3,242, 190; baclofen and compounds disclosed in 3,471 ,548; phaclofen; quisqualamine; ZAPA; zaleplon
• GABA-A modulators include compounds described in 6,503,925; 6,218,547; 6,399,604; 6,646,124; 6,515,140; 6,451,809; 6,448,259;
• the GABA-A modulator is a subunit-selective modulator.
• Non-limiting examples of GABA-A modulator having specificity for the alpha 1 subunit include alpidem and Zolpidem.
• Non-limiting examples of GABA-A modulator having specificity for the alpha2 and/or alpha3 subunits include compounds described in
• Non-limiting examples of GABA-A modulator having specificity for the alpha2, alpha3 and/or alpha5 subunits include compounds described in 6,730,676 and 6,936,608.
• Non-limiting examples of GABA-A modulators having specificity for the alpha5 subunit include compounds described in 6,534,505; 6,426,343; 6,313,125 ; 6,310,203; 6,200,975 and 6,399,604.
• Additional non-limiting subunit selective GABA-A modulators include CL218,872 and related compounds disclosed in Squires et al., Pharmacol. Biochem. Behav., 10: 825 (1979); and beta-carboline-3-carboxylic acid esters described in Nielsen et al., Nature, 286: 606 (1980).
• the GABA-A receptor modulator is a reported allosteric modulator.
• allosteric modulators modulate one or more aspects of the activity of GABA at the target GABA receptor, such as potency, maximal effect, affinity, and/or responsiveness to other GABA modulators.
• allosteric modulators potentiate the effect of GABA (e.g., positive allosteric modulators), and/or reduce the effect of GABA (e.g., inverse agonists).
• Non-limiting examples of benzodiazepine GABA-A modulators include alprazolam, bentazepam, bretazenil, bromazepam, brotizolam, cannazepam, chlordiazepoxide, clobazam, clonazepam, cinolazepam, clotiazepam, cloxazolam, clozapin, delorazepam, diazepam, dibenzepin, dipotassium chlorazepat, divaplon, estazolam, ethyl-loflazepat, etizolam, fludiazepam, flumazenil, flunitrazepam, flurazepam IHCl, flutoprazepam, halazeparn, haloxazolam, imidazenil, ketazolam, lorazepam, loprazolam, lormetazepam, medazepam, metacla
• benzodiazepine GABA-A modulators include Rol5-4513, CL218872, CGS 8216, CGS 9895, PK 9084, U-93631, beta-CCM, beta- CCB, beta-CCP, Ro 19-8022, CGS 20625, NNC 14-0590, Ru 33-203, 5-amino-l- bromouracil, GYKI-52322, FG 8205, Ro 19-4603, ZG-63, RWJ46771, SX-3228, and L- 655,078; NNC 14-0578, NNC 14-8198, and additional compounds described in Wong et al., Eur J Pharmacol 209: 319-325 (1995); Y-23684 and additional compounds in Yasumatsu et al., Br J Pharmacol 111 : 1170-1178 (1994); and compounds described in U.S. Patent 4,513,135.
• Non-limiting examples of barbiturate or barbituric acid derivative GABA-A modulators include phenobarbital, pentobarbital, pentobarbitone, primidone, barbexaclon, dipropyl barbituric acid, eunarcon, hexobarbital, mephobarbital, methohexital, Na- methohexital, 2,4,6(1 H,3H,5)-pyrimidintrion, secbutabarbital and/or thiopental.
• Non-limiting examples of neurosteroid GABA-A modulators include alphaxalone, allotetrahydrodeoxycorticosterone, tetrahydrodeoxycorticosterone, estrogen, progesterone 3-beta-hydroxyandrost-5-en-17-on-3-sulfate, dehydroepianrosterone, eltanolone, ethinylestradiol, 5-pregnen-3-beta-ol-20 on-sulfate, 5a-pregnan-3 ⁇ -ol-20-one (5PG), allopregnanolone, pregnanolone, and steroid derivatives and metabolites described in 5,939,545, 5,925,630, 6,277,838, 6,143,736, RE35,517, 5,925,630, 5,591,733, 5,232,917, 20050176976, WO 96116076, WO 98/05337, WO 95/21617, WO 94/27608, WO
• beta-carboline GABA-A modulators include abecarnil, 3,4-dihydro-beta-carboline, gedocarnil, 1 -methyl- l-vinyl-2,3, 4-trihydro-beta- carboline-3-carboxylic acid, 6-methoxy-l,2,3,4-tetrahydro-beta-carboline, N-BOC-L- 1,2, 3,4- tetrahydro-beta-carboline-3-carboxylic acid, tryptoline, pinoline, methoxyharmalan, tetrahydro-beta-carboline (THBC), 1-methyl-THBC, 6-methoxy-THBC, 6-hydroxy-THBC, 6-methoxyharmalan, norharman, 3,4-dihydro-beta-carboline, and compounds described in Nielsen et al., Nature, 286: 606 (1980).
• the GABA modulator modulates GABA-B receptor activity.
• GABA-B receptor modulators useful in methods described herein include CGP36742; CGP-64213; CGP 56999A; CGP 54433 A; CGP 36742; SCH 50911; CGP 7930; CGP 13501; baclofen and compounds disclosed in 3,471,548; saclofen; phaclofen; 2-hydroxysaclofen; SKF 97541; CGP 35348 and related compounds described in Olpe, et al, Eur. J. Pharmacol., 187, 27 (1990); phosphinic acid derivatives described in Hills, et al, Br. J. Pharmacol., 102, pp.
• the GABA modulator modulates GABA-C receptor activity.
• GABA-C receptor modulators useful in methods described herein include cis-aminocrotonic acid (CACA); l,2,5,6-tetrahydropyridine-4-yl methyl phosphinic acid (TPMPA) and related compounds such as P4MPA, PPA and SEPI; 2- methyl-TACA; (+A)-TAMP; muscimol and compounds disclosed in 3,242,190; ZAPA; THIP and related analogues, such as aza-THIP; pricotroxin; imidazole-4-acetic acid (IMA); and CGP36742.
• CACA cis-aminocrotonic acid
• TPMPA l,2,5,6-tetrahydropyridine-4-yl methyl phosphinic acid
• 2- methyl-TACA (+A)-TAMP
• ZAPA ZAPA
• THIP and related analogues such
• the GABA modulator modulates the activity of glutamic acid decarboxylase (GAD).
• GAD glutamic acid decarboxylase
• the GABA modulator modulates GABA transaminase (GTA).
• GTA modulators include the GABA analog vigabatrin, and compounds disclosed in 3,960,927.
• the GABA modulator modulates the reuptake and/or transport of GABA from extracellular regions. In other embodiments, the GABA modulator modulates the activity of the GABA transporters, GAT-I, GAT-2, GAT-3 and/or BGT-I.
• Non-limiting examples of GABA reuptake and/or transport modulators include nipecotic acid and related derivatives, such as CI 966; SKF 89976A; TACA; stiripentol; tiagabine and GAT-I inhibitors disclosed in 5,010,090; (R)-l-(4,4-di ⁇ henyl-3-butenyl)-3- piperidinecarboxylic acid and related compounds disclosed in 4,383,999; (R)-l-[4,4-bis(3- methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid and related compounds disclosed in Anderson et al., J. Med. Chem.
• the GABA modulator is the benzodiazepine clonazepam, which is described, e.g., in 3,121,076 and 3,116,203; the benzodiazepine diazepam, which is described, e.g., in 3,371,085; 3,109,843; and 3,136,815; the short-acting diazepam derivative midazolam, which is a described, e.g., in 4,280,957; the imidazodiazepine flumazenil, which is described, e.g., in 4,316,839; the benzodiazepine lorazepam is described, e.g., in 3,296,249; the benzodiazepine L-655708, which is described, e.g., in Quirk et al.
• GABA-A agonist isoguvacine which is described, e.g., in Chebib et al., Clin. Exp. Pharmacol. Physiol. 1999, 26, 937-940; Leinekugel et al. J. Physiol. 1995, 487, 319-29; and White et al., J. Neurochem. 1983, 40(6), 1701-8; the GABA-A agonist gaboxadol (THIP), which is described, e.g., in 4,278,676 and Krogsgaard-Larsen, Acta. Chem. Scand.
• THIP GABA-A agonist gaboxadol
• the GABA-A agonist muscimol which is described, e.g., in 3,242,190 and 3,397,209
• the inverse GABA-A agonist beta-CCP which is described, e.g., in Nielsen et al., J. Neurochem., 36(l):276-85 (1981)
• the GABA-A potentiator riluzole which is described, e.g., in 4,370,338 and EP 50,551 ;
• GABA-B agonist and GABA-C antagonist SKF 97541 which is described, e.g., in Froestl et al., J.Med. Chem. 38 3297 (1995); Hoskison et al., Neurosci. Lett. 2004, 365(1), 48-53 and Hue et al., J. Insect Physiol. 1997, 43(12), 1125-1131; the GABA-B agonist baclofen, which is described, e.g., in U.S. Patent 3,471,548; the GABA-C agonist cis-4-aminocrotonic acid (CACA), which is described, e.g., in Ulloor et al. J. Neurophysiol.
• CACA GABA-C agonist cis-4-aminocrotonic acid
• GABA-A antagonist phaclofen which is described, e.g., in Kerr et al. Brain Res. 1987, 405, 150; Karlsson et al. Eur. J Pharmacol. 1988, 148, 485; and Hasuo, Gallagher Neurosci. Lett. 1988, 86, 77; the GABA-A antagonist SR 95531, which is described, e.g., in Stell et al. J. Neurosci. 2002, 22(10), RC223; Wermuth et al., J.Med.Chem. 30 239 (1987); and Luddens and Korpi, J.Neurosci.
• the selective GABA-B antagonist CGP 55845 which is a GABA-receptor antagonist described, e.g., in Davies et al. Neuropharmacology 1993, 32, 1071; Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127; and Deisz Neuroscience 1999, 93, 1241; the selective GABA-B antagonist Saclofen, which is described, e.g., in Bowery, TiPS, 1989, 10, 401; and Kerr et al. Neurosci Lett.
• Patent 4,024,175 the lipid-soluble GABA agonist progabide, which is metabolized in vivo into GABA and/or pharmaceutically active GABA derivatives in vivo. Progabide is described, e.g., in U.S. Patents 4,094,992 and 4,361,583; the GATl inhibitor Tiagabine, which is described, e.g., in U.S. Patent 5,010,090 and Andersen et al. J. Med. Chem. 1993, 36, 1716; the GABA transaminase inhibitor valproic acid (2-propylpentanoic acid or dispropylacetic acid), which is described, e.g., in U.S.
• the neurogenic agent in combination with an angiotensin agent may be a neurogenic sensitizing agent that is a reported anti-epileptic agent.
• Non-limiting examples of such agents include carbamazepine or tegretol (CAS RN 298-46-4), clonazepam (CAS RN 1622-61-3), BPA or 3-(p-boronophenyl)alanine (CAS RN 90580-64-6), gabapentin or neurontin (CAS RN 60142-96-3), phenytoin (CAS RN 57-41-0), topiramate, lamotrigine or lamictal (CAS RN 84057-84-1), phenobarbital (CAS RN 50-06-6), oxcarbazepine (CAS RN 28721-07-5), primidone (CAS RN 125-33-7), ethosuximide (CAS RN 77-67-8), levetiracetam (CAS RN 102767-28-2), zonisamide, tiagabine (CAS RN 115103-54-3), depakote or divalproex sodium (CAS RN 76584-70-8), felbamate (N
• the neurogenic sensitizing agent may be a reported direct or indirect modulator of dopamine receptors.
• Such agents include the indirect dopamine agonists methylphenidate (CAS RN 113-45-1) or methylphenidate hydrochloride (also known as Ritalin® CAS RN 298-59-9), amphetamine (CAS RN 300-62-9) and methamphetamine (CAS RN 537-46-2), and the direct dopamine agonists sumanirole (CAS RN 179386-43-7), roprinirole (CAS RN 91374-21-9), and rotigotine (CAS RN 99755-59-6). Additional non-limiting examples include 7-OH-DPAT, quinpirole, haloperidole, or clozapine.
• bromocriptine (CAS RN 25614-03- 3), adrogolide (CAS RN 171752-56-0), pramipexole (CAS RN 104632-26-0), ropinirole (CAS RN 91374-21-9), apomorphine (CAS RN 58-00-4) or apomorphine hydrochloride (CAS RN 314-19-2), lisuride (CAS RN 18016-80-3), sibenadet hydrochloride or viozan (CAS RN 154189-24-9), L-DOPA or levodopa (CAS RN 59-92-7), melevodopa (CAS RN 7101-51-1), etilevodopa (CAS RN 37178-37-3), talipexole hydrochloride (CAS RN 36085- 73-1) or talipexole (CAS RN 101626-70-4), nolomirole (CAS RN 90060-42-7), quinelor
• the neurogenic agent used in combination with an angiotensin agent may be a reported dual sodium and calcium channel modulator.
• Non- limiting examples of such agents include saf ⁇ namide and zonisamide. Additional non- limiting examples include enecadin (CAS RN 259525-01-4), levosemotiadil (CAS RN 116476-16-5), bisaramil (CAS RN 89194-77-4), SL-34.0829 (see U.S.
• Patent 6,897,305 lifarizine (CAS RN 119514-66-8), JTV-519 (4-[3-(4-benzylpiperidin-l-yl)propionyl]-7- methoxy-2,3,4,5-tetrahydro-l,4-benzothiazepine monohydrochloride), and delapril.
• the neurogenic agent in used in combination with an angiotensin agent may be a reported calcium channel antagonist such as amlodipine (CAS RN 88150-42-9) or amlodipine maleate (CAS RN 88150-47-4), nifedipine (CAS RN 21829- 25-4), MEM- 1003 (CAS RN see Rose et al. "Efficacy of MEM 1003, a novel calcium channel blocker, in delay and trace eyeblink conditioning in older rabbits.” Neurobiol Aging.
• nisoldipine (CAS RN 63675-72-9), semotiadil (CAS RN 116476-13-2), palonidipine (CAS RN 96515-73-0) or palonidipine hydrochloride (CAS RN 96515-74-1), SL-87.0495 (see U.S.
• Patent 6,897,305 YM430 (4(((S)-2-hydroxy-3-phenoxypropyl)amino)butyl methyl 2,6- dimethyl-((S)-4-(m-nitrophenyl))-l ,4-dihydropyridine-3,5-dicarboxylate), barnidipine (CAS RN 104713-75-9), and AM336 or CVID (see Adams et al. "Omega-Conotoxin CVID Inhibits a Pharmacologically Distinct Voltage-sensitive Calcium Channel Associated with
• the neurogenic agent used in combination with an angiotensin agent may be a reported modulator of a melatonin receptor.
• modulators include the melatonin receptor agonists melatonin, LY-156735 (CAS RN 118702-11-7), agomelatine (CAS RN 138112-76-2), 6-chloromelatonin (CAS RN 63762-74-3), ramelteon (CAS RN 196597-26-9), 2-Methyl-6,7-dichloromelatonin (CAS RN 104513-29-3), and ML 23 (CAS RN 108929-03-9).
• the neurogenic agent in combination with an angiotensin agent may be a reported modulator of a melanocortin receptor.
• melanocortin receptor agonists selected from melanotan II (CAS RN 121062-08-6), PT-141 or bremelanotide (CAS RN 189691-06-3), HP-228 (see Getting et al. "The melanocortin peptide HP228 displays protective effects in acute models of inflammation and organ damage.” Eur J Pharmacol. 2006 Jan 24), or AP214 from Action Pharma A/S.
• the agent used in combination with an angiotensin agent may be a reported compound (or "monoamine modulator") that modulates neurotransmission mediated by one or more monoamine neurotransmitters (referred to herein as “monoamines”) or other biogenic amines, such as trace amines (TAs) as a non-limiting example.
• TAs are endogenous, CNS-active amines that are structurally related to classical biogenic amines (e.g., norepinephrine, dopamine (4-(2-aminoethyl)benzene-l,2-diol), and/or serotonin (5- hydroxytryptamine (5-HT), or a metabolite, precursor, prodrug, or analog thereof.
• the methods of the disclosure thus include administration of one or more reported TAs in a combination with an angiotensin agent.
• Additional CNS-active monoamine receptor modulators are well known in the art, and are described, e.g., in the Merck Index, 12th Ed. (1996).
• Certain food products e.g., chocolates, cheeses, and wines, can also provide a significant dietary source of TAs and/or TA-related compounds.
• mammalian TAs useful as constitutive factors include, but are not limited to, tryptamine, p- tyramine, m-tyramine, octopamine, synephrine or ⁇ -phenylethylamine ( ⁇ -PEA).
• Additional useful TA-related compounds include, but are not limited to, 5-hydroxytryptamine, amphetamine, bufotenin, 5-methoxytryptamine, dihydromethoxytryptamine, phenylephrine, or a metabolite, precursor, prodrug, or analogue thereof.
• the constitutive factor is a biogenic amine or a ligand of a trace amine-associated receptor (TAAR), and/or an agent that mediates one or more biological effects of a TA.
• TAs have been shown to bind to and activate a number of unique receptors, termed TAARs, which comprise a family of G-protein coupled receptors (TAARl- TAAR9) with homology to classical biogenic amine receptors.
• TAARl is activated by both tyramine and ⁇ -PEA.
• non-limiting embodiments include methods and combination compositions wherein the constitutive factor is ⁇ -PEA, which has been indicated as having a significant neuromodulatory role in the mammalian CNS and is found at relatively high levels in the hippocampus (e.g., Taga et al., Biomed Chromatogr., 3(3): 118-20 (1989)); a metabolite, prodrug, precursor, or other analogue of ⁇ -PEA, such as the ⁇ -PEA precursor L- phenylalanine, the ⁇ -PEA metabolite ⁇ -phenylacetic acid ( ⁇ -PAA), or the ⁇ -PEA analogues methylphenidate, amphetamine, and related compounds.
• ⁇ -PEA which has been indicated as having a significant neuromodulatory role in the mammalian CNS and is found at relatively high levels in the hippocampus (e.g., Taga et al., Biomed Chromatogr., 3(3): 118-20 (1989
• TAs and monoamines have a short half-life (e.g., less than about 30 s) due, e.g., to their rapid extracellular metabolism.
• a monoamine "metabolic modulator” which increases the extracellular concentration of one or more monoamines by inhibiting monoamine metabolism
• the metabolic modulator is an inhibitor of the enzyme monoamine oxidase (MAO), which catalyzes the extracellular breakdown of monoamines into inactive species.
• MAO-A and/or MAO-B provide the major pathway for TA metabolism.
• TA levels are regulated by modulating the activity of MAO-A and/or MAO-B.
• endogenous TA levels are increased (and TA signaling is enhanced) by administering an inhibitor of MAO-A and/or MAO-B, in combination with an angiotensin agent as described herein.
• Non-limiting examples of inhibitors of monoamine oxidase include reported inhibitors of the MAO-A isoform, which preferentially deaminates 5- hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE), and/or the MAO-B isoform, which preferentially deaminates phenylethylamine (PEA) and benzylamine (both MAO-A and MAO-B metabolize Dopamine (DA)).
• MAO inhibitors may be irreversible or reversible (e.g., reversible inhibitors of MAO-A (RIMA)), and may have varying potencies against MAO-A and/or MAO-B (e.g., non-selective dual inhibitors or isoform-selective inhibitors).
• RIMA reversible inhibitors of MAO-A
• MAO-B e.g., non-selective dual inhibitors or isoform-selective inhibitors.
• Non-limiting examples of MAO inhibitors useful in methods described herein include clorgyline, L-deprenyl, isocarboxazid (Marplan®), ayahuasca, nialamide, iproniazide, iproclozide, moclobemide (Aurorix®), phenelzine (Nardil®), tranylcypromine (Parnate®) (the congeneric of phenelzine), toloxatone, levo-deprenyl (Selegiline®), harmala, RIMAs (e.g., moclobemide, described in Da Prada et al., J Pharmacol Exp Ther 248: 400-414 (1989); brofaromine; and befloxatone, described in Curet et al., J Affect Disord 51: 287-303 (1998)), lazabemide (Ro 19 6327), described in Ann. Neurol., 40(1): 99-107 (1996)
• the monoamine modulator is an "uptake inhibitor," which increases extracellular monoamine levels by inhibiting the transport of monoamines away from the synaptic cleft and/or other extracellular regions.
• the monoamine modulator is a monoamine uptake inhibitor, which may selectively/preferentially inhibit uptake of one or more monoamines relative to one or more other monoamines.
• uptake inhibitors includes compounds that inhibit the transport of monoamines (e.g., uptake inhibitors) and/or the binding of monoamine substrates (e.g., uptake blockers) by transporter proteins (e.g., the dopamine transporter (DAT), the NE transporter (NET), the 5-HT transporter (SERT), and/or the extraneuronal monoamine transporter (EMT)) and/or other molecules that mediate the removal of extracellular monoamines.
• Monoamine uptake inhibitors are generally classified according to their potencies with respect to particular monoamines, as described, e.g., in Koe, J. Pharmacol. Exp. Ther. 199: 649-661 (1976).
• references to compounds as being active against one or more monoamines are not intended to be exhaustive or inclusive of the monoamines modulated in vivo, but rather as general guidance for the skilled practitioner in selecting compounds for use in therapeutic methods provided herein.
• the modulator may be (i) a norepinephrine and dopamine reuptake inhibitor, such as bupropion (described, e.g., in U.S. Pat. 3,819,706 and 3,885,046), or (S,S)-hydroxybupropion (described, e.g., in U.S. Pat. 6,342,496); (ii) selective dopamine reuptake inhibitors, such as medifoxamine, amineptine (described, e.g., in U.S. Pat.
• a norepinephrine and dopamine reuptake inhibitor such as bupropion (described, e.g., in U.S. Pat. 3,819,706 and 3,885,046), or (S,S)-hydroxybupropion (described, e.g., in U.S. Pat. 6,342,496)
• selective dopamine reuptake inhibitors such as medifoxamine, amineptine (described,
• monoamine releasers which stimulates the release of monoamines, such as biogenic amines from presynaptic sites, e.g., by modulating presynaptic receptors (e.g., autoreceptors, heteroreceptors), modulating the packaging (e.g., vesicular formation) and/or release (e.g., vesicular fusion and release) of monoamines, and/or otherwise modulating monoamine release.
• presynaptic receptors e.g., autoreceptors, heteroreceptors
• the packaging e.g., vesicular formation
• release e.g., vesicular fusion and release
• monoamine releasers provide a method for increasing levels of one or more monoamines within the synaptic cleft or other extracellular region independently of the activity of the presynaptic neuron.
• Monoamine releasers useful in combinations provided herein include fenfluramine or p-chloroamphetamine (PCA) or the dopamine, norepinephrine, and serotonin releasing compound amineptine (described, e.g., in U.S. Pat. 3,758,528 and 3,821,249).
• the agent used with an angiotensin agent may be a reported phosphodiesterase (PDE) inhibitor.
• a reported inhibitor of PDE activity include an inhibitor of a cAMP-specific PDE.
• cAMP specific PDE inhibitors useful in the methods described herein include a pyrrolidinone, such as a compound disclosed in U.S. Pat. 5,665,754, US20040152754 or US20040023945; a quinazolineone, such as a compound disclosed in U.S. Pat.
• a substituted phenyl compound such as a compound disclosed in U.S. Pats. 6,297,264, 5,866,593,65 5,859,034, 6,245,774, 6,197,792, 6,080,790, 6,077,854, 5,962,483, 5,674,880, 5,786,354, 5,739,144, 5,776,958, 5,798,373, 5,891,896, 5,849,770, 5,550,137, 5,340,827, 5,780,478, 5,780,477, or 5,633,257, or WO 95/35283; a substituted biphenyl compound, such as that disclosed in U.S. Pat. 5,877,190; or a quinilinone, such as a compound described in U.S. Pat. 6,800,625 or WO 98/14432.
• Additional non-limiting examples of reported cAMP-specific PDE inhibitors useful in methods disclosed herein include a compound disclosed in U.S. Pats. 6,818,651, 6,737,436, 6,613,778, 6,617,357, 6,146,876, 6,838,559, 6,884,800, 6,716,987, 6,514,996, 6,376,535, 6,740,655, 6,559,168, 6,069,151, 6,365,585, 6,313,116, 6,245,774, 6,011,037, 6,127,363, 6,303,789, 6,316,472, 6,348,602, 6,331,543, 6,333,354, 5,491,147, 5,608,070, 5,622,977, 5,580,888, 6,680,336, 6,569,890, 6,569,885, 6,500,856, 6,486,186, 6,458,787, 6,455,562, 6,444,671, 6,423,710, 6,376,489, 6,372,777, 6,362,213, 6,313,156,
• the reported cAMP-specific PDE inhibitor is cilomilast (SB-207499); filaminast; tibenelast (LY-186655); ibudilast; piclamilast (RP 73401); theophylline, doxorylline; cipamfylline (HEP-688); atizoram (CP-80633); isobutylmethylxanthine; mesopram (ZK-117137); zardaverine; vinpocetine; rolipram (ZK- 62711); arofylline (LAS-31025); roflumilast (BY-217); pumafentrin (BY-343); denbufylline; EHNA; milrinone; siguazodan; zaprinast; tolafentrine; Isbufylline; IBMX; lC-485; dyphylline; verolylline; bamifylline; pentoxyfilline;
• Non-limiting examples of a cGMP specific PDE inhibitor for use in the combinations and methods described herein include a pyrimidine or pyrimidinone derivative, such as a compound described in U.S. Pats. 6,677,335, 6,458,951, 6,251,904, 6,787,548, 5,294,612, 5,250,534, or 6,469,012, WO 94/28902, WO96/16657, EP0702555, and Eddahibi, Br. J. Pharmacol., 125(4): 681-688 (1988); a griseolic acid derivative, such as a compound disclosed in U.S. Pat.
• the PDE inhibitor used in a combination or method disclosed herein is caffeine.
• the caffeine is administered in a formulation comprising an angiotensin agent.
• the caffeine is administered simultaneously with an angiotensin agent.
• the caffeine is administered in a formulation, dosage, or concentration lower or higher than that of a caffeinated beverage such as coffee, tea, or soft drinks, hi further embodiments, the caffeine is administered by a non-oral means, including, but not limited to, parenteral (e.g., intravenous, intradermal, subcutaneous, inhalation), transdermal (topical), transmucosal, rectal, or intranasal (including, but not limited to, inhalation of aerosol suspensions for delivery of compositions to the nasal mucosa, trachea and bronchioli) administration.
• parenteral e.g., intravenous, intradermal, subcutaneous, inhalation
• transdermal (topical) transmucosal
• rectal or intranasal (including, but not limited to, inhalation of aerosol suspensions for delivery of compositions to the nasal mucosa, trachea and bronchioli) administration
• the caffeine is in an isolated form, such as that which is separated from one or more molecules or macromolecules normally found with caffeine before use in a combination or method as disclosed herein.
• the caffeine is completely or partially purified from one or more molecules or macromolecules normally found with the caffeine.
• Exemplary cases of molecules or macromolecules found with caffeine include a plant or plant part, an animal or animal part, and a food or beverage product.
• Non-limiting examples of a reported PDEl inhibitor include IBMX; vinpocetine; MMPX; KS-505a; SCH-51866; W-7; PLX650; PLX371; PLX788; a phenothiazines; or a compound described in U.S. Pat. 4,861,891.
• Non-limiting examples of a PDE2 inhibitor include EHNA; PLX650; PLX369; PLX788; PLX 939; Bay 60-7550 or a related compound described in Boess et al., Neuropharmacology, 47(7):1081-92 (2004); or a compound described in US20020132754.
• Non-limiting examples of reported PDE3 inhibitors include a dihydroquinolinone compound such as cilostamide, cilostazol, vesnarinone, or OPC 3911; an imidazolone such as piroximone or enoximone; a bipyridine such as milrinone, amrinone or olprinone; an imidazoline such as imazodan or 5-methyl-imazodan; a pyridazinone such as indolidan; LY181512 (see Komas et al. "Differential sensitivity to cardiotonic drugs of cyclic AMP phosphodiesterases isolated from canine ventricular and sinoatrial-enriched tissues.” J Cardiovasc Pharmacol.
• Non-limiting examples of reported PDE4 inhibitors include a pyrrolidinone, such as a compound disclosed in U.S. Pat. 5,665,754, US20040152754 or US20040023945; a quinazolineone, such as a compound disclosed in U.S. Pats. 6,747,035 or 6,828,315, WO 97/49702 or WO 97/42174; a xanthine derivative; a phenylpyridine, such as a compound disclosed in U.S. Pat.
• a substituted phenyl compound such as a compound disclosed in U.S. Pats. 6,297,264, 5,866,593,65 5,859,034, 6,245,774, 6,197,792, 6,080,790, 6,077,854, 5,962,483, 5,674,880, 5,786,354, 5,739,144, 5,776,958, 5,798,373, 5,891,896, 5,849,770, 5,550,137, 5,340,827, 5,780,478, 5,780,477, or 5,633,257, or WO
• Additional examples of reported PDE4 inhibitors useful in methods provided herein include a compound disclosed in U.S. Pats. 6,716,987, 6,514,996, 6,376,535, 6,740,655, 6,559,168, 6,069,151, 6,365,585, 6,313,116, 6,245,774, 6,011,037, 6,127,363, 6,303,789, 6,316,472, 6,348,602, 6,331,543, 6,333,354, 5,491,147, 5,608,070, 5,622,977, 5,580,888, 6,680,336, 6,569,890, 6,569,885, 6,500,856, 6,486,186, 6,458,787, 6,455,562, 6,444,671, 6,423,710, 6,376,489, 6,372,777, 6,362,213, 6,313,156, 6,294,561, 6,258,843, 6,258,833, 6,121,279, 6,043,263, RE38,624, 6,297,257, 6,251,923, 6,61
• Non-limiting examples of a reported PDE5 inhibitor useful in a combination or method described herein include a pyrimidine or pyrimidinone derivative, such as a compound described in U.S. Pats. 6,677,335, 6,458,951, 6,251,904, 6,787,548, 5,294,612, 5,250,534, or 6,469,012, WO 94/28902, WO96/16657, EP0702555, or Eddahibi, Br. J.
• a griseolic acid derivative such as a compound disclosed in U.S. Pat. 4,460,765
• a 1-arymaphthalene lignan such as that described in Ukita, J. Med. Chem. 42(7): 1293-1305 (1999)
• a quinazoline derivative such as 4-[[3',4'- (methylenedioxy)benzyl] amino] -6-methoxyquinazoline) or a compound described in U.S. Pats. 3,932,407 or 4,146,718, or RE31,617
• a pyrroloquinolones or pyrrolopyridinone such as that described in U.S. Pats.
• a reported PDE5 inhibitor is zaprinast; MY-5445; dipyridamole; vinpocetine; FR229934; l-methyl-3-isobutyl-8-(methylamino)xanthine; furazlocillin; Sch-51866; E4021; GF-196960; IC-351; T-1032; sildenafil; tadalafil; vardenafil; DMPPO; RX-RA-69; KT-734; SKF-96231; ER-21355; BF/GP-385; NM-702; PLX650; PLX134; PLX369; PLX788; or vesnarinone.
• the reported PDE5 inhibitor is sildenafil or a related compound disclosed in U.S. Pats. 5,346,901, 5,250,534, or 6,469,012; tadalafil or a related compound disclosed in U.S. Pat. 5,859,006, 6,140,329, 6,821,975, or 6,943,166; or vardenafil or a related compound disclosed in U.S. Pat. 6,362,178.
• Non-limiting examples of a reported PDE6 inhibitor useful in a combination or method described herein include dipyridamole or zaprinast.
• Non-limiting examples of a reported PDE7 inhibitor for use in the combinations and methods described herein include BRL 50481; PLX369; PLX788; or a compound described in U.S. Pats. 6,818,651; 6,737,436, 6,613,778, 6,617,357; 6,146,876, 6,838,559, or 6,884,800, US20050059686; US20040138279; US20050222138; US20040214843; US20040106631; US 20030045557; US 20020198198; US20030162802, US20030092908, US 20030104974; US20030100571; 20030092721; or US20050148604.
• a non-limiting examples of a reported inhibitor of PDE8 activity is dipyridamole.
• Non-limiting examples of a reported PDE9 inhibitor useful in a combination or method described herein include SCH-51866; IBMX; or BAY 73-6691.
• Non-limiting examples of a PDElO inhibitor include sildenafil; SCH-51866; papaverine; zaprinast; dipyridamole; E4021; vinpocetine; EHNA; milrinone; rolipram; PLX107; or a compound described in U.S. Pat. 6,930,114, US20040138249, or US20040249148.
• Non-limiting examples of a PDEl 1 inhibitor includes IC-351 or a related compound described in WO 9519978; E4021 or a related compound described in WO 9307124; UK-235,187 or a related compound described in EP 579496; PLX788; zaprinast; dipyridamole; or a compound described in US20040106631 or Maw et al., Bioorg Med Chem Lett. 2003 Apr 17;13(8):1425-8.
• the reported PDE inhibitor is a compound described in U.S. Pats. 5,091,431, 5,081,242, 5,066,653, 5,010,086, 4,971,972, 4,963,561, 4,943,573, 4,906,628, 4,861,891, 4,775,674, 4,766,118, 4,761,416, 4,739,056, 4,721,784, 4,701,459, 4,670,434, 4,663,320, 4,642,345, 4,593,029, 4,564,619, 4,490,371, 4,489,078, 4,404,380, 4,370,328, 4,366,156, 4,298,734, 4,289,772, RE30.511, 4,188,391, 4,123,534, 4,107,309, 4,107,307, 4,096,257, 4,093,617, 4,051,236, or 4,036,840.
• the reported PDE inhibitor inhibits dual-specificity PDE.
• a dual-specificity PDE inhibitor useful in a combination or method described herein include a cAMP-specific or cGMP-specific PDE inhibitor described herein; MMPX; KS-505a; W-7; a phenothiazine; Bay 60-7550 or a related compound described in Boess et al., Neuropharmacology, 47(7):1081-92 (2004); UK-235,187 or a related compound described in EP 579496; or a compound described in U.S. Pats.
• a reported PDE inhibitor exhibits dual-selectivity, being substantially more active against two PDE isozymes relative to other PDE isozymes.
• a reported PDE inhibitor is a dual PDE4/PDE7 inhibitor, such as a compound described in US20030104974; a dual PDE3/PDE4 inhibitor, such as zardaverine, tolafentrine, benafentrine, trequinsine, Org-30029, L-686398, SDZ-ISQ-844, Org-20241, EMD-54622, or a compound described in U.S. Pats.
• a dual PDE1/PDE4 inhibitor such as KF19514 (5-phenyl-3-(3-pyridyl)methyl-3H- imidazo[4,5-c] [ 1 ,8]naphthyridin-4 (5H)-one).
• the neurogenic agent in combination with an angiotensin agent may be a reported neurosteroid.
• a neurosteroid include pregnenolone and allopregnenalone.
• the neurogenic sensitizing agent may be a reported non-steroidal anti-inflammatory drug (NSAID) or an anti-inflammatory mechanism targeting agent in general.
• NSAID non-steroidal anti-inflammatory drug
• Non-limiting examples of a reported NSAID include a cyclooxygenase inhibitor, such as indomethacin, ibuprofen, celecoxib, cofecoxib, naproxen, or aspirin.
• Additional non- limiting examples for use in combination with an angiotensin agent include rofecoxib, meloxicam, piroxicam, valdecoxib, parecoxib, etoricoxib, etodolac, nimesulide, acemetacin, bufexamac, diflunisal, ethenzamide, etofenamate, flobufen, isoxicam, kebuzone, lonazolac, meclofenamic acid, metamizol, mofebutazone, niflumic acid, oxyphenbutazone, paracetamol, phenidine, propacetamol, propyphenazone, salicylamide, tenoxicam, tiaprofenic acid, oxaprozin, lornoxicam, nabumetone, minocycline, benorylate, aloxiprin, salsalate, flurbiprofen, ketoprofen, fenoprof
• the neurogenic agent in combination with an angiotensin agent may be a reported agent for treating migraines.
• an agent include a triptan, such as almotriptan or almotriptan malate; naratriptan or naratriptan hydrochloride; rizatriptan or rizatriptan benzoate; sumatriptan or sumatriptan succinate; zolmatriptan or zolmitriptan, frovatriptan or frovatriptan succinate; or eletriptan or eletriptan hydrobromide.
• Embodiments of the disclosure may exclude combinations of triptans and an SSRI or SNRI that result in life threatening serotonin syndrome.
• Non-limiting examples include an ergot derivative, such as dihydroergotamine or dihydroergotamine mesylate, ergotamine or ergotamine tartrate; diclofenac or diclofenac potassium or diclofenac sodium; flurbiprofen; amitriptyline; nortriptyline; divalproex or divalproex sodium; propranolol or propranolol hydrochloride; verapamil; methysergide (CAS RN 361-37-5); metoclopramide; prochlorperazine (CAS RN 58-38-8); acetaminophen; topiramate; GW274150 ([2-[(l-iminoethyl) amino] ethyl] -L- homocysteine); or ganaxalone (CAS RN 38398-32-2).
• Additional non-limiting examples include a COX-2 inhibitor, such as celecoxib.
• the neurogenic agent in combination with an angiotensin agent may be a reported modulator of a nuclear hormone receptor.
• Nuclear hormone receptors are activated via ligand interactions to regulate gene expression, in some cases as part of cell signaling pathways.
• Non-limiting examples of a reported modulator include a dihydrotestosterone agonist such as dihydrotestosterone; a 2-quinolone like LG121071 (4-ethyl-l,2,3,4-tetrahydro-6- (trifluoromethyl)-8-pyridono[5,6-g]- quinoline); a non-steroidal agonist or partial agonist compound described in U.S. Pat.
• a reported modulator examples include a selective androgen receptor modulator (SARM) such as andarine, ostarine, prostarin, or andromustine (all from GTx, Inc.); bicalutamide or a bicalutamide derivative such as GTx-007 (U.S. Pat. 6,492,554); or a SARM as described in U.S. Pat. 6,492,554.
• SARM selective androgen receptor modulator
• a reported modulator examples include an androgen receptor antagonist such as cyproterone, bicalutamide, flutamide, or nilutamide; a 2- quinolone such as LGl 20907, represented by the following structure:
• a reported modulator examples include a retinoic acid receptor agonist such as all-trans retinoic acid (Tretinoin®); isotretinoin (13-cis-retinoic acid); 9-cis retinoic acid; bexarotene; TAC-101 (4-[3,5-to (trimethylsilyl) benzamide] benzoic acid); AC-261066 (see Lund et al. "Discovery of a potent, orally available, and isoform-selective retinoic acid beta2 receptor agonist.” J Med Chem.
• LGDl 550 ((2E,4E,6E)-3-methyl-7-(3,5-di-ter-butylphen-yl)octatrienoic acid); E6060 (E6060 [4- ⁇ 5-[7-fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-lH-2-pyrrolyl ⁇ benzoic acid]; agonist 1 or 2 as described by Schapira et al. ("In silico discovery of novel Retinoic Acid Receptor agonist structures.” BMC Struct Biol.
• Agonist 1 was purchased from Bionet Research (catalog number 1G-433S).
• Agonist 2 was purchased from Sigma- Aldrich (Sigma Aldrich library of rare chemicals. Catalog number S08503-1"); a synthetic acetylenic retinoic acid, such as AGN 190121 (CAS RN: 132032-67- 8), AGN 190168 (or tazarotene or CAS RN 118292-40-3), or its metabolite AGN 190299 (CAS RN 118292-41-4); etretinate; acitretin; an acetylenic retinoate, such as AGN 190073 (CAS 132032-68-9), or AGN 190089 (or 3- ⁇ yridinecarboxylic acid, 6-(4-(2,6,6-trimethyl-l- cyclohexen-l-yl)-3-buten-l-ynyl)-, ethyl ester or CAS RN 11
• the additional agent for use in combination with an angiotensin agent may be a reported modulator selected from thyroxin, tri-iodothyronine, or levothyroxine.
• the additional agent is a vitamin D (1,25-dihydroxyvitamine D 3 ) receptor modulator, such as calcitriol or a compound described in Ma et al. ("Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators.” J Clin Invest. 2006 116(4):892-904) or Molnar et al. (“Vitamin D receptor agonists specifically modulate the volume of the ligand-binding pocket.” J Biol Chem. 2006 281(15):10516-26) or Milliken et al. (“EB1089, a vitamin D receptor agonist, reduces proliferation and decreases tumor growth rate in a mouse model of hormone-induced mammary cancer.” Cancer Lett.
• a vitamin D (1,25-dihydroxyvitamine D 3 ) receptor modulator such as calcitriol or a compound described in Ma et al. (“Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal
• the additional agent may be a reported Cortisol receptor modulator, such as methylprednisolone or its prodrug methylprednisolone suleptanate; PI- 1020 (NCX- 1020 or budesonide-21-nitrooxymethylbenzoate); fluticasone furoate; GW- 215864; betamethasone valerate; beclomethasone; prednisolone; or BVT-3498 (AMG-311).
• PI- 1020 NCX- 1020 or budesonide-21-nitrooxymethylbenzoate
• fluticasone furoate GW- 215864
• betamethasone valerate betamethasone valerate
• beclomethasone prednisolone
• prednisolone or BVT-3498
• the additional agent may be a reported aldosterone (or mineralocorticoid) receptor modulator, such as spironolactone or eplerenone.
• the additional agent may be a reported progesterone receptor modulator such as asoprisnil (CAS RN 199396-76-4 ); mesoprogestin or Jl 042; J956; medroxyprogesterone acetate (MPA); R5020; tanaproget; trimegestone; progesterone; norgestomet; melengestrol acetate; mifepristone; onapristone; ZK137316; ZK230211 (see Fuhrmann et al.
• the additional agent may be a reported i) peroxisome proliferator-activated receptor (PPAR) agonist such as muraglitazar; tesaglitazar; reglitazar; GW-409544 (see Xu et al. "Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors.” Proc Natl Acad Sci U S A. 2001 98(24):13919- 24); or DRL 11605 (Dr.
• PPAR peroxisome proliferator-activated receptor
• a peroxisome proliferator-activated receptor alpha agonist like clofibrate; ciprofibrate; fenofibrate; gemfibrozil; DRF- 10945 (Dr.
• a peroxisome proliferator-activated receptor delta agonist such as GW501516 (CAS RN 317318-70-0); or iv) a peroxisome proliferator-activated gamma receptor agonist like a hydroxyoctadecadienoic acid (HODE);
• a prostaglandin derivative such as 15-deoxy-Deltal2,14-prostaglandin J2; a thiazolidinedione (glitazone), such as pioglitazone, troglitazone; rosiglitazone or rosiglitazone maleate; ciglitazone; balaglitazone or DRF-2593; AMG 131 (from Amgen); or G1262570 (from Glaxo Wellcome).
• a PPAR ligand is a PP ARy antagonist such as T0070907 (CAS RN 313516- 66-4) or GW
• the additional agent may be a reported modulator of an "orphan" nuclear hormone receptor.
• embodiments include a reported modulator of a liver X receptor, such as a compound described in U.S. Pat. 6,924,311 ; a farnesoid X receptor, such as GW4064 as described by Maloney et al. ("Identification of a chemical tool for the orphan nuclear receptor FXR.” J Med Chem.
• a RXR receptor a RXR receptor
• a CAR receptor such as l,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP); or a PXR receptor, such as SR-12813 (terra-ethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-l, 1- bisphosphonate).
• the agent in combination with an angiotensin agent is ethyl eicosapentaenoate or ethyl-EPA (also known as 5,8,11,14,17-eicosapentaenoic acid ethyl ester or miraxion, CAS RN 86227-47-6), docosahexaenoic acid (DHA), or a retinoid acid drug.
• the agent may be omacor, a combination of DHA and EPA, or idebenone (CAS RN 58186-27-9).
• a reported nootropic compound may be used as an agent in combination with an angiotensin agent.
• Non-limiting examples of such a compound include piracetam (Nootropil®), aniracetam, xxiracetam, pramiracetam, pyritinol (Enerbol®), ergoloid mesylates (Hydergine®), galantamine or galantamine hydrobromide, selegiline, centrophenoxine (Lucidril®), desmopressin (DDAVP), nicergoline, vinpocetine, picamilon, vasopressin, milacemide, FK-960, FK-962, levetiracetam, nef ⁇ racetam, or hyperzine A (CAS RN: 102518-79-6). Additional non-limiting examples of such a compound include anapsos (CAS RN: 102518-79-6). Additional non-limiting examples of such a compound include anapsos (CAS RN: 102518-
• nebracetam (CAS RN 97205-34-0 or 116041-13-5), metrifonate, ensaculin (or CAS RN 155773-59-4 or KA-672) or ensaculin HCl, rokan (CAS RN 122933-57-7 or EGb 761), AC-3933 (5-(3-methoxyphenyl)-3-(5-methyl-l,2,4-oxadiazol-3-yl)-2-oxo-l,2- dihydro-l,6-naphthyridine) or its hydroxylated metabolite SX-5745 (3-(5-hydroxymethyl- l,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-2-oxo-l,2-dihydro-l,6-naphthyridine), JTP-2942 (CAS RN 148152-77-6), sabeluzole (CAS RN 148152-77-6
• SR-46559A (3- [N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl), dihydroergocristine (CAS RN 17479-19-5), dabelotine (CAS RN 118976-38-8), zanapezil (CAS RN 142852-50-4).
• NBI-113 from Neurocrine
• an agent in combination with an angiotensin agent may be a reported modulator of the nicotinic receptor.
• Non-limiting examples of such a modulator include nicotine, acetylcholine, carbamylcholine, epibatidine, ABT-418 (structurally similar to nicotine, with an ixoxazole moiety replacing the pyridyl group of nicotine), epiboxidine (a structural analogue with elements of both epibatidine and ABT-418), ABT-594 (azetidine analogue of epibatidine), lobeline, SSR-591813, represented by the following formula:
• an agent used in combination with an angiotensin agent is a reported aromatase inhibitor.
• Reported aromatase inhibitors include, but are not limited to, nonsteroidal or steroidal agents.
• Non-limiting examples of the former, which inhibit aromatase via the heme prosthetic group include anastrozole (Arimidex®), letrozole (Femara®), or vorozole (Rivisor®).
• Non-limiting examples of steroidal aromatase inhibitors AIs which inactivate aromatase, include, but are not limited to, exemestane (Aromasin®), androstenedione, or formestane (Lentaron®). Additional non-limiting examples of a reported aromatase for use in a combination or method as disclosed herein include aminoglutethimide, 4-androstene-3,6,17- trione (or "6-OXO"), or zoledronic acid or Zometa® (CAS RN 118072-93-8).
• an angiotensin agent and a reported selective estrogen receptor modulator (SERM) may be used as described herein.
• SERM reported selective estrogen receptor modulator
• Non-limiting examples include tamoxifen, raloxifene, toremifene, clomifene, apeledoxifene, arzoxifene, or lasofoxifene.
• Additional non-limiting examples include a steroid antagonist or partial agonist, such as centchroman, clomiphene, or droloxifene.
• a combination of an angiotensin agent and a reported cannabinoid receptor modulator may be used as described herein.
• Non-limiting examples include synthetic cannabinoids, endogenous cannabinoids, or natural cannabinoids.
• the reported cannabinoid receptor modulator is rimonabant (SR141716 or Acomplia), nabilone, levonantradol, marinol, or sativex (an extract containing both THC and CBD).
• Non-limiting examples of endogenous cannabinoids include arachidonyl ethanolamine (anandamide); analogs of anandamide, such as docosatetraenylethanolamide or homo- ⁇ -linoenylethanolamide; N-acyl ethanolamine signalling lipids, such as the noncannabimimetic palmitoylethanolamine or oleoylethanolamine; or 2-arachidonyl glycerol.
• Non-limiting examples of natural cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), or cannabigerol monoethyl ether (CBGM).
• THC tetrahydrocannabinol
• CBD cannabidiol
• CBD cannabinol
• CBG cannabigerol
• CBC cannabichromene
• CBD cannabicyclol
• CBV cannabivarol
• THCV cannabidivarin
• CBDV cannabichromevarin
• an agent used in combination with an angiotensin agent is a reported FAAH (fatty acid amide hydrolase) inhibitor.
• reported inhibitor agents include URB597 (3'-carbamoyl-biphenyl-3-yl- cyclohexylcarbamate); CAY10401 (l-oxazolo[4,5-b]pyridin-2-yl-9-octadecyn-l-one); OL135 (l-oxo-l[5-(2-pyridyl)-2-yl]-7-phenylheptane); anandamide (CAS RN 94421-68-8); AA- 5-HT (see Bisogno et al.
• SSR 411298 from Sanofi-Aventis
• JNJ28614118 from Johnson & Johnson
• SSR 101010 from Sanofi-Aventis
• an agent in combination with an angiotensin agent may be a reported modulator of nitric oxide function.
• sildenafil Viagra®
• an agent in combination with an angiotensin agent may be a reported modulator of prolactin or a prolactin modulator.
• an agent in combination with an angiotensin agent is a reported anti-viral agent, with ribavirin and amantadine as non-limiting examples.
• an agent in combination with an angiotensin agent may be a component of a natural product or a derivative of such a component.
• the component or derivative thereof is in an isolated form, such as that which is separated from one or more molecules or macromolecules normally found with the component or derivative before use in a combination or method as disclosed herein.
• the component or derivative is completely or partially purified from one or more molecules or macromolecules normally found with the component or derivative.
• Exemplary cases of molecules or macromolecules found with a component or derivative as described herein include a plant or plant part, an animal or animal part, and a food or beverage product.
• a component include folic acid; a flavinoid, such as a citrus flavonoid; a flavonol, such as quercetin, kaempferol, myricetin, or isorhamnetin; a flavone, such as luteolin or apigenin; a flavanone, such as hesperetin, naringenin, or eriodictyol; a flavan-3-ol (including a monomelic, dimeric, or polymeric flavanol), such as (+)-catechin, (+)-gallocatechin, (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechin 3-gallate, (-)-epigallocatechin 3-gallate, theaflavin, theaflavin
• a component of Gingko biloba such as a flavo glycoside or a terpene.
• the component is a flavanoid, such as a flavonol or flavone glycoside, or a quercetin or kaempferol glycoside, or rutin; or a terpenoid, such as ginkgolides A, B, C, or M, or bilobalide.
• Non-limiting examples include a component that is a flavanol, or a related oligomer, or a polyphenol as described in US2005/245601AA, US2002/018807AA, US2003/180406AA, US2002/086833AA, US2004/0236123, WO9809533, or WO9945788; a procyanidin or derivative thereof or polyphenol as described in US2005/171029AA; a procyanidin, optionally in combination with L-arginine as described in US2003/104075AA; a low fat cocoa extract as described in US2005/031762AA; lipophilic bioactive compound containing composition as described in US2002/107292AA; a cocoa extract, such as those containing one or more polyphenols or procyanidins as described in US2002/004523 AA; an extract of oxidized tea leaves as described in US Pat. 5,139,802 or 5,130,154; a food supplement as described in WO 2002/024002.
• an agent in combination with an angiotensin agent may be a reported calcitonin receptor agonist such as calcitonin or the Orphan peptide' PHM- 27 (see Ma et al. "Discovery of novel peptide/receptor interactions: identification of PHM-27 as a potent agonist of the human calcitonin receptor.” Biochem Pharmacol. 2004 67(7): 1279-84).
• a further non-limiting example is the agonist from Kemia, Inc.
• the agent may be a reported modulator of parathyroid hormone activity, such as parathyroid hormone, or a modulator of the parathyroid hormone receptor.
• an agent in combination with an angiotensin agent may a reported antioxidant, such as N-acetylcysteine or acetylcysteine; disufenton sodium (or CAS RN 168021-79-2 or Cerovive); activin (CAS RN 104625-48-1); selenium; L- methionine; an alpha, gamma, beta, or delta, or mixed, tocopherol; alpha lipoic acid; Coenzyme Q; benzimidazole; benzoic acid; dipyridamole; glucosamine; IRFI-016 (2(2,3- dihydro-5-acetoxy-4,6,7-trimethylbenzofuranyl) acetic acid); L-carnosine; L-Histidine; glycine; flavocoxid (or LIMBREL®; baicalin, optionally with catechin (3,3',4',5,7- pentahydroxyflavan (2R,3S form)), and/or
• Additional non-limiting examples include a vitamin, such as vitamin A (Retinol) or C (Ascorbic acid) or E (including tocotrienol and/or tocopherol); a vitamin cofactors or mineral, such as coenzyme QlO (CoQlO), manganese, or melatonin; a carotenoid terpenoid, such as lycopene, lutein, alpha-carotene, beta-carotene, zeaxanthin, astaxanthin, or canthaxantin; a non-carotenoid terpenoid, such as eugenol; a flavonoid polyphenolic (or bioflavonoid); a flavonol, such as resveratrol, pterostilbene (methoxylated analogue of resveratrol), kaempferol, myricetin, isorhamnetin, a proanthocyanidin, or a tannin;
• Non-limiting examples include l-(carboxymethylthio)tetradecane; 2,2,5, 7,8-pentamethyl-l-hydroxychroman; 2,2,6,6-tetramethyl-4-piperidinol-N-oxyl; 2,5-di- tert-butylhydroquinone; 2-tert-butylhydroquinone; 3,4-dihydroxyphenylethanol; 3- hydroxypyridine; 3-hydroxytamoxifen; 4-coumaric acid; 4-hydroxyanisole; A- hydroxyphenylethanol; 4-methylcatechol; 5,6,7, 8-tetrahydrobiopterin; 6,6'-methylenebis(2,2- dimethyl-4-methanesulfonic acid-1 ,2-dihydroquinoline); 6-hydroxy-2, 5,7,8- tetramethylchroman-2-carboxylic acid; 6-methyl-2-ethyl-3-hydroxypyridine; 6-O- palmitoylascorbic acid; acetovanillone; acteoside; act
• an agent in combination with an angiotensin agent may be a reported modulator of a norepinephrine receptor.
• Non-limiting examples include atomoxetine (Strattera®); a norepinephrine reuptake inhibitor, such as talsupram, tomoxetine, nortriptyline, nisoxetine, reboxetine (described, e.g., in U.S. Pat. 4,229,449), or tomoxetine (described, e.g., in U.S. Pat. 4,314,081); or a direct agonist, such as a beta adrenergic agonist.
• alpha adrenergic agonist such as etilefrine or a reported agonist of the ⁇ 2-adrenergic receptor (or ⁇ 2 adrenoceptor) like clonidine (CAS RN 4205-90-7), yohimbine, mirtazepine, atipamezole, carvedilol; dexmedetomidine or dexmedetomidine hydrochloride; ephedrine, epinephrine; etilefrine; lidamidine; tetramethylpyrazine; tizanidine or tizanidine hydrochloride; apraclonidine; bitolterol mesylate; brimonidine or brimonidine tartrate; dipivefrin (which is converted to epinephrine in vivo); guanabenz; guanfacine; methyldopa; alphamethylnoradrenaline; mivazerol; natural
• adrenergic antagonist such as a reported antagonist of the ⁇ 2-adrenergic receptor like yohimbine (CAS RN 146-48-5) or yohimbine hydrochloride, idazoxan, fluparoxan, mirtazepine, atipamezole, or RX781094 (see Elliott et al. "Peripheral pre and postjunctional alpha 2-adrenoceptors in man: studies with RX781094, a selective alpha 2 antagonist.” J Hypertens Suppl. 1983 l(2):109-l l).
• Non-limiting embodiments include a reported modulator of an ⁇ l -adrenergic receptor such as cirazoline; modafinil; ergotamine; metaraminol; methoxamine; midodrine (a prodrug which is metabolized to the major metabolite desglymidodrine formed by deglycination of midodrine); oxymetazoline; phenylephrine; phenylpropanolamine; or pseudoephedrine.
• a reported modulator of an ⁇ l -adrenergic receptor such as cirazoline; modafinil; ergotamine; metaraminol; methoxamine; midodrine (a prodrug which is metabolized to the major metabolite desglymidodrine formed by deglycination of midodrine); oxymetazoline; phenylephrine; phenylpropanolamine; or pseudoephedrine.
• Non-limiting embodiments include a reported modulator of a beta adrenergic receptor such as arbutamine, befunolol, cimaterol, higenamine, isoxsuprine, mefhoxyphenamine, oxyfedrine, ractopamine, tretoquinol, or TQ-1016 (from TheraQuest Biosciences, LLC), or a reported ⁇ l -adrenergic receptor modulator such as prenalterol, Ro 363, or xamoterol or a reported ⁇ 1 -adrenergic receptor agonist like dobutamine.
• a reported modulator of a beta adrenergic receptor such as arbutamine, befunolol, cimaterol, higenamine, isoxsuprine, mefhoxyphenamine, oxyfedrine, ractopamine, tretoquinol, or TQ-1016 (from TheraQuest Biosciences, LLC), or a reported ⁇ l -ad
• the reported modulator may be of a ⁇ 2-adrenergic receptor such as levosalbutamol (CAS RN 34391-04-3), metaproterenol, MN-221 or KUR-1246 ((-)-bis(2- ⁇ [(2S)-2-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl) phenyl] ethyl ⁇ amino)- 1,2,3 ,4- tetrahydronaphthalen-7-yl]oxy ⁇ -N,N-dimethylacetamide)monosulfate or bis(2-[[(2S)-2- ([(2R)-2-hydroxy-2-[4-hydroxy-3 -(2-hydroxyethyl)-phenyl] ethyl] amino)- 1 ,2,3 ,4- tetrahydronaphthalen-7-yl]oxy]-N,N-dimethylacetamide) sulfate or CAS RN
• Additional non-limiting embodiments include a reported modulator of a ⁇ 3- adrenergic receptor such as AJ-9677 or TAK677 ([3-[(2R)-[[(2R)-(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]-lH-indol-7-yloxy] acetic acid), or a reported ⁇ 3-adrenergic receptor agonist like SR5861 IA (described in Simiand et al., Eur J Pharmacol, 219:193-201 (1992), BRL 26830A, BRL 35135, BRL 37344, CL 316243 or ICI D7114.
• a reported modulator of a ⁇ 3- adrenergic receptor such as AJ-9677 or TAK677 ([3-[(2R)-[[(2R)-(3-chlorophenyl)-2- hydroxyethyl]amino]
• Further alternative embodiments include a reported nonselective alpha and beta adrenergic receptor agonist such as epinephrine or ephedrine; a reported nonselective alpha and beta adrenergic receptor antagonist such as carvedilol; a ⁇ l and ⁇ 2 adrenergic receptor agonist such as isopreoterenol; or a ⁇ l and ⁇ 2 adrenergic receptor antagonist such as CGP 12177, fenoterol, or hexoprenaline.
• Non-limiting examples of reported adrenergic agonists include albuterol, albuterol sulfate, salbutamol (CAS RN 35763-26-9), clenbuterol, adrafinil, and SR5861 IA (described in Simiand et al., Eur J Pharmacol, 219:193-201 (1992)), clonidine (CAS RN 4205-90-7), yohimbine (CAS RN 146-48-5) or yohimbine hydrochloride, arbutamine; befunolol; BRL 26830A; BRL 35135; BRL 37344; bromoacetylalprenololmenthane; broxaterol; carvedilol; CGP 12177; cimaterol; cirazoline; CL 316243; clenbuterol; denopamine; dexmedetomidine or dexmedetomidine hydrochloride; dobutamine, dopexamine,
• Additional non-limiting examples include apraclonidine, bitolterol mesylate, brimonidine or brimonidine tartrate, dipivefrin (which is converted to epinephrine in vivo), epinephrine, ergotamine, guanabenz, guanfacine, metaproterenol, metaraminol, methoxamine, methyldopa, midodrine (a prodrug which is metabolized to the major metabolite desglymidodrine formed by deglycination of midodrine), oxymetazoline, phenylephrine, phenylpropanolamine, pseudoephedrine, alphamethylnoradrenaline, mivazerol, natural ephedrine or D(-)ephedrine, any one or any mixture of two, three, or four of the optically active forms of ephedrine, CHF1035 or nolomirole hydrochloride
• a reported adrenergic antagonist such as idazoxan or fluparoxan, may be used as an agent in combination with a nootropic agent as described herein.
• an agent in combination with an angiotensin agent may be a reported modulator of carbonic anhydrase.
• an agent in combination with an angiotensin agent may be a reported modulator of carbonic anhydrase.
• Non-limiting examples of such an agent include acetazolamide, benzenesulfonamide, benzolamide, brinzolamide, dichlorphenamide, dorzolamide or dorzolamide HCl, ethoxzolamide, flurbiprofen, mafenide, methazolamide, sezolamide, zonisamide, bendroflumethiazide, benzthiazide, chlorothiazide, cyclothiazide, dansylamide, diazoxide, ethinamate, furosemide, hydrochlorothiazide, hydroflumethiazide, mercuribenzoic acid, methyclothiazide, trichloromethazide, amlodipine, cyan
• Such an agent include (4S- Trans)-4-(Ethylamino)-5,6-dihydro-6-methyl-4H-thieno(2,3-B)thiopyran-2-sulfonamide-7,7- dioxide; (4S-trans)-4-(methylamino)-5,6-dihydro-6-methyl-4H-thieno(2,3-B)thiopyran-2- sulfonamide-7,7-dioxide; (R)-N-(3 -indol- 1 -Yl-2-methyl-propyl)-4-sulfamoyl-benzamide; (S)-N-(3 -indol- 1 - Yl-2-methyl-propyl)-4-sulfamoyl-benzamide; 1 ,2,4-triazole; 1 -methyl-3 - oxo-l,3-dihydro-benzo[C]isothiazole-5-sulfonic acid
• an agent in combination with an angiotensin agent may be a reported modulator of a catechol-O-methyltransferase (COMT), such as floproprione, or a COMT inhibitor, such as tolcapone (CAS RN 134308-13-7), nitecapone (CAS RN 116313-94-1), or entacapone(CAS RN 116314-67-1 or 130929-57-6).
• a catechol-O-methyltransferase such as floproprione
• COMT inhibitor such as tolcapone (CAS RN 134308-13-7), nitecapone (CAS RN 116313-94-1), or entacapone(CAS RN 116314-67-1 or 130929-57-6).
• an agent in combination with an angiotensin agent may be a reported modulator of hedgehog pathway or signaling activity such as cyclopamine, jervine, ezetimibe, regadenoson (CAS RN 313348-27-5, or CVT-3146), a compound described in U.S. Pat. 6,683,192 or identified as described in U.S. Pat. 7,060,450, or CUR- 61414 or another compound described in U.S. Pat. 6,552,016.
• an agent in combination with an angiotensin agent may be a reported modulator of IMPDH, such as mycophenolic acid or mycophenolate mofetil (CAS RN 128794-94-5).
• an agent in combination with an angiotensin agent may be a reported modulator of a sigma receptor, including sigma-1 and sigma-2.
• a modulator include an agonist of sigma-1 and/or sigma-2 receptor, such as (+)-pentazocine, SKF 10,047 (N-allylnormetazocine), or 1,3-di-O- tolylguanidine (DTG).
• a modulator include (+)-pentazocine, SKF 10,047 (N-allylnormetazocine), or 1,3-di-O- tolylguanidine (DTG).
• SKF 10,047 N-allylnormetazocine
• TMG 1,3-di-O- tolylguanidine
• Additional non-limiting examples include SPD-473 (from Shire
• Additional non-limiting examples include igmesine; BD 1008 and related compounds disclosed in U.S. Publication No. 20030171347; cis-isomers of U50488 and related compounds described in de Costa et al, J. Med. Chem., 32(8): 1996-2002 (1989); U101958; SKF10,047; apomorphine; OPC-14523 and related compounds described in Oshiro et al., J Med Chem.; 43(2): 177-89 (2000); arylcyclohexamines such as PCP; (+)-morphinans such as dextrallorphan; phenylpiperidines such as (+)-3-PPP and OHBQs; neurosteroids such as progesterone and desoxycorticosterone; butryophenones; BD614; or PRX-00023.
• Non-limiting examples include a sigma- 1 agonist, such as IPAG (l-(4- iodophenyl)-3-(2-adamantyl)guanidine); pre-084; carbetapentane; 4-IBP; L-687,384 and related compounds described in Middlemiss et al., Br. J.
• IPAG l-(4- iodophenyl)-3-(2-adamantyl)guanidine
• pre-084 carbetapentane
• 4-IBP 4-IBP
• L-687,384 and related compounds described in Middlemiss et al., Br. J.
• Alternative non-limiting examples include a sigma-1 antagonist such as BD- 1047 (N(-)[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamin-o)ethylamine), BD-1063 (l(-)[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine, rimcazole, haloperidol, BD-1047, BD-1063, BMY 14802, DuP 734, NE-100, AC915, or R-(+)-3-PPP.
• BD- 1047 N(-)[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamin-o)ethylamine
• BD-1063 l(-)[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine, rimcazole, haloperidol, BD
• Particular non-limiting examples include fluoxetine, fluvoxamine, citalopram, sertaline, clorgyline, imipramine, igmesine, opipramol, siramesine, SL 82.0715, imcazole, DuP 734, BMY 14802, SA 4503, OPC 14523, panamasine, or PRX-00023.
• an agent in combination with an angiotensin agent include acamprosate (CAS RN 77337-76-9); a growth factor, like LIF, EGF, FGF, bFGF or VEGF as non-limiting examples; octreotide (CAS RN 83150-76-9); an NMDA modulator like ketamine, DTG, (+)-pentazocine, DHEA, Lu 28-179 (l'-[4-[l-(4- fluorophenyl)-lH-indol-3-yl]-l-butyl]-spiro[isobenzofuran-l(3H), 4'-piperidine]), BD 1008 (CAS RN 138356-08-8), ACEA1021 (Licostinel or CAS RN 153504-81-5), GV150526A (Gavestinel or CAS RN 153436-22-7), sertraline, clorgyline, or memantine as non-
• the agent used with an angiotensin agent may be a reported 5HTIa receptor agonist (or partial agonist) such as buspirone (buspar).
• a reported 5HTIa receptor agonist is an azapirone, such as, but not limited to, tandospirone, gepirone and ipsapirone.
• Non-limiting examples of additional reported 5HTIa receptor agonists include flesinoxan(CAS RN 98206-10-1), MDL 72832 hydrochloride, U- 92016A, (+)-UH 301, F 13714, F 13640, 6-hydroxy-buspirone (see US 2005/0137206), S-6- hydroxy-buspirone (see US 2003/0022899), R-6-hydroxy-buspirone (see US 2003/0009851 ), adatanserin, buspirone-saccharide (see WO 00/12067) or 8-hydroxy-2-dipropylaminotetralin (8-OHDPAT).
• Additional non-limiting examples of reported 5HTIa receptor agonists include OPC-14523 (l-[3-[4-(3-chlorophenyl)-l-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[lH]- quinolinone monomethanesulfonate); BMS-181100 or BMY 14802 (CAS RN 105565-56-8); flibanserin (CAS RN 167933-07-5); repinotan (CAS RN 144980-29-0); lesopitron (CAS RN 132449-46-8); piclozotan (CAS RN 182415-09-4); Aripiprazole, Org-13011 (l-(4- trifluoromethyl-2-pyridinyl)-4- [4-[2-oxo-l -pyrrolidinyl]butyl]piperazine (E)-2- butenedioate); SDZ-MAR-327 (see Christian et al
• G protein-coupled receptors In silico drug discovery in 3D" PNAS 2004 101(31):l 1304-11309); umespirone (CAS RN 107736-98-1); SLV-308; bifeprunox; and zalospirone (CAS RN 114298-18-9).
• angiotensin agent may be a reported
• a reported 5HT4 receptor agonist or partial agonist is a substituted benzamide, such as cisapride; individual, or a combination of, cisapride enantiomers ((+) cisapride and (-) cisapride); mosapride; and renzapride as non-limiting examples.
• the chemical entity is a benzofuran derivative, such as prucalopride. Additional embodiments include indoles, such as tegaserod, or benzimidazolones.
• 5HT4 receptor agonist or partial agonist examples include zacopride (CAS RN 90182-92-6), SC-53116 (CAS RN 141196-99-8) and its racemate SC-49518 (CAS RN 146388-57-0), BIMUl (CAS RN 127595-43-1), TS-951 (CAS RN 174486-39-6), or ML10302 CAS RN 148868-55-7).
• Additional non-limiting chemical entities include metoclopramide, 5-methoxytryptamine, RS67506, 2-[l-(4-piperonyl) ⁇ iperazinyl]benzothiazole, RS66331, BIMU8, SB 205149 (the n-butyl quaternary analog of renzapride), or an indole carbazimidamide as described by Buchheit et al. ("The serotonin 5-HT4 receptor. 2. Structure-activity studies of the indole carbazimidamide class of agonists.” J Med Chem. (1995) 38(13):2331-8).
• norcisapride (CAS RN 102671-04-5) which is the metabolite of cisapride; mosapride citrate; the maleate form of tegaserod (CAS RN 189188-57-6); zacopride hydrochloride (CAS RN 99617-34-2); mezacopride (CAS RN 89613-77-4); SK- 951 ((+-)-4-amino-N-(2-(l-azabicyclo(3.3.0)octan-5-yl)ethyl)-5-chloro-2,3-dihydro-2- methylbenzo(b)furan-7-carboxamide hemifumarate); ATI-7505, a cisapride analog from ARYx Therapeutics; SDZ-216-454, a selective 5HT4 receptor agonist that stimulates cAMP formation in a concentration dependent manner (see Markstein et al.
• 5HT4 receptor agonists and partial agonists for use in combination with an angiotensin agent include metoclopramide (CAS RN 364-62-5), 5-methoxytryptamine (CAS RN 608-07-1), RS67506 (CAS RN 168986-61-6), 2-[l-(4- piperonyl)piperazinyl]benzothiazole (CAS RN 155106-73-3), RS66331 (see Buccafusco et al.
• metoclopramide dihydro chloride CAS RN 2576-84-3
• metoclopramide dihydrochloride CAS RN 5581-45-3
• metoclopramide hydrochloride CAS RN 7232-21-5 or 54143-57-6
• the agent used with an angiotensin agent may be a reported 5HT3 receptor antagonist such as azasetron (CAS RN 123039-99-6); Ondansetron (CAS RN 99614-02-5) or Ondansetron hydrochloride (CAS RN 99614-01-4); Cilansetron (CAS RN 120635-74-7); Aloxi or Palonosetron Hydrochloride (CAS RN 135729-62-3); Palenosetron (CAS RN 135729-61-2 or 135729-56-5); Cisplatin (CAS RN 15663-27-1); Lotronex or Alosetron hydrochloride (CAS RN 122852-69-1); Anzemet or Dolasetron mesylate (CAS RN 115956-13-3); zacopride or R-Zacopride; E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8- methyl- 8-azabicyclo[3.2.1-]oct-3-yl-2
• Patent 6,846,823, such as DDP 225 or MCI 225 (CAS RN 135991-48-9); Marinol or Dronabinol (CAS RN 1972-08- 3); or Lac Hydrin or Ammonium lactate (CAS RN 515-98-0); Kytril or Granisetron hydrochloride (CAS RN 107007-99-8); Bemesetron (CAS RN 40796-97-2); Tropisetron (CAS RN 89565-68-4); Zatosetron (CAS RN 123482-22-4); Mirisetron (CAS RN 135905- 89-4) or Mirisetron maleate (CAS RN 148611-75-0); or renzapride (CAS RN 112727-80-7).
• DDP 225 or MCI 225 CAS RN 135991-48-9
• Marinol or Dronabinol CAS RN 1972-08- 3
• Lac Hydrin or Ammonium lactate CAS RN 515-98-0
• the agent used with an angiotensin agent may be a reported 5HT2A/2C receptor antagonist such as Ketanserin (CAS RN 74050-98-9) or ketanserin tartrate; risperidone; olanzapine; adatanserin (CAS RN 127266-56-2); Ritanserin (CAS RN 87051-43-2); etoperidone; nefazodone; deramciclane (CAS RN 120444-71-5); Geoden or Ziprasidone hydrochloride (CAS RN 138982-67-9); Zeldox or Ziprasidone or Ziprasidone hydrochloride; EMD 281014 (7-[4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-l-carbonyl]-lH- indole-3-carbonitrile HCl); MDL 100907 or Ml 00907 (CAS RN 139290-65-6); Effexor XR (Venlafax
• modulators include reported 5-HT2C agonists or partial agonists, such as m-chlorophenylpiperazine; or 5-HT2A receptor inverse agonists, such as ACP 103 (CAS RN: 868855-07-6), APD 125 (from Arena Pharmaceuticals), AVE 8488 (from Sanofi-Aventis) or TGWOOAD/ AA(from Fabre Kramer Pharmaceuticals).
• 5-HT2C agonists or partial agonists such as m-chlorophenylpiperazine
• 5-HT2A receptor inverse agonists such as ACP 103 (CAS RN: 868855-07-6), APD 125 (from Arena Pharmaceuticals), AVE 8488 (from Sanofi-Aventis) or TGWOOAD/ AA(from Fabre Kramer Pharmaceuticals).
• the agent used with an angiotensin agent may be a reported 5HT6 receptor antagonist such as SB-357134 (N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy- 3-piperazin-l-ylbenzenesulfonamide); SB-271046 (5-chloro-N-(4-methoxy-3-(piperazin-l- yl)phenyl)-3-methylbenzo[b]thiophene-2-sulfonamide); Ro 04-06790 (N-(2,6- bis(methylamino)pyrimidin-4-yl)-4-aminobenzenesulfonamide); Ro 63-0563 (4-amino-N- (2,6 bis-methylamino-pyridin-4-yl)-benzene sulfonamide); clozapine or its metabolite N- desmethylclozapine; olanzapine (CAS RN 132539-06-1); fluperlap
• the reported 5HT6 modulator may be SB-258585 (4-Iodo-N-[4-methoxy-3-(4-methyl-piperazin-l-yl)-phenyl]-benzen esulphonamide); PRX 07034 (from Predix Pharmaceuticals) or a partial agonist, such as E- 6801 (6-chloro-N-(3-(2-(dimethylamino)ethyl)-lH-indol-5-yl)imidazo[2,l-b]thiazole-5- sulfonamide) or E-6837 (5-chloro-N-(3-(2-(dimethylamino)ethyl)-lH-mdol-5- yl)naphthalene-2-sulfonamide) .
• the neurogenic agent is ethyl eicosapentaenoate or ethyl-EPA (also known as 5,8,11,14,17-eicosapentaenoic acid ethyl ester or miraxion, Chemical Abstracts Registry number 86227-47-6), docosahexaenoic acid (DHA), or a retinoid acid drug.
• ethyl eicosapentaenoate or ethyl-EPA also known as 5,8,11,14,17-eicosapentaenoic acid ethyl ester or miraxion, Chemical Abstracts Registry number 86227-47-6
• DHA docosahexaenoic acid
• retinoid acid drug a retinoid acid drug
• Example 1 Effect of alacepril on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 1, which shows dose response curves of neuronal differentiation after background media values are subtracted.
• the dose response curve of the neuronal positive control is included as a reference.
• the data is presented as a percent of neuronal positive control.
• the data indicate that alacepril promoted neuronal differentiation.
• Example 2- Effect of enalapril on neuronal differentiation of human neural stem cells hNSCs were prepared and treated with varying concentrations of enalapril (test compound), and stained with TUJ-I antibody, as described in Example 1. Mitogen-free test media with a positive control for neuronal differentiation was used along with basal media without growth factors as a negative control. Results are shown in Figure 2, which shows dose response curves of neuronal differentiation after background media values are subtracted. The dose response curve of the neuronal positive control is included as a reference. The data is presented as a percent of neuronal positive control. The data indicate that enalapril promoted neuronal differentiation.
• Example 3- Effect of lisinopril on neuronal differentiation of human neural stem cells hNSCs were prepared and treated with varying concentrations of lisinopril (test compound), and stained with TUJ-I antibody, as described in Example 1. Mitogen-free test media with a positive control for neuronal differentiation was used along with basal media without growth factors as a negative control.
• Results are shown in Figure 3, which shows dose response curves of neuronal differentiation after background media values are subtracted.
• the dose response curve of the neuronal positive control is included as a reference.
• the data is presented as a percent of neuronal positive control.
• the data indicate that lisinopril promoted neuronal differentiation.
• Example 4- Effect of captopril on neuronal differentiation of human neural stem cells hNSCs were prepared and treated with varying concentrations of captopril (test compound), and stained with TUJ-I antibody, as described in Example 1. Mitogen-free test media with a positive control for neuronal differentiation was used along with basal media without growth factors as a negative control. Results are shown in Figure 4, which shows dose response curves of neuronal differentiation after background media values are subtracted. The dose response curve of the neuronal positive control is included as a reference. The data is presented as a percent of neuronal positive control. The data indicate that captopril promoted neuronal differentiation.
• Example 5- Effect of losartan on neuronal differentiation of human neural stem cells hNSCs were prepared and treated with varying concentrations of losartan (test compound), and stained with TUJ-I antibody, as described in Example 1. Mitogen-free test media with a positive control for neuronal differentiation was used along with basal media without growth factors as a negative control.
• Results are shown in Figure 5, which shows dose response curves of neuronal differentiation after background media values are subtracted.
• the dose response curve of the neuronal positive control is included as a reference.
• the data is presented as a percent of neuronal positive control.
• the data indicate that losartan promoted neuronal differentiation.
• Example 6- Effect of benazepril on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 6, which shows dose response curves of neuronal differentiation after background media values are subtracted.
• the dose response curve of the neuronal positive control is included as a reference.
• the data is presented as a percent of neuronal positive control.
• the data indicate that benazepril promoted neuronal differentiation.
• hNSCs Human neural stem cells
• Results are shown in Figure 7, which shows dose response curves of neuronal differentiation after background media values are subtracted.
• the dose response curve of the neuronal positive control is included as a reference.
• the data is presented as a percent of neuronal positive control.
• the data indicate that trandolapril promoted neuronal differentiation.
• Example 8 Effect of Candesartan on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 8, which shows dose response curves of neuronal differentiation after background media values are subtracted.
• the dose response curve of the neuronal positive control is included as a reference.
• the data is presented as a percent of neuronal positive control. The data indicate that candesartan promoted neuronal differentiation.
• hNSCs Human neural stem cells
• Results are shown in Figure 9, which shows dose response curves of neuronal differentiation after background media values are subtracted.
• the dose response curve of the neuronal positive control is included as a reference.
• the data is presented as a percent of neuronal positive control.
• the data indicate that telmisartan promoted neuronal differentiation.
• Example 10- Effect of combining captopril and ibudilast on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 10, which shows concentration response curves of neuronal differentiation after background media values are subtracted.
• the concentration response curve of the combination of ibudilast and captopril is shown with the concentration response curves of ibudilast or captopril alone.
• the data is presented as a percent of neuronal positive control. The data indicate that the combination of ibudilast with captopril resulted in synergistically enhanced neuronal differentiation relative to that that produced by either agent alone.
• Example 11 Effect of combining captopril and enoximone on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 11 , which shows concentration response curves of neuronal differentiation after background media values are subtracted.
• the concentration response curve of the combination of enoximone and captopril is shown with the concentration response curves of enoximone or captopril alone.
• the data is presented as a percent of neuronal positive control. The data indicate that the combination of enoximone with captopril resulted in synergistically enhanced neuronal differentiation relative to that that produced by either agent alone.
• Example 12- Effect of combining ibudilast and candesartan on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 12, which shows concentration response curves of neuronal differentiation after background media values are subtracted.
• the concentration response curve of the combination of ibudilast and candesartan is shown with the concentration response curves of ibudilast or candesartan alone.
• the data is presented as a percent of neuronal positive control. The data indicate that the combination of ibudilast with candesartan resulted in synergistically enhanced neuronal differentiation relative to that that produced by either agent alone.
• Example 13 Effect of combining captopril and baclofen on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 13, which shows concentration response curves of neuronal differentiation after background media values are subtracted.
• the concentration response curve of the combination of baclofen and captopril is shown with the concentration response curves of baclofen or captopril alone.
• the data is presented as a percent of neuronal positive control. The data indicate that the combination of baclofen with captopril resulted in synergistically enhanced neuronal differentiation relative to that that produced by either agent alone.
• hNSCs Human neural stem cells
• Results are shown in Figure 14, which shows concentration response curves of neuronal differentiation after background media values are subtracted.
• the concentration response curve of the combination of donepezil and captopril is shown with the concentration response curves of donepezil or captopril alone.
• the data is presented as a percent of neuronal positive control. The data indicate that the combination of donepezil with captopril resulted in synergistically enhanced neuronal differentiation relative to that that produced by either agent alone.
• Example 15 Effect of combining captopril and vardenafil on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 15, which shows concentration response curves of neuronal differentiation after background media values are subtracted.
• the concentration response curve of the combination of vardenafil and captopril is shown with the concentration response curves of vardenafil or captopril alone.
• the data is presented as a percent of neuronal positive control. The data indicate that the combination of vardenafil with captopril resulted in synergistically enhanced neuronal differentiation relative to that that produced by either agent alone.
• Example 16 Effect of combining telmisartan and rolipram on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 16, which shows concentration response curves of neuronal differentiation after background media values are subtracted.
• the concentration response curve of the combination of rolipram and telmisartan is shown with the concentration response curves of rolipram or telmisartan alone.
• the data is presented as a percent of neuronal positive control. The data indicate that the combination of rolipram with telmisartan resulted in synergistically enhanced neuronal differentiation relative to that that produced by either agent alone.
• the presence of synergy was determined by use of a combination index (CI).
• the CI based on the EC 5O was used to determine whether a pair of compounds had an additive, synergistic (greater than additive), or antagonistic effect when run in combination.
• the CI is a quantitative measure of the nature of drug interactions, comparing the EC 50 1 S of two compounds, when each is assayed alone, to the EC 5O of each compound when assayed in combination.
• the combination index (CI) is equal to the following formula:
• Cl and C2 are the concentrations of a first and a second compound, respectively, resulting in 50% activity in neuronal differentiation when assayed in combination; and ICl and IC2 are the concentrations of each compound resulting in 50% activity when assayed independently.
• a CI of less than 1 indicates the presence of synergy; a CI equal to 1 indicates an additive effect; and a CI greater than 1 indicates antagonism between the two compounds.
• the two compounds have a synergistic effect in neuronal differentiation.
• the above is based on the selection of EC 50 as the point of comparison for the two compounds.
• the comparison is not limited by the point used, but rather the same comparison may be made at another point, such as EC 2O , EC 3O , EC 40 , EC 60 , EC 70 , ECgo, or any other EC value above, below, or between any of those points.
• Example 18 Effect of combining captopril and theophylline on neuronal differentiation of human neural stem cells
• hNSCs Human neural stem cells
• Results are shown in Figure 17, which shows concentration response curves of neuronal differentiation after background media values are subtracted.
• the concentration response curve of the combination of theophylline and captopril is shown with the concentration response curves of theophylline or captopril alone.
• the data is presented as a percent of neuronal positive control. The data indicate that the combination of theophylline with captopril resulted in synergistically enhanced neuronal differentiation relative to that that produced by either agent alone.

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