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WO2009070164A1 - Amélioration de la vigueur par administration de dérivés de pyrimidine - Google Patents

Amélioration de la vigueur par administration de dérivés de pyrimidine Download PDF

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Publication number
WO2009070164A1
WO2009070164A1 PCT/US2007/085765 US2007085765W WO2009070164A1 WO 2009070164 A1 WO2009070164 A1 WO 2009070164A1 US 2007085765 W US2007085765 W US 2007085765W WO 2009070164 A1 WO2009070164 A1 WO 2009070164A1
Authority
WO
WIPO (PCT)
Prior art keywords
dihydro
oxo
pyrro
pyrimidine
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2007/085765
Other languages
English (en)
Inventor
Kiminobu Sugaya
Angel Alvarez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Central Florida
Original Assignee
University of Central Florida
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Central Florida filed Critical University of Central Florida
Priority to EP07854812.0A priority Critical patent/EP2324023B1/fr
Priority to CA2670341A priority patent/CA2670341C/fr
Priority to PCT/US2007/085765 priority patent/WO2009070164A1/fr
Publication of WO2009070164A1 publication Critical patent/WO2009070164A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • stem cell research Much research is being conducted to study stem cells and to devise ways of utilizing stem cells in treating various neurological pathologies and injuries, as well as pathologies of other organ systems. It is generally recognized that stem cell technologies hold tremendous promise for ultimately treating and even curing neurologically related diseases, injuries or dysfunctions. It is understandable why stem cell research has focused on these areas. However, finding new and more diverse ways of utilizing stem cells is an ongoing challenge. It is important that stem cell research be directed to beneficial areas that do not necessarily include the traditional areas of developing treatments and cures for disease and injuries. Furthermore, agents that affect the characteristics of stem cells should be studied as this may reveal certain useful compounds that can be utilized to manipulate endogenous stem cells and thus leading to novel therapies.
  • the '523 patent teaches that the agents stimulate the migration of cells toward the wound.
  • the present inventors have discovered that the same agents actually stimulate the proliferation of stem cells, which in turn, led to the discovery that the agents may be used in circumstances where tissues have not been wounded.
  • Typical illustrative compounds of formula (2) include:
  • the pyrimidine derivatives of formulae (I) and (II) is administered at a concentration of between about 0.01 mg/kg/day to 50 mg/kg/day, more preferably between about 0.1 mg/kg/day to 10 mg/kg/day, even more preferably between about 1 mg/kg/day to 5 mg/kg/day, and even more preferably about 3 mg/kg/day.
  • an increase in vigor caused by administration of an SCPA may pertain to an increase in one or more of a subject's disposition characteristics or to specific tissue characteristics as compared to that where no administration of an SCPA is made. It is contemplated that the increase in vigor is not necessarily targeted to a pathology or disease. Accordingly, the methods taught herein can serve as a vigor boost to even a clinically healthy subject.
  • the subject invention pertains to maintaining juvenescence of tissues in a subject comprising administering a therapeutically effective amount of a composition comprising a SCPA.
  • the active compound of certain composition embodiments, SCPA may be included in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated.
  • the therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo systems (see, e.g., Rosenthal et al. (1996) Antimicrob. Agents Chemother. 40(7): 1600-1603; Dominguez et al. (1997) J. Med. Chem. 40:2726-2732; Clark et al. (1994) Molec. Biochem. Parasitol. 17: 129; Ring et al. (1993) Proc. Natl. Acad. Sci.
  • the concentration of active compound in the pharmaceutical composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • a therapeutically effective dosage should produce a serum concentration of active compound of from about 0.1 ng/ml to about 50-100 ⁇ g/ml.
  • the pharmaceutical compositions typically should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilo-gram of body weight per day.
  • Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and preferably from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form.
  • the active compound may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
  • Preferred pharmaceutically acceptable derivatives include acids, bases, enol ethers and esters, salts, esters, hydrates, solvates and prodrug forms.
  • the derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound.
  • compositions described herein or pharmaceutically acceptable derivatives thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions.
  • concentration of active compound in the composition will depend on absorption, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.
  • compositions are intended to be administered by a suitable route depending on the target outcome, including orally, parenterally (including intraventrically), rectally, topically (including intraocularly) and locally.
  • Parenteral administration generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein.
  • Parenteral administration as contemplated herein also pertains to other modes of internal administration that do not involve oral administration, such as direct introduction into specific tissues and organs including, but not limited to, into the central nervous system (e.g. intraventrically), the liver, heart, pancreas, kidneys, bone, and/or connective tissue (including tendons, ligaments, fascia etc.).
  • capsules and tablets are presently preferred.
  • the compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
  • the preferred modes of administration include parenteral and oral modes of administration.
  • the subject invention pertains to a method of increasing density of bone in a subject comprising administering an effective amount of a composition comprising a SCPA according to a regimen such that new bone is formed and bone density is increased.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent
  • antimicrobial agents such as benzyl alcohol and methyl parabens
  • antioxidants such as ascorbic acid and sodium bisul
  • solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
  • cosolvents such as dimethylsulfoxide (DMSO)
  • surfactants such as TWEEN®
  • dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
  • the resulting mixture may be a solution, suspension, emulsion or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected earner oi vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
  • compositions are provided for administration to humans and animals m unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
  • the pharmaceutically therapeutically active compounds and de ⁇ vatives thereof are typically formulated and admimsteied m unit-dosage forms or multiple-dosage forms.
  • Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art.
  • Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the requued pharmaceutical earner, vehicle or diluent.
  • unit-dose forms include ampoules and synnges and individually packaged tablets or capsules
  • Unit-dose forms may be administered m fractions or multiples thereof
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be admmisteied in segregated unit-dose form.
  • Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons.
  • multiple dose form is a multiple of unit-doses which are not segregated m packaging.
  • composition embodiments can contain along with the active compound a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatm, glucose, molasses, polvmylpyrrohdme.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
  • a lubricant such as magnesium stearate, calcium stearate and talc
  • a binder such as starch, natural gums, such as gum acaciagelatm, glucose, molasses, polvmylpyrrohdme.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants m a carrier, such as, for example, water, saline, aqueous dextiose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension
  • a carrier such as, for example, water, saline, aqueous dextiose, glycerol, glycols, ethanol, and the like
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubihzmg agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextnne denvatives, sorbitan monolaurate, triethanolamme sodium acetate, tnethanolamme oleate, and other such agents.
  • composition or formulation to be administered will, in any event, contain a quantity of the active compound in an amount sufficient to alleviate the symptoms of the treated subject.
  • compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art.
  • the contemplated compositions may contain 0.001%- 100% active ingredient, preferably 0.1-85%, typically 75-95%.
  • the active compounds or pharmaceutically acceptable derivatives may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
  • the solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • a buffer such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation.
  • the resulting solution will be apportioned into vials for lyophilization.
  • Each vial will contain a single dosage (10-1000 mg, preferably 100-500 mg) or multiple dosages of the compound.
  • the lyophilized powder can be stored under appropriate conditions, such as at about 4° C. to room temperature.
  • Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration.
  • about 1-50 mg, preferably 5-35 mg, more preferably about 9-30 mg of lyophilized powder is added per mL of sterile water or other suitable carrier.
  • the precise amount depends upon the selected compound. Such amount can be empirically determined.
  • Topical mixtures are prepared as described for the local and systemic administration.
  • the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
  • the compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma).
  • These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.
  • the compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, liquid drops, creams, and lotions and for application to the eye or for intracisternal or intraspinal application.
  • Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
  • topical compositions of the present invention also includes at least one of the following: a surface smoother, a skin plumper, an optical diffuser, a sunscreen, an exfoliation promoter, and an antioxidant.
  • a surface smoother provides the functional benefits of enhancing skin smoothness and reducing the appearance of fine lines and coarse wrinkles.
  • Examples include silicas, talcs, isopropyl myristate, petrolatum, isopropyl lanolate, silicones (e.g., methicone, dimethicone), polymethylmethacrylate (PMMA), or any mixtures thereof.
  • the surface smoother is preferably present from about 0.1 wt % to about 50 wt % of the total weight of the composition.
  • a sunscreen protects the skin from damaging ultraviolet rays.
  • the sunscreen would provide both UVA and UVB protection, by using either a single sunscreen or a combination of sunscreens.
  • the sunscreens that can be employed in the present compositions are avobenzone, cinnamic acid derivatives (such as octylmethoxy cinnamate), octyl salicylate, oxybenzone, titanium dioxide, zinc oxide, or any mixtures thereof.
  • the sunscreen is present from about 1 wt % to about 30 wt % of the total weight of the composition.
  • the addition of a sunscreen is preferred to prevent/reduce the photodegradation of retinoid while in the package and/or on the skin.
  • rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
  • Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids.
  • Agents to raise the melting point of suppositories include spermaceti and wax.
  • Rectal suppositories may be prepared either by the compressed method or by molding.
  • the typical weight of a rectal suppository is about 2 to 3 gm.
  • the subject invention pertains to a method of improving the outcome of a stem cell implantation therapy comprising the co-administration of stem cells with a SCPA.
  • the cells are administered by injecting one or a plurality of stem cells with a syringe, inserting the stem cells with a catheter or surgically implanting the stem cells.
  • the stem cells are administered into a body cavity fluidly connected to a target tissue.
  • the body cavity is a brain ventricle.
  • the stem cells are inserted using a syringe or catheter, or surgically implanted directly at the target tissue site.
  • the stem cells are administered systemically (e.g., parenterally).
  • the inventors have found that co-administration of secondary cells with primary cells can influencing the transplant loci so as to be more conducible to acceptance and differentiation of the primary cells to their target cell type.
  • mesenchymal cells may reduce the amount of inflammation at the site of implantation of hematopoietic or neural stem cells.
  • external factors are co-administered with the stem cells.
  • such factors arc provided at the site of administration.
  • Such external factors may optimize the implantation site environment, or may serve to bias differentiation of the implanted stem cells.

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

Abstract

L'invention concerne des procédés d'amélioration de la vigueur globale d'un sujet et/ou de la vigueur de tissus cibles d'un sujet. L'utilisation de dérivés de pyrimidine qui agissent en stimulant la prolifération de cellules souches est donnée en exemple ici. En plus d'augmenter la vigueur, de tels agents de prolifération de cellules souches (SCPA) peuvent être utilisés pour augmenter et/ou améliorer le résultat d'autres thérapies et peuvent être utilisés pour des applications psychiatriques. L'augmentation de la vigueur chez des sujets n'est pas nécessairement ciblée au traitement d'une maladie. Les procédés peuvent ainsi inclure l'administration à des animaux cliniquement sains.
PCT/US2007/085765 2006-11-28 2007-11-28 Amélioration de la vigueur par administration de dérivés de pyrimidine Ceased WO2009070164A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP07854812.0A EP2324023B1 (fr) 2006-11-28 2007-11-28 Amélioration de la vigueur par administration de dérivés de pyrimidine
CA2670341A CA2670341C (fr) 2006-11-28 2007-11-28 Amelioration de la vigueur par administration de derives de pyrimidine
PCT/US2007/085765 WO2009070164A1 (fr) 2007-11-28 2007-11-28 Amélioration de la vigueur par administration de dérivés de pyrimidine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2007/085765 WO2009070164A1 (fr) 2007-11-28 2007-11-28 Amélioration de la vigueur par administration de dérivés de pyrimidine

Publications (1)

Publication Number Publication Date
WO2009070164A1 true WO2009070164A1 (fr) 2009-06-04

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PCT/US2007/085765 Ceased WO2009070164A1 (fr) 2006-11-28 2007-11-28 Amélioration de la vigueur par administration de dérivés de pyrimidine

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WO (1) WO2009070164A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190183898A1 (en) * 2016-06-06 2019-06-20 University Of Central Florida Research Foundation, Inc. Combination therapy to improve brain function or promote neurogenesis for treating neurodegenerative conditions

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
US4364923A (en) 1972-04-20 1982-12-21 Allen & Hanburs Limited Chemical compounds
US4959368A (en) 1986-02-24 1990-09-25 Mitsui Petrochemical Industries Ltd. Therapeutic agent for neurological diseases
US5033352A (en) 1989-01-19 1991-07-23 Yamaha Corporation Electronic musical instrument with frequency modulation
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5323907A (en) 1992-06-23 1994-06-28 Multi-Comp, Inc. Child resistant package assembly for dispensing pharmaceutical medications
US5976523A (en) 1995-05-16 1999-11-02 Mitsui Pharmaceuticals, Inc. Method for healing compromised tissues using pyrimidine derivatives
US20030113912A1 (en) * 1996-08-13 2003-06-19 Fujisawa Pharmaceutical Co. Ltd. Hematopoietic stem cell proliferating agents
US20030139410A1 (en) * 2002-01-14 2003-07-24 Kiminobu Sugaya Use of modified pyrimidine compounds to promote stem cell migration and proliferation
US20060003919A1 (en) * 2004-05-26 2006-01-05 Nicolas Fortunel Cosmetic/dermatological applications of LIF
US20060147435A1 (en) * 2004-12-30 2006-07-06 Moon Randall T Methods for regulation of stem cells
US20060257449A1 (en) * 2005-05-16 2006-11-16 Didier Billy Methods, compositions, systems, and devices for bone fusion

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
US4364923A (en) 1972-04-20 1982-12-21 Allen & Hanburs Limited Chemical compounds
US4414209A (en) 1972-04-20 1983-11-08 Allen & Hanburys Limited Micronized aerosol steroids
US4959368A (en) 1986-02-24 1990-09-25 Mitsui Petrochemical Industries Ltd. Therapeutic agent for neurological diseases
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5033352A (en) 1989-01-19 1991-07-23 Yamaha Corporation Electronic musical instrument with frequency modulation
US5323907A (en) 1992-06-23 1994-06-28 Multi-Comp, Inc. Child resistant package assembly for dispensing pharmaceutical medications
US5976523A (en) 1995-05-16 1999-11-02 Mitsui Pharmaceuticals, Inc. Method for healing compromised tissues using pyrimidine derivatives
US20030113912A1 (en) * 1996-08-13 2003-06-19 Fujisawa Pharmaceutical Co. Ltd. Hematopoietic stem cell proliferating agents
US20030139410A1 (en) * 2002-01-14 2003-07-24 Kiminobu Sugaya Use of modified pyrimidine compounds to promote stem cell migration and proliferation
US20060003919A1 (en) * 2004-05-26 2006-01-05 Nicolas Fortunel Cosmetic/dermatological applications of LIF
US20060147435A1 (en) * 2004-12-30 2006-07-06 Moon Randall T Methods for regulation of stem cells
US20060257449A1 (en) * 2005-05-16 2006-11-16 Didier Billy Methods, compositions, systems, and devices for bone fusion

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Title
"Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING COMPANY
CLARK ET AL., MOLEC. BIOCHEM. PARASITOL., vol. 17, 1994, pages 129
DOMINGUEZ ET AL., J. MED. CHEM., vol. 40, 1997, pages 2726 - 2732
ENGEL ET AL., J. EXP. MED., vol. 188, no. 4, 1998, pages 725 - 734
LECHNER ET AL.: "Stem/progenitor cells derived from adult tissues: potential for the treatment of diabetes mellitus", AM J PHYSIOL ENDOCRINOL METAB, vol. 284, February 2003 (2003-02-01), pages E259 - E266, XP009056159 *
LI ET AL., J. MED. CHEM., vol. 38, 1995, pages 5031
RING ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 3583 - 3587
ROSENTHAL ET AL., ANTIMICROB. AGENTS CHEMOTHER., vol. 40, no. 7, 1996, pages 1600 - 1603
See also references of EP2324023A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190183898A1 (en) * 2016-06-06 2019-06-20 University Of Central Florida Research Foundation, Inc. Combination therapy to improve brain function or promote neurogenesis for treating neurodegenerative conditions
US10751340B2 (en) * 2016-06-06 2020-08-25 University Of Central Florida Research Foundation, Inc. Combination therapy to improve brain function or promote neurogenesis for treating neurodegenerative conditions

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